Next Article in Journal
Does Wim Hof Method Improve Breathing Economy during Exercise?
Next Article in Special Issue
Glycemic Challenge Is Associated with the Rapid Cellular Activation of the Locus Ceruleus and Nucleus of Solitary Tract: Circumscribed Spatial Analysis of Phosphorylated MAP Kinase Immunoreactivity
Previous Article in Journal
Impact of the COVID-19 Pandemic on Maternal Well-Being during Pregnancy
Previous Article in Special Issue
Fibroblast Growth Factor 21 Facilitates the Homeostatic Control of Feeding Behavior
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Mediators of Amylin Action in Metabolic Control

Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, 8057 Zurich, Switzerland
Author to whom correspondence should be addressed.
J. Clin. Med. 2022, 11(8), 2207;
Submission received: 1 March 2022 / Revised: 8 April 2022 / Accepted: 13 April 2022 / Published: 15 April 2022
(This article belongs to the Special Issue Molecular Mechanisms of Appetite Regulation)


Amylin (also called islet amyloid polypeptide (IAPP)) is a pancreatic beta-cell hormone that is co-secreted with insulin in response to nutrient stimuli. The last 35 years of intensive research have shown that amylin exerts important physiological effects on metabolic control. Most importantly, amylin is a physiological control of meal-ending satiation, and it limits the rate of gastric emptying and reduces the secretion of pancreatic glucagon, in particular in postprandial states. The physiological effects of amylin and its analogs are mediated by direct brain activation, with the caudal hindbrain playing the most prominent role. The clarification of the structure of amylin receptors, consisting of the calcitonin core receptor plus receptor-activity modifying proteins, aided in the development of amylin analogs with a broad pharmacological profile. The general interest in amylin physiology and pharmacology was boosted by the finding that amylin is a sensitizer to the catabolic actions of leptin. Today, amylin derived analogs are considered to be among the most promising approaches for the pharmacotherapy against obesity. At least in conjunction with insulin, amylin analogs are also considered important treatment options in diabetic patients, so that new drugs may soon be added to the only currently approved compound pramlintide (Symlin®). This review provides a brief summary of the physiology of amylin’s mode of actions and its role in the control of the metabolism, in particular energy intake and glucose metabolism.

1. A Brief History of Amylin and Scope of Review

In 1986, two independent research groups identified amylin, also known as diabetes-associated peptide (DAP) or islet amyloid polypeptide (IAPP), as the major component of pancreatic islet amyloid deposits [1,2], which had been a known pathological hallmark of type 2 diabetes (2DM) and feline diabetes since the early 20th century [3,4]. Non-aggregated amylin was then shown to be present in the same secretory granules of the pancreatic beta cells as insulin [5] and was identified as a novel hormone in circulating plasma in 1989 [6]. It was subsequently shown that insulin and amylin were simultaneously secreted from the beta cells in response to glucose and arginine stimuli, and that a selective loss of amylin secretion was observed in rat models of a mild form of type 1 diabetes (1DM) [7]. In viewing 1DM and late-stage 2DM as amylin-deficient conditions, amylin replacement therapy soon became a target for glucose control in patients with diabetes. Because human amylin, by the nature of its physiochemical properties, is prone to aggregation, scientists at Amylin Pharmaceuticals Inc. searched for an analogue that would replicate the physiological actions of amylin, in the absence of the challenges of the native peptide. The front-running analog, pramlintide, was patented by Amylin Pharmaceuticals in 1997 and was heralded as the first anti-diabetic peptide-based drug (Symlin®) since the discovery of insulin in 1921. No other amylin based drug has received approval since then, but several newly developed analogs have shown very promising results as anti-obesity and anti-diabetes treatments [8,9,10,11,12,13].
Amylin has mainly been researched in the context of two overarching themes: amylin as a soluble, monomeric hormone, whose physiological role is to control glucose appearance in the blood; and amylin as a constituent of amyloid plaques that eventually lead to the dysfunction and destruction of pancreatic islets that underlie some forms of diabetes. The goal of this review is to summarize the role of amylin in both the etiology and treatment of various forms of metabolic control, including diabetes and glucose control. Following an introduction to the basic properties of amylin and its receptors, we will present some of the foundational literature that demonstrated how the hormone amylin and its analogs can influence eating and blood glucose levels. We will then discuss how amylin and its function is altered in disease states where glucose control is compromised and how both traditional and new amylin-replacement therapies are being tested and applied in clinical populations. Along the way, we will highlight modern approaches to further uncover the structure and function of amylin and its receptors under both physiological and pathological conditions (as well as a target for the treatment of 2DM). We will also provide an overview of a new generation of amylin-based compounds, including DACRAs (dual amylin and calcitonin [CT] receptor agonists) and LAMAs (long-acting amylin agonists), which have more recently revived interest in this second beta cell hormone [8,9,10,14].

2. Introduction to Amylin

2.1. Amylin as a Pancreatic Beta-Cell Hormone

Amylin is derived from a precursor proamylin [15]. Following eventual cleavage by prohormone convertase 1/3 (PC1/3) and PC2, the 37-amino-acid, the biologically active monomeric form of amylin is formed. The amino acid sequence of amylin displays similarities with CT, α-, β-CT gene-related peptide (CGRP), adrenomedullin (AM) and AM2, which together comprise the CT peptide family [16]. The primary structure of amylin is highly conserved across species [17,18], with the exception of amino acid residues 20–29. While this region does not seem critical for the physiological action of amylin, residues 20–29 constitute the amyloidogenic region that promotes (or prevents) the formation of beta-sheet structures. The presence of multiple proline residues within this region, as is observed in rats and mice, appears to prevent beta-sheet formation [18,19]. Therefore, unlike humans, primates and cats, non-transgenic rats and mice do not develop amylin amyloids and, therefore, lack this pathological hallmark of 2DM (reviewed in: [20,21]). In an effort to understand the cause and effect of amyloid plaques, rat and mouse models have been engineered to overexpress human amylin (hIAPP; e.g., [22,23]) and the prevention or removal of these plaques may become a new anti-diabetic treatment strategy [24].
Expression levels of amylin and insulin are controlled by common promoter elements and the hormones are stored in and co-secreted from the same islet secretory vesicles at a ratio of approximately 1:100 of amylin to insulin [25]. Secretion from the islets is stimulated by glucose, arginine, and fatty acids [26,27,28,29], following a similar molar ratio [30]. Thus, in healthy individuals, amylin levels in the plasma are lowest during a fast (5–10 pM) and peak at around 20 pM after a meal [31]. The influence of various metabolic disease states on basal and stimulated amylin levels are discussed in Section 5.
While amylin was first thought to be synthesized exclusively in the pancreas [32], it was later shown that synthesis also occurs in other parts of the gastrointestinal tract and in spinal ganglia [33,34,35,36,37]. More recently, several independent groups have also identified amylin mRNA and protein in discrete areas of the brain. Amylin was first shown to be dramatically upregulated in the medial preoptic area of lactating rat dams [38] and later found to be highly co-expressed with prodynorphin-expressing neurons in the lateral hypothalamic area [39]. The latter study demonstrated that mRNA levels of amylin varied widely with sex, diet composition, and leptin levels [39]. Still, the functional significance of this centrally produced amylin has not be fully determined but it has been suggested that amylin signaling in the medial preoptic area may be involved in the control of maternal behavior [40].

2.2. Amylin Receptors and Pharmacology

Like other peptides of the CT family, amylin acts on class B G-protein-coupled receptors (GPCRs) [41]. In mammals, there are two GPCRs which the peptide family acts on: the CT receptor (CTR) and the CT receptor-like receptor (CLR, also known as CRLR). These receptors can be further modified by receptor activity-modifying proteins (RAMPs) [42,43]. In humans, rats, and mice, there are three known RAMPs which enable different receptors for this peptide family: CLR and RAMP1 form the CGRP receptor and CLR, together with RAMP2 and 3, forms AM1 and AM2 receptors, respectively. CTR acts as a CT receptor but forms amylin receptors when co-expressed with RAMPs 1, 2, and 3, which are named AMY1, 2, and 3 receptors, respectively. Unlike CTR, CLR alone is not a known receptor on any cell surfaces as there is no known ligand to it.
The expression of the necessary AMY components CTR plus RAMPs has mainly been studied in the brain and their presence has been described in multiple brain areas [14,44]. Surprisingly, only very few studies have tested the expression of these components in the same cell, which, according to our understanding, is necessary to form fully active AMY receptors. Such co-expression in the same cell has been shown for the area postrema (AP) in the caudal hindbrain and in parts of the hypothalamus [45,46]. Further, we are not aware of studies characterizing AMY receptors with all their receptor components in the periphery since the first description of RAMPs in 1998 [42]. Hence, whether the peripheral effects of amylin that have been described early after the discovery of amylin (e.g., induction of insulin resistance, inhibition of insulin secretion; summarized in [47,48,49]) are truly mediated by the AMY awaits further investigation.

2.2.1. Receptor Agonism of CT Family Peptide Receptors

Amylin shows low affinity to CTR, but if associated with the RAMPs, CTR forms AMY receptors and responds preferentially to amylin [43,50]. There are species differences in structure and receptor affinity of CT. Salmon CT (sCT) seems to be a potent agonist of both CT and amylin receptors [51] and can therefore be seen as a natural dual receptor (AMY and CTR) agonist. While rat CT is a much weaker agonist of all amylin receptors [50], human CT, on the other hand, shows similar potency to CTR and AMY1 receptors, but a 10-fold lower potency to AMY3 receptor [43]. Due to these findings, the fact that AMY receptors expression requires CTR and the lack of subtype specific receptor antagonists it is currently not possible to test the activation and effect of AMY and CT receptors separately using pharmacological approaches [43].
Furthermore, CT/CGRP family peptide receptors are also, at least partially, responsive to many different peptides of this family. For example, although amylin is a very weak CGRP receptor agonist, AMY1 and AMY3 receptors show high affinity towards CGRP binding [50,52]. In rodents, it was shown that rat α-CGRP displayed a similar affinity to rat AMY1 and AMY3 receptors as rat amylin. Both peptides also showed a partial agonism towards rat CTR, which was 20-fold weaker than rat CT [50]. In contrast to findings in rodents, human α-CGRP showed a lower potency than amylin on a human AMY3 receptor [43]. Rat CT acts 10-fold weaker than rat amylin and rat α-CGRP on AMY1 and AMY3 receptors [43]. Another difference between both species was the comparison between α and β-CGRP: while rat β-CGRP displayed lower potency on rat CT, AMY1, and AMY3 receptors compared to rat α-CGRP [50], human β-CGRP was equipotent to human α-CGRP on human AMY3 and even more potent on human CT and AMY1 receptors [43].
As demonstrated by these findings, it remains challenging to 1. test the response of individual AMY receptors to amylin, 2. to assess amylin’s effect in the absence of other CT family peptides in vivo, and 3. to translate knowledge gathered from animal experiments into clinical applications in humans, in particular when it comes to specificity for certain receptor subtypes. In fact, so far, it can be assumed that some of amylin’s effects observed in vivo may also be partially due to other peptides and receptors [53]; this may be particularly true for brain-mediated effects because CGRP is a wide-spread neurotransmitter in the central nervous system [54]. As will be discussed later, it is interesting to note that the most promising candidates of amylin analogs for the treatment of metabolic disease are, in fact, rather unspecific (dual) CTR and AMY agonists (see Section 6).

2.2.2. Role of Specific Amylin Receptors for Endogenous Amylin Action

Despite the challenges mentioned above, there are approaches to distinguishing the exact function of single CT family peptide receptors. A recent study examined the consequences of the knockout of the RAMP1, RAMP3, and both RAMP1 and RAMP3 genes in mice [55]. It seems that effects requiring RAMP1 are mainly responsible for fat utilization and storage (see also [56]), while RAMP3 is important for controlling glucose homeostasis and food intake. Only mice with a knockout of both RAMP1 and RAMP3 fed on a high-fat diet displayed increased bodyweight, indicating potential redundancy of amylin actions via distinct receptor subtypes. This study provided a first insight into the importance of single amylin receptor components for endogenous amylin action.
An interesting finding provided by multiple studies is that the knockout of RAMP genes, the gene for CTR [55], or administration amylin antagonists lead to metabolic changes, such as increased body weight and food intake [57,58], while mice that are deficient in the amylin gene do not show lasting differences in body weight or weight gain compared to WT mice [59]. The latter also display a higher response to amylin infusion, perhaps indicating a potential up-regulation of amylin receptors and/or amylin signaling pathways. However, it is unclear how the lack of endogenous amylin is compensated for or whether the remaining CT family peptides are involved.

2.2.3. Differences in Internalization and Regulation of Receptor Subtypes

Despite multiple similarities and reported action of CGRP on the AMY1 receptor, a recent study by Gingell and colleagues showed that AMY1 (CTR + RAMP1) and CGRP (CLR + RAMP1) receptors differ strongly in internalization properties [60]. By using fluorescent CGRP and amylin analogs, it was shown that the CGRP receptor is rapidly internalized from the cell surface into the cytoplasm after binding to CGRP analogs, while the AMY1 receptor remains on the cell surface after binding to different agonists. Furthermore, the same study showed that the CGRP receptor was degraded significantly after 4 h of agonist stimulation, while the AMY1 showed no degradation after agonist stimulation [60]. This could be an explanation for the retained amylin sensitivity in hyperamylinemic rats [61]. These findings clearly indicate that there are differences in regulation of and responses to ligand binding. This may be even more important for natural receptor agonists like sCT or synthetic compounds that seem to display irreversible binding to the receptor complex, which may lead to continuing receptor activation [62,63]. Overall, it is clear that further research is needed to assess the exact differences in amylin receptor function, if and how this affects the overall function of the peptides, and how these findings translate to humans.

3. Physiological Role of Amylin in Appetite Control

The role of amylin in controlling eating has recently been amply reviewed (e.g., [14,64,65,66]). The most important points will be briefly summarized here. Meal-ending satiation is the major physiological effect induced by amylin in the control of food intake [67]. Amylin dose-dependently reduces the size and length of a meal, with a rapid onset of this effect within minutes [68]. A large number of studies have shown the physiological relevance of this action (e.g., [57,69,70]). Together with amylin’s effect to slow gastric emptying and to reduce pancreatic glucagon secretion, which will be discussed later, the meal size effect of amylin is the most relevant aspect for the regulation of nutrient fluxes [71]; amylin, by controlling the rate of nutrient appearance, complements the action of insulin, which mainly controls the disappearance of nutrients from the primary nutrient pool.
More than three decades of work have resulted in a clear picture about the mechanisms underlying the satiation-inducing effect of amylin and its analogs. When treated acutely with peripheral amylin, rodents demonstrate significant reductions in food intake for approximately two hours [72,73], which primarily results from reduced meal size [68]. Acute or chronic infusion of amylin directly into the brain also significantly reduces food intake and body weight [74], and pre-meal treatment with AC187 leads to an increase in food intake, demonstrating that endogenous amylin contributes to the control of eating [70,75]. Lesion studies have shown that an intact AP, but not vagal or non-vagal afferents, is required for amylin-induced satiation [72,76]. This was confirmed recently in mice whose CTR was depleted in the caudal hindbrain. CTR-depleted mice had a blunted response to amylin injection and, under baseline conditions, the duration of meals was inversely related to the number of neurons expressing CTR [69]. Interestingly, the vast majority of amylin-responsive cells in the AP are also glucose-responsive [77], and it has been proposed that a certain level of blood glucose is permissive for some of amylin’s actions [77,78]. This also seems to apply specifically to amylin’s effect on food intake because our data in rats during hyperinsulinemic euglycemic or hypoglycemic clamp indicated that the acute eating inhibitory effect of amylin was reduced in hypoglycemia (approx. 55 mg/dL [3.0 mmol/L]) [79].
Amylin-induced Fos activation is present in the AP, several downstream brain nuclei, including the nucleus of the solitary (NTS), the lateral parabrachial nucleus (LPBN), and the central nucleus of the amygdala [80]. In addition to blocking the inhibitory effect on food intake, lesions of the AP also reduced the presence of Fos in these downstream nuclei, which supports the idea that the AP is the primary mediator of amylin’s effect on eating [80]; one exception was reported recently because peripheral amylin induced a positive pERK response in the hypothalamus, independent of amylin action in the AP [45,81], but a functional correlate for this effect has not yet been determined.
Collectively, the AP lesioning data and other data indicate that the amylin-induced signal seems to be transmitted via the NTS, the LPBN, and the central nucleus of the amygdala and possibly other higher brain centers [76,82,83,84] (reviewed in [14,44,65]). Several studies showed that the eating inhibitory effect of amylin relies on noradrenaline signaling within the caudal hindbrain. This involves AP neurons that project directly or indirectly to the LPBN [44,83,85]. Direct input from CTR carrying neurons in the NTS [86] with converging projections to the LPBN may also participate in amylin’s effect on eating, but the physiological relevance of the latter projections is not yet clear. Interestingly, nothing is known as yet about the neurotransmitter systems necessary for amylin’s effect in the LPBN and its more rostral projection areas [84]; CGRPergic neurons, which had been suggested previously [87], do not seem to be involved [84].
Despite the pivotal role of the caudal hindbrain in mediating amylin’s effect on eating, amylin and its receptor agonists clearly also affect other brain areas, including the reward system encompassing the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Whether effects in these brain areas are direct or indirect is still under debate (e.g., [88,89,90,91]).
Direct action of amylin and its agonists in various neuronal populations in the hypothalamic arcuate nucleus (ARC) has also been demonstrated [45,92] but such activation has not yet been linked unequivocally to specific amylin actions. We believe that it is likely that they contribute to amylin’s effects to control eating and metabolism, but future studies will need to investigate their exact contribution in this respect, as well as their interaction with caudal hindbrain mechanisms.
One of the best investigated functions of amylin is the role of amylin as a leptin sensitizing hormone. The earliest studies suggesting a functionally relevant interaction between amylin and leptin showed that animals with defective leptin signaling (e.g., ob/ob mice, Zucker fa/fa rats) present a reduced response to the administration of sCT [93] and that central leptin administration increased the effect of peripheral amylin to acutely reduce eating [94]. We confirmed the former results, showing that leptin receptor deficient db/db mice and Zucker diabetic fatty rats are less sensitive to the satiating effect of peripheral amylin compared to wildtype control mice and rats, respectively [95]. Many follow-up studies investigated the type of interaction, mode of interaction, and potential site(s) of interaction between amylin and leptin [96,97,98,99,100,101,102,103]; most of these clearly indicated an important role of the hypothalamus, in particular the ventromedial hypothalamus (VMH), which encompasses the ARC and ventromedial nucleus of the hypothalamus (VMN). This is also consistent with the co-distribution of amylin receptor components and leptin receptors in many brain areas, especially in the hypothalamus [104,105,106,107,108]. Amylin stimulates the production of interleukin-6 (IL-6), selectively in hypothalamic microglia, but not neurons or astrocytes [109]. Because the amylin-induced effects on leptin signaling in the VMH were reduced in IL-6 knockout mice or in rats pretreated with an IL-6 antibody [109], IL-6 may be the mediator increasing the leptin response, as has also been confirmed in dissociated VMN neurons [110]. Furthermore, [111] showed that VMN neurons from diet-induced obese (DIO) rats also express less of the Bardet Biedl Syndrome-6 protein (BBS6) mRNA, which contributes to the trafficking of the leptin receptor to the cell surface [112,113]. Interestingly, IL-6 restored leptin receptor (LepRb) and BBS6 expression in VMN neurons from DIO rats to levels similar to those found in DR rats [110]. Overall, these and other results implied that IL-6 (potentially via BBS6) may link amylin to enhanced VMH leptin signaling [105,109]. Despite the strong evidence for a critical role of the VMH in mediating the leptin sensitizing effect of amylin, some important experiments (e.g., the abolition of the interaction in the absence of specific hypothalamic neurons) have not yet been performed; furthermore, a recent study cast doubt on microglia being the sole source of IL-6 in this respect [114].

4. Physiological Role of Amylin in Glucose Control

Since the discovery of insulin in the 1920s, insulin and later glucagon were seen as the major controllers of glucose metabolism. However, in the late 1980s and early 1990s, amylin was recognized as another pancreatic hormone which also influences glucose metabolism [115]. In simple terms, as insulin controls the rate of glucose uptake from the blood, amylin complements insulin by delaying glucose inflow into the circulation [116]. Amylin controls glucose appearance via three primary mechanisms. Amylin decreases gastric emptying, thus delaying the inflow of nutrients into the small intestine, and, by doing so, slows the uptake of meal-derived glucose into the circulation [117,118]. Amylin blocks meal-induced glucagon release, which therefore suppresses glucagon-stimulated hepatic gluconeogenesis [119]. Additionally, as described above, amylin induces meal-ending satiation [72,73,120] and, chronically, also reduces body adiposity and increases energy expenditure [121,122]. In addition to these three main effects, historically being one of the first effects of amylin that was reported, amylin has an inhibitory effect on the secretion of insulin [123,124] and increases the activity of muscle glycogen phosphorylase, thus stimulating muscle glycogenolysis [125]. The physiological or pathophysiological relevance of the latter two effects is, however, still unclear.

4.1. Amylin Slows Gastric Emptying

The first study to observe the effect of amylin administration on gastric emptying in humans came from Kolterman and colleagues in 1995 [126]. Diabetes mellitus is often associated with accelerated gastric emptying; subjects with 1DM were treated with pramlintide prior to a meal, along with their usual dose of insulin. When the meal was consumed orally, pramlintide reduced meal-induced glucose excursions; however, pramlintide did not affect glucose appearance after an intravenous glucose load [126]. These data show that while pramlintide decelerated glucose uptake from the meal-derived carbohydrates, it did not affect post-absorptive glucose metabolism.
By tracking the appearance of tritium-labelled glucose in the plasma after glucose gavage, a similar effect of rat amylin and sCT was observed in rats [124,127]. When further probing the mechanism of action in rats, it was shown that both an intact AP [128] and an intact vagus nerve (most likely via parasympathetic efferents) were required for amylin to slow gastric emptying [129]. In obese Zucker rats, a higher dose of amylin was required to observe an effect on gastric emptying [130]. This reduced sensitivity to amylin was postulated to result from the hyperamylinemia—and presumably reduced amylin sensitivity—observed in this model, though it is also possible that the deficiency in leptin receptor which underlies the Zucker rat’s obese phenotype—and hence an attenuated amylin/leptin synergy—could contribute to reduced amylin action [95]. The latter idea receives indirect support from our findings that the acute eating inhibitory effect of amylin is not reduced during prevailing hyperamylinemia [61].
For patient safety, it was important to next determine if this action of amylin could place diabetic patients who are dependent on insulin at a higher risk for insulin-induced hypoglycemia, but it was found that this action of amylin depends on the glycemic state. Treatment with amylin or pramlintide in a normoglycemic state will essentially block gastric emptying during a 20 min test [78]. If amylin was provided along with insulin, which then caused a hypoglycemic state, then gastric emptying was accelerated at a similar rate as when insulin induced hypoglycemia in the absence of amylin. In essence, the presence of hypoglycemia seemed to prevent amylin’s ability to slow gastric emptying, which was proposed as a protective brake to prevent the further deepening of hypoglycemia [78]; similar findings have also been reported in respect to amylin’s eating inhibitory effect [79]. It is possible that this hypoglycemic break on amylin action resides in the brain, as more than 90% of amylin-responsive cells in the area postrema are also responsive to glucose [77].

4.2. Amylin Suppresses Meal-Induced Glucagon Secretion

Insulin, amylin, and glucagon work together to control metabolism and blood glucose levels [131]. As glucagon works to mobilize stored energy by acutely stimulating glycogenolysis or gluconeogenesis in the liver, it is released from the pancreatic alpha cells in response to hypoglycemia. Glucagon release is also stimulated by a meal, primarily to buffer and fine-tune the hypoglycemic potential of meal-induced insulin, and it also contributes to meal-ending satiation [132,133]. Diabetes mellitus is often associated with paradoxical postprandial hyperglucagonemia; like insulin, amylin was shown to inhibit glucagon release, which therefore generates a preference for glucose accretion via meal-related glucose over endogenous stores [134]. Notably, amylin does not suppress glucagon secretion in response to hypoglycemia, similar to the fail-safe mechanism discussed above for gastric emptying; in other words, amylin specifically inhibits nutrient- or arginine-stimulated glucagon secretion [135]. Furthermore, this glucagonostatic effect does not occur at the level of the alpha cell, as amylin has no effect on stimulated-glucagon secretion from isolated pancreas or islets [135]. Co-treatment with the amylin receptor antagonist AC187 blocked amylin’s glucagonostatic effect [119,134,136], suggesting that it is likely mediated via amylin receptors, potentially in the AP, however, the precise mechanism or critical site of action has not been determined.

5. Role of Amylin in Disease States with Compromised Glucose Control

5.1. Type 1 and Type 2 Diabetes

Like insulin, people with 1DM have deficient or absent amylin secretion [31,137]. While people exhibiting glucose intolerance or early-stage 2DM tend to have elevated amylin levels in accordance with hyperinsulinemia [31,138,139], amylin levels at later stages of insulin-deficient 2DM have been described as normal [140] or deficient [139]. Similar effects have been observed at the level of the pancreas. In one study, the majority of beta cell samples collected postmortem from humans with 2DM exhibited no amylin immunoreactivity, while all maintained reactivity for insulin; obviously, this finding must be interpreted with caution because the affinity and sensitivity of antibodies to detect amylin or insulin may differ. Nonetheless, beta cells from subjects without diabetes were positive for both amylin and insulin [141]. Thus, similar to insulin secretion, amylin levels initially increase in response to insulin resistance and glucose intolerance, but progression to 2DM and the eventual failure of beta cell secretion results in a state of amylin-deficiency, which seems to precede, and potentially even contributes to, insulin deficiency [139,142].
These findings are consistent across several rodent models of 1DM and 2DM. [143,144]. For example, Goto-Kakizaki rats, which are nonobese but spontaneously develop 2DM at around 4 months of age, exhibit no increase in plasma amylin following a glucose challenge [145]. Furthermore, streptozotocin, which leads to beta-cell damage and a reduction in beta-cell mass, reduced insulin and amylin expression in rats but, depending on the extent of damage, the amylin to insulin ratio was differentially affected. Specifically, the amylin to insulin ratio was higher when the beta-cell damage was more extensive (i.e., when a higher streptozotocin dose had been used) or when moderate beta-cell damage occurred in combination with insulin resistance. Whether and how changes in the amylin to insulin ratio may affect the pathogenesis or the progression of diabetes, remains unknown, however [146].
Typically associated with 1DM and 2DM are abnormally high glucagon concentrations, in particular in the prandial and postprandial phase. This leads to a paradoxical increase in hepatic gluconeogenesis, which contributes to the hyperglycemic state. The pathophysiological importance of excessive glucagon secretion can, e.g., be demonstrated in insulin-deficient mice with a genetic deletion of the glucagon receptor [147] or rats treated with glucagon receptor antibodies [148]. In both cases, insulin-deficient hyperglycemia could be completely normalized when glucagon signaling was abolished, without any insulin substitution.
Because insulin alone, despite its glucagonostatic effect, often does not lead to optimal glycemic control in particular in the periprandial stage, the observation that amylin also reduces (postprandial) glucagon secretion was the basis of studies investigating the clinical utility of this approach. In fact, it was shown that physiological concentrations of amylin suppressed glucagon release [119,134]. Subsequent studies showed that the effect is of clinical relevance because patients with 1DM or 2DM and exaggerated postprandial secretion of glucagon could successfully be treated by the administration of pramlintide [149,150]. Pramlintide in particular prevented the excessive meal-related rise in glucagon in insulin treated diabetics [151,152]. Importantly, no glucagonostatic effects of pramlintide was seen during hypoglycemia [153], similar to the effect of amylin on eating [79] and on gastric emptying [78]. These are very relevant aspects for drug safety. Hence, the inhibitory effect of amylin on glucagon secretion in rodents could be translated to diabetes treatment and lead to the approval of pramlintide (Symlin®) as antidiabetic drug.

5.2. Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is characterized by hyperglycemia, resulting from an inability of the maternal pancreas to secrete enough insulin to compensate for insulin resistance that is a normal metabolic adaptation of pregnancy. While glucose-stimulated amylin levels were also shown to increase during pregnancy, a diagnosis of GDM did not seem to have additional influence on increased amylin secretion [154]. Pilot experiments from our group demonstrated that rats in mid-gestation exhibited a normal satiation response to exogenous amylin, suggesting that differently to insulin resistance, amylin resistance does not seem to occur during pregnancy—at least in respect to the eating inhibitory effect [155,156]. While these data would suggest that changes in amylin levels or sensitivity during pregnancy do not contribute to the pathogenesis of GDM, a more recent study showed that pregnant transgenic human-amylin (hIAPP) mice exhibit GDM-like pathologies [157]. Though there is currently no evidence that GDM in pregnant women results from increased deposition of toxic amylin aggregates in the beta cells, this recent study not only presents a new rodent model of GDM, but also introduces the hypothesis that amylin aggregation in women could contribute to GDM during pregnancy or the increased risk for 2DM in the years following pregnancy [157].

5.3. Obesity

Most of the recent amylin research concentrated on its eating inhibitory and weight-reducing properties. This has led to several questions with respect to the potential links between amylin and obesity, including (1) whether amylin action could be exploited pharmacologically to combat obesity, and (2) whether a dysfunction of the amylin system may contribute to the development of obesity. There is very good evidence for the former [8,9,10,63,158,159], and this aspect will be covered in the following Section 6.
In respect to the second aspect, amylin, along with leptin and insulin, seems to be an important signal for adiposity [74,75,160], in that it informs the brain about the body’s fat stores. Furthermore, mice lacking the RAMP1 component of the AMY1 receptor are characterized by increased adiposity, and male RAMP1/3 double knockout mice gain more weight when exposed to a high fat diet [55]. Nonetheless, there is currently no clear evidence that a dysfunction in the amylin system (e.g., defects in amylin secretion, changes in receptor distribution or sensitivity) is a primary driver of common forms of obesity. Importantly, high prevailing levels of baseline amylin (e.g., induced by obesity or high fat feeding [143]) do not seem to reduce the efficiency of amylin in reducing eating after acute administration [61]. In other words, we believe that the meal-induced fluctuations of amylin still produce a satiating effect even in obese individuals whose baseline levels are high, and that downregulation of amylin receptors by chronic exposure to high amylin levels may not occur. The latter, however, has not yet been studied formally.
Similar to the correlation of amylin levels with fat mass in rats [143] under weight-stable conditions, basal and glucose-stimulated levels of amylin are elevated in obese men with either normal or impaired glucose tolerance compared to lean controls [139]. The correlation between fat mass and baseline amylin in rats, similar to leptin and insulin, is lost during dynamic periods of weight change, for example, when rats that had been previously forced-fed are returned to ad libitum eating, their fasting amylin levels drop much faster than the reduction in adiposity [161]. However, the functional implications of the finding of this “disconnect” in respect to amylin is unclear.
An important animal model for the study of amylin’s role in obesity in general, and in the amylin-leptin interactions in particular, has been the selectively-bred DIO rat. The intrinsic leptin resistance in DIO rats is already present before the development of overt obesity [162,163]. Leptin resistance is characterized by reduced LepRb expression in the VMH [110,164], reduced leptin receptor binding [104], reduced leptin-induced pSTAT3 [105,163,165,166], and reduced behavioral responses to leptin, e.g., a reduced anorectic effect [162]. Interestingly, lean DIO rats already have reduced amylin binding in the dorsal VMN [105]. It is unclear whether this directly contributes to the reduced leptin sensitivity in DIO rats. However, the depletion of CTR mRNA in the VMH in rats that are diet resistant (DR) reduced their leptin receptor binding and leptin-induced STAT3 phosphorylation. In other words, depletion of the CTR in the VMN rendered a more DIO-like phenotype in the DR rats and led to increased adiposity [105]. Other studies lend support to the important role of CTR signaling on leptin responsive hypothalamic neurons for metabolic control [167,168]. The discovery that leptin receptor deficient db/db mice have less CTR expression in the AP adds to these findings [95], but they cannot easily be translated to humans because primary leptin receptor deficiency is not the cause of common obesity.
Despite the well documented finding that amylin increases leptin sensitivity [94,97,99,100,101,103], amylin administration in rats that were severely obese (approx. 700 g of body weight) produced weight loss (see also [72]), but adding leptin to amylin produced no additional effect [102]. Even when weight loss was induced in these rats by dietary restriction, amylin attenuated the weight regain when the rats were fed ad libitum again, but leptin had no suppressive effect on this weight regain either alone or in combination with amylin [102]. Hence, the synergistic and sensitizing effects of amylin on leptin signaling may reach limits in very obese rodents and possibly extremely obese humans.
It is currently not clear whether the extreme level of obesity or the long duration of high fat feeding, which produces extensive hypothalamic inflammation and gliosis in rodents [169,170,171,172] and humans [170] and subsequently reduced leptin sensitivity and signaling, was responsible for this finding of a missing synergism. It seems possible that leptin resistance due to high leptin levels simply cannot be overcome by amylin administration. The implications for humans are not yet clear, i.e., the effectiveness of amylin–leptin co-administration in obese individuals who are placed on a low fat diet or who were calorically restricted still needs to be investigated.

5.4. Bariatric Surgery and Post-Bariatric Surgery Hypoglycemia

Bariatric surgery is currently the most effective treatment of obesity and in many cases results in the rapid improvement of 2DM. Two studies that investigated glucose and mixed-meal stimulated hormone release showed that following Roux-en-Y gastric bypass (RYGB) surgery, but not sleeve gastrectomy or gastric banding, amylin levels were markedly suppressed [173,174]. This is unlike the many other gut hormones, such as GLP-1, PYY, and glucagon, which are typically increased in the weeks and years following RYGB surgery [173,175]. However, some studies in rats indicated that postprandial amylin levels post-RYGB are elevated rather than suppressed [176]. The reasons for these discrepant findings are, as yet, unclear, but study outcome may depend on the time after surgery and on the level of improved insulin sensitivity post-RYGB, hence the strain on beta-cells to secrete insulin (and amylin).
Regardless of the changes of endogenous amylin post-RYGB, amylin was recently discussed in the context of post-bariatric complications. In particular, there is a sub-population of patients who experience post-bariatric surgery hypoglycemia (PBH) in the years following their surgery [177]. PBH has been estimated to occur in between 22 to 75% of patients undergoing bariatric surgery [178,179,180]. It has been suggested that surgical restructuring of the gut after RYGB and the resulting rapid delivery of undigested food into the small intestine causes exaggerated prandial glucose excursions, which leads to a hyperinsulemic response, followed by a hypoglycemic rebound, within one to three hours after the meal [181,182]. While elevated levels of insulin, GLP-1, and glucagon seem even more pronounced in the sub-population most prone to PBH [175], it has not been tested if this same group demonstrates significant changes in the nutrient-induced amylin release compared to the general RYGB population. So, while we do not know if amylin levels are lower in patients with PBH, it was recently hypothesized that amylin and its analogs could be useful in controlling PBH. Based on amylin’s ability to inhibit meal-stimulated glucagon, pre-meal dosing of amylin has the potential to limit glucagon-induced release of endogenous glucose and blunt the amplified glucose excursions observed in patients with PBH. It was hypothesized that suppression of these amplified excursions, including the initial prandial hyperglycemia, could be an important factor in preventing the hypoglycemic rebound that follows a meal. However, a recent pilot study was rather discouraging because pramlintide did not modulate the glycemic excursions or insulin responses in a mix meal test and glycemic excursions remained unaltered [183].
Another unexplored area is whether treatment with amylin or its analogs may be beneficial to curbing weight regain post-bariatric interventions. An important challenge after any weight loss intervention, including bariatric surgery, is the prevention of weight regain [184]. It could therefore be hypothesized that amylin-based pharmacotherapy may be used to prevent weight regain after weight loss. Importantly, it has been shown in rats that had undergone calorie restriction that amylin reduced the weight regain when the animals were again given ad libitum access to food [102]. A translation of these findings could have important clinical implications.

5.5. Amylin and Alzheimer’s Disease (AD)

Neurodegenerative diseases, including Alzheimer’s disease (AD) seem to be often associated with metabolic disease, including 2DM [185]. Amylin has recently been suggested as being one potential causal link between these two disease entities, in part because of the biochemical similarities between the amylin-derived islet amyloid and β-amyloid (Aβ) deposition, which is one histological hallmark of AD. Both peptides are prone to aggregation in certain conditions, and the toxic principle of these amyloid aggregates seems to be similar. Furthermore, certain groups of AD patients seem to have amylin-derived amyloid plaques co-localized with Aβ plaques in the central nervous system. Other data, however, suggest that amylin—or at least its non-fibrillar analogs—may reduce Aβ-derived amyloid formation and could in fact be helpful in the treatment of AD. These ambiguities are far from clear, and more research is necessary to better understand the role of amylin in AD and the role of amylin in metabolic changes during ageing in general [186,187].

6. Amylin-Based Therapies for the Treatment of Diabetes and Obesity

Diabetes and obesity are both relevant health issues, affecting millions of people all over the world and with an increasing prevalence. Even though lifestyle modification is the first-line intervention for patients suffering, in particular, from 2DM, pharmacological approaches for effective and safe weight loss are needed. Amylin and amylin analogs have been in the focus of interest due to their effects on food intake, body weight, but also on glycemic control. Amylin-based drugs that are currently available or in testing are presented in the following sections.

6.1. Pramlintide

Pramlintide (Symlin®) was the first approved amylin analogue, and it is still the only approved amylin-based drug so far. Pramlintide only differs in three amino acids from human amylin, which markedly reduces its amyloidogenic properties. Pramlintide has similar potency and biological activity as human amylin and is approved for patients with 1DM and 2DM who use insulin [188,189]. Pramlintide treatment provides a series of benefits such as reduced food intake and body weight, lower glycated hemoglobin level, and it also lowers the insulin dose needed to reach glycemic control in both 1DM and 2DM [189,190,191,192,193]. Additionally, as in the case of amylin, pramlintide slows gastric emptying, inhibits postprandial glucagon rises, and reduces caloric intake, thus delaying glucose appearance in the circulation and controlling glucose homeostasis [118,149,194,195]. While pramlintide was also shown not to compromise the counterregulatory responses to hypoglycemia [196], it can heighten insulin-induced hypoglycemia, and patients combining insulin and amylin therapy are recommended to reduce their normal insulin dose by fifty percent when also taking amylin at mealtimes [197]. Nausea is the most common negative side effect observed in patients taking pramlintide. In addition to contributing to enhanced glucose control in patients suffering from 1DM and 2DM, pramlintide is also considered as a potential drug to treat obesity due to its effect on food intake and body weight [64,198,199], but more modern analogs show greater promise in this respect, not for their main mode of action, but for heightened efficacy and duration of effect because pramlintide requires injections with each major meal, i.e., usually three times daily [192].

6.2. Dual Amylin and Insulin-Based Therapies for the Treatment of 1DM and 2DM

Pramlintide is not used as single treatment but is prescribed as an adjunctive treatment in combination with insulin. In fact, the administration of pramlintide plus insulin in a fixed molar ratio improves glycemic control in 1DM [200,201] and also 2DM. Traditionally, insulin and pramlintide had to be administered separately because the coformulation of both peptides was unstable; potentially, this may be a reason why the combination of the drugs is used less frequently than may be indicated. A recent study indicated that a novel approach using a coformulation of supramolecularly stabilized insulin and pramlintide may be possible and that the coformulation was stable over several days; its administration was shown to enhance mealtime glucagon suppression in diabetic pigs [202]. To our knowledge, clinical trials with this new coformulation have not yet been published.
Another indirect approach has been described recently. Insulin-degrading enzymes (IDE) not only metabolize and degrade insulin but also amylin. A recent study showed that the inhibition of IDE modulated the activity of both insulin and amylin in a way that glycemia was markedly improved in preclinical mouse models of metabolic disease [203]. Respective clinical trials have not yet been performed; hence it is unclear if this approach will show therapeutic efficacy.

6.3. Long-Acting Amylin Agonists and Dual Amylin and CT Receptor Agonists (DACRAs)

Even though pramlintide shows many benefits in patients with diabetes and obesity, its short half-life and potency limit its efficacy as a medication because it needs to be administered three times daily, i.e., with every main meal [190,192,204]. Thus, more potent and long-lasting amylin analogs have been developed and tested in an effort to provide greater therapeutic benefit.
Davalintide is an amylin analogue with higher potency, efficacy, and a longer half-life [205]. Davalintide shares 49% amino acid homology with amylin and, like amylin and pramlintide, davalintide shows high affinity for amylin receptors, but at the same time it also displays affinity for CT receptors [205]. Preclinical studies in rodents showed that davalintide led to a prolonged receptor activation and also caused a greater reduction of food intake and body weight compared to amylin and pramlintide [205,206]. Additionally, davalintide administration in mice provided glucoregulatory effects such as decreased fasting glucose level [206]. The higher potency is most likely due to the slow dissociation of davalintide from the receptors, similar to sCT [63], as it has a similar circulating half-life as amylin [205,206].
Another approach to enhancing the action of amylin analogs is by modifying their structure. A prolonged half-life can be reached by modifications such as the coupling of a polyethylene glycol (PEG) or by glycosylation. These modified peptides showed prolonged action, though further research is needed to assess their therapeutic utility [207,208].
Recent studies confirmed that the dual agonists, which are able to activate both amylin and CT receptors (DACRAs), similar to sCT, displayed higher potency in the reduction of food intake and body weight compared to amylin and current amylin analogs [209,210,211]. DACRA is a working class of molecules which activates both amylin and CT receptors in a prolonged fashion [209,210,212]. Recent studies showed that DACRAs were superior in terms of typical amylin-induced effects as reduction of body weight, food intake, glucagon secretion, and gastric emptying rate when compared to amylin and other amylin receptor analogs [12,210,211]. Furthermore, DACRA treatment resulted in improvement of glucose homeostasis in obese rodents, shown by reduced fasting blood glucose, lower glucose levels after oral glucose tolerance test, lower glycated hemoglobin, and lower insulin levels [209,210,213]. Altogether, preclinical studies in animals showed that DACRAs display higher potency in eliciting classical amylin-mediated effects compared to amylin and amylin analogs and result in improved glucose homeostasis. Therefore, DACRAs have recently been in the focus of research as a potent drug in obesity and diabetes.
The first known DACRAs was salmon CT (sCT), which acts on both amylin and CT binding sites [51]. Metabolic effects of sCT seem to be, at least partially, due to amylin receptor activation [82,124,214]. Interestingly, rat CT does not exhibit high affinity to amylin receptors [214]. As sCT was at first only considered and used as an amylin analogue, many of its effects have been considered as amylin receptor effects, which has yet to be decisively proven. Current studies are also investigating the effects of various engineered DACRAs, including KBP-042, KBP-088, and KBP-089 [11,13,209,215,216,217]. KBP-088 has been directly compared to davalintide [210] and amylin [12] and was superior in both cases in terms of food intake and body weight reduction and improved glucose control. It is important to note that these experiments were conducted in animals, thus it is still unclear what effect DACRAs will elicit in humans suffering from metabolic disease.

6.4. DACRA Mechanism

Even though many studies have examined the beneficial effect of DACRA in metabolism and glucose control, little is known about its exact mechanism. Studies with sCT suggest that the metabolic effect of DACRA and its inhibition of gastric emptying are mediated, like amylin, by neurons in the AP, as sCT administration results in prolonged excitation of these neurons compared to amylin [82,214,218]. In vitro studies found that DACRAs activate both CT and amylin receptors potently but that DACRAs show low affinity to the CGRP receptor [13,209]. However, a link between the receptor activation in vitro and DACRA’s effect in vivo has not been established. Recent studies by Larsen et al. reported that some changes in glucose metabolism, such as an improvement in glucose tolerance and a reduction in fasting blood glucose, could only be achieved by using DACRA or amylin and CT analogs simultaneously, but neither by amylin nor by CT analogs on its own [211]. The authors of this study concluded that the CT receptor is needed for DACRA’s full action on glucose control, while it contributes little to other effects such as body weight and food intake reduction. However, the same study also showed that the co-activation of amylin and CT receptors by using amylin and CT analogs were not enough to modify other parameters of glucose metabolism, such as glycated hemoglobin or plasma insulin level, though DACRA effectively changes these parameters. Thus, further research is needed to explore how exactly the CT receptor, independently of the amylin receptor, contributes to DACRA’s effect in metabolism and glucose control.

6.5. Specific Role of the CTR in Metabolism

The results of these DACRA investigations suggest that CT and CTR may play a specific role in metabolism. Even though CT was discovered 60 years ago, its exact physiological significance in controlling metabolism is unclear and the importance of CT and the CTR in metabolism is still incompletely defined. Bartelt and colleagues showed in 2017 that CTR knockout in male mice on a high-fat diet led to negative metabolic changes, such as impaired glucose tolerance and higher serum lipids, suggesting the importance of CTR in metabolic control [219]. The same study, however, also showed that a knockout of Calca, the gene coding for CT and CGRP, resulted in improvements in metabolic parameters such as lower fasting glucose, improved glucose tolerance and decreased white adipocyte tissue weight. These improvements seem mainly due to the absence of CT, as a CGRP knockout alone only merely improved glucose tolerance and lowered the weight of white adipocyte tissue to a much lower content [219]. These findings suggest that CTR signaling contributes to improved metabolic control while CT seemed to be detrimental for metabolic health. The latter has also been confirmed by Nakamura and colleagues who showed in 2018 that mice with global knockout of the CT gene displayed lower body weight, decreased serum lipids and visceral fat, lower fasting glucose, and higher insulin sensitivity [220]. It is unclear why the absence of CTR seems to be deleterious to the metabolism, while the absence of its natural ligand CT may lead to improved metabolic control. In order to establish further knowledge about and the exact mechanism of DACRAs, it is necessary to answer this question.

6.6. New Developments of Amylin Analogs

One of the most modern and most potent agonists, which is also a DACRA, is the rather unspecific CTR and AMY agonist AM833 (cagrilintide). Cagrilintide produced sustained and marked weight loss when given alone; when combined with the GLP-1 agonist semaglutide, AM833 produced even stronger responses that exceeded the effect of most other pharmacotherapies [158,221,222,223]. Studies of the exact mechanism of action of this and other long acting amylin analogs are ongoing [8,63,218,221,222,224,225] and at least some of the effects seem to be mediated by the necessary interaction with specific amylin receptor subtypes [218,225]. All results obtained so far allow us to conclude that amylin-based weight loss pharmacotherapy can be considered an interesting strategy for the further development of highly effect weight lowering agents.

7. Conclusions

This review provides a brief update of the status of the pancreatic hormone amylin as a key player in the control of energy and glucose metabolism. Amylin’s main physiological actions, the reduction of eating, the inhibition of gastric emptying, and the inhibition of glucagon secretion are mediated by the caudal hindbrain. At least in the case of the eating inhibitory effect, we have learned a lot about the underlying brain mechanisms and interactions with other hormones. Soon after the discovery of these effects, it became clear that amylin analogs may be interesting therapeutic targets for the treatment of metabolic disease, in particular obesity and 2DM. Some of these analogs may now be among the most promising future anti-obesity treatments.


This research was funded by Swiss National Science Foundation. TAL also received funding for collaborative projects from Novo Nordisk and Boehringer Ingelheim.


We gratefully acknowledge the long term support of our research by the Swiss National Science Foundation. TAL also received funding for collaborative projects from Novo Nordisk and Boehringer Ingelheim. These collaborations had no influence on the contents of this review.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Westermark, P.; Wernstedt, C.; Wilander, E.; Hayden, D.W.; O’Brien, T.D.; Johnson, K.H. Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Proc. Natl. Acad. Sci. USA 1987, 84, 3881–3885. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Cooper, G.J.; Willis, A.C.; Clark, A.; Turner, R.C.; Sim, R.B.; Reid, K.B. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc. Natl. Acad. Sci. USA 1987, 84, 8628–8632. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Opie, E.L. On the Relation of Chronic Interstitial Pancreatitis to the Islands of Langerhans and to Diabetes Melutus. J. Exp. Med. 1901, 5, 397–428. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Ahronheim, J.H. The Nature of the Hyaline Material in the Pancreatic Islands in Diabetes Mellitus. Am. J. Pathol. 1943, 19, 873–882. [Google Scholar]
  5. Lukinius, A.; Wilander, E.; Westermark, G.T.; Engstrom, U.; Westermark, P. Co-localization of islet amyloid polypeptide and insulin in the B cell secretory granules of the human pancreatic islets. Diabetologia 1989, 32, 240–244. [Google Scholar] [CrossRef] [Green Version]
  6. Nakazato, M.; Asai, J.; Kangawa, K.; Matsukura, S.; Matsuo, H. Establishment of radioimmunoassay for human islet amyloid polypeptide and its tissue content and plasma concentration. Biochem. Biophys. Res. Commun. 1989, 164, 394–399. [Google Scholar] [CrossRef]
  7. Ogawa, A.; Harris, V.; McCorkle, S.K.; Unger, R.H.; Luskey, K.L. Amylin secretion from the rat pancreas and its selective loss after streptozotocin treatment. J. Clin. Investig. 1990, 85, 973–976. [Google Scholar] [CrossRef]
  8. Dehestani, B.; Stratford, N.R.; le Roux, C.W. Amylin as a Future Obesity Treatment. J. Obes. Metab. Syndr. 2021, 30, 320–325. [Google Scholar] [CrossRef]
  9. Mathiesen, D.S.; Bagger, J.I.; Knop, F.K. Long-acting amylin analogues for the management of obesity. Curr. Opin. Endocrinol. Diabetes Obes. 2022, 29, 183–190. [Google Scholar] [CrossRef]
  10. Mathiesen, D.S.; Lund, A.; Vilsbøll, T.; Knop, F.K.; Bagger, J.I. Amylin and Calcitonin: Potential Therapeutic Strategies to Reduce Body Weight and Liver Fat. Front. Endocrinol. 2020, 11, 617400. [Google Scholar] [CrossRef]
  11. Larsen, A.T.; Gydesen, S.; Sonne, N.; Karsdal, M.A.; Henriksen, K. The dual amylin and calcitonin receptor agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile. BMC Endocr. Disord. 2021, 21, 10. [Google Scholar] [CrossRef] [PubMed]
  12. Larsen, A.T.; Sonne, N.; Andreassen, K.V.; Gehring, K.; Karsdal, M.A.; Henriksen, K. The Dual Amylin and Calcitonin Receptor Agonist KBP-088 Induces Weight Loss and Improves Insulin Sensitivity Superior to Chronic Amylin Therapy. J. Pharm. Exp. Ther. 2019, 370, 35–43. [Google Scholar] [CrossRef] [PubMed]
  13. Sonne, N.; Larsen, A.T.; Andreassen, K.V.; Karsdal, M.A.; Henriksen, K. The Dual Amylin and Calcitonin Receptor Agonist, KBP-066, Induces an Equally Potent Weight Loss Across a Broad Dose Range While Higher Doses May Further Improve Insulin Action. J. Pharmacol. Exp. Ther. 2020, 373, 92–102. [Google Scholar] [CrossRef] [PubMed]
  14. Hay, D.L.; Chen, S.; Lutz, T.A.; Parkes, D.G.; Roth, J.D. Amylin: Pharmacology, Physiology, and Clinical Potential. Pharmacol. Rev. 2015, 67, 564–600. [Google Scholar] [CrossRef] [Green Version]
  15. Betsholtz, C.; Johnson, K.H.; Westermark, P. ‘Amylin’ hormone. Nature 1989, 338, 211. [Google Scholar] [CrossRef]
  16. Wimalawansa, S.J. Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: A peptide superfamily. Crit. Rev. Neurobiol. 1997, 11, 167–239. [Google Scholar] [CrossRef]
  17. Betsholtz, C.; Christmansson, L.; Engstrom, U.; Rorsman, F.; Svensson, V.; Johnson, K.H.; Westermark, P. Sequence divergence in a specific region of islet amyloid polypeptide (IAPP) explains differences in islet amyloid formation between species. FEBS Lett. 1989, 251, 261–264. [Google Scholar] [CrossRef] [Green Version]
  18. Moriarty, F.D.; Raleigh, D.P. Effects of sequential proline substitutions on amyloid formation by human Amylin20–29±. Biochemistry 1999, 38, 1811–1818. [Google Scholar] [CrossRef]
  19. Ridgway, Z.; Lee, K.H.; Zhyvoloup, A.; Wong, A.; Eldrid, C.; Hannaberry, E.; Thalassinos, K.; Abedini, A.; Raleigh, D.P. Analysis of Baboon IAPP Provides Insight into Amyloidogenicity and Cytotoxicity of Human IAPP. Biophys. J. 2020, 118, 1142–1151. [Google Scholar] [CrossRef]
  20. Cooper, G.J. Amylin compared with calcitonin gene-related peptide: Structure, biology, and relevance to metabolic disease. Endocr. Rev. 1994, 15, 163–201. [Google Scholar] [CrossRef]
  21. Westermark, P.; Andersson, A.; Westermark, G.T. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol. Rev. 2011, 91, 795–826. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Butler, A.E.; Jang, J.; Gurlo, T.; Carty, M.D.; Soeller, W.C.; Butler, P.C. Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): A new model for type 2 diabetes. Diabetes 2004, 53, 1509–1516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Hull, R.L.; Andrikopoulos, S.; Verchere, C.B.; Vidal, J.; Wang, F.; Cnop, M.; Prigeon, R.L.; Kahn, S.E. Increased dietary fat promotes islet amyloid formation and beta-cell secretory dysfunction in a transgenic mouse model of islet amyloid. Diabetes 2003, 52, 372–379. [Google Scholar] [CrossRef] [PubMed]
  24. Roesti, E.S.; Boyle, C.N.; Zeman, D.T.; Sande-Melon, M.; Storni, F.; Cabral-Miranda, G.; Knuth, A.; Lutz, T.A.; Vogel, M.; Bachmann, M.F. Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus. Vaccines 2020, 8, 116. [Google Scholar] [CrossRef] [Green Version]
  25. Gedulin, B.; Cooper, G.J.; Young, A.A. Amylin secretion from the perfused pancreas: Dissociation from insulin and abnormal elevation in insulin-resistant diabetic rats. Biochem. Biophys. Res. Commun. 1991, 180, 782–789. [Google Scholar] [CrossRef]
  26. Inoue, K.; Hisatomi, A.; Umeda, F.; Nawata, H. Release of amylin from perfused rat pancreas in response to glucose, arginine, beta-hydroxybutyrate, and gliclazide. Diabetes 1991, 40, 1005–1009. [Google Scholar] [CrossRef]
  27. Kanatsuka, A.; Makino, H.; Ohsawa, H.; Tokuyama, Y.; Yamaguchi, T.; Yoshida, S.; Adachi, M. Secretion of islet amyloid polypeptide in response to glucose. FEBS Lett. 1989, 259, 199–201. [Google Scholar] [CrossRef] [Green Version]
  28. Qi, D.; Cai, K.; Wang, O.; Li, Z.; Chen, J.; Deng, B.; Qian, L.; Le, Y. Fatty acids induce amylin expression and secretion by pancreatic beta-cells. Am. J. Physiol. Endocrinol. Metab. 2010, 298, E99–E107. [Google Scholar] [CrossRef]
  29. Inoue, K.; Hisatomi, A.; Umeda, F.; Nawata, H. Release of amylin from perfused rat pancreas in response to glucose and glucagon. Diabetes Res. Clin. Pract. 1992, 15, 85–88. [Google Scholar] [CrossRef]
  30. Alam, T.; Chen, L.; Ogawa, A.; Leffert, J.D.; Unger, R.H.; Luskey, K.L. Coordinate regulation of amylin and insulin expression in response to hypoglycemia and fasting. Diabetes 1992, 41, 508–514. [Google Scholar] [CrossRef]
  31. Koda, J.E.; Fineman, M.; Rink, T.J.; Dailey, G.E.; Muchmore, D.B.; Linarelli, L.G. Amylin concentrations and glucose control. Lancet 1992, 339, 1179–1180. [Google Scholar] [CrossRef]
  32. Leffert, J.D.; Newgard, C.B.; Okamoto, H.; Milburn, J.L.; Luskey, K.L. Rat amylin: Cloning and tissue-specific expression in pancreatic islets. Proc. Natl. Acad. Sci. USA 1989, 86, 3127–3130. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. D’Este, L.; Wimalawansa, S.J.; Renda, T.G. Amylin-immunoreactivity is co-stored in a serotonin cell subpopulation of the vertebrate stomach and duodenum. Arch. Histol. Cytol. 1995, 58, 537–547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Ferrier, G.J.; Pierson, A.M.; Jones, P.M.; Bloom, S.R.; Girgis, S.I.; Legon, S. Expression of the rat amylin (IAPP/DAP) gene. J. Mol. Endocrinol. 1989, 3, R1–R4. [Google Scholar] [CrossRef] [PubMed]
  35. Miyazato, M.; Nakazato, M.; Shiomi, K.; Aburaya, J.; Toshimori, H.; Kangawa, K.; Matsuo, H.; Matsukura, S. Identification and characterization of islet amyloid polypeptide in mammalian gastrointestinal tract. Biochem. Biophys. Res. Commun. 1991, 181, 293–300. [Google Scholar] [CrossRef]
  36. Mulder, H.; Lindh, A.C.; Ekblad, E.; Westermark, P.; Sundler, F. Islet amyloid polypeptide is expressed in endocrine cells of the gastric mucosa in the rat and mouse. Gastroenterology 1994, 107, 712–719. [Google Scholar] [CrossRef]
  37. Nicholl, C.G.; Bhatavdekar, J.M.; Mak, J.; Girgis, S.I.; Legon, S. Extra-pancreatic expression of the rat islet amyloid polypeptide (amylin) gene. J. Mol. Endocrinol. 1992, 9, 157–163. [Google Scholar] [CrossRef]
  38. Dobolyi, A. Central amylin expression and its induction in rat dams. J. Neurochem. 2009, 111, 1490–1500. [Google Scholar] [CrossRef]
  39. Li, Z.; Kelly, L.; Heiman, M.; Greengard, P.; Friedman, J.M. Hypothalamic Amylin Acts in Concert with Leptin to Regulate Food Intake. Cell Metab. 2015, 22, 1059–1067. [Google Scholar] [CrossRef] [Green Version]
  40. Yoshihara, C.; Tokita, K.; Maruyama, T.; Kaneko, M.; Tsuneoka, Y.; Fukumitsu, K.; Miyazawa, E.; Shinozuka, K.; Huang, A.J.; Nishimori, K.; et al. Calcitonin receptor signaling in the medial preoptic area enables risk-taking maternal care. Cell Rep. 2021, 35, 109204. [Google Scholar] [CrossRef]
  41. Poyner, D.R.; Sexton, P.M.; Marshall, I.; Smith, D.M.; Quirion, R.; Born, W.; Muff, R.; Fischer, J.A.; Foord, S.M. International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol. Rev. 2002, 54, 233–246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. McLatchie, L.M.; Fraser, N.J.; Main, M.J.; Wise, A.; Brown, J.; Thompson, N.; Solari, R.; Lee, M.G.; Foord, S.M. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 1998, 393, 333–339. [Google Scholar] [CrossRef] [PubMed]
  43. Hay, D.L.; Christopoulos, G.; Christopoulos, A.; Poyner, D.R.; Sexton, P.M. Pharmacological discrimination of calcitonin receptor: Receptor activity-modifying protein complexes. Mol. Pharmacol. 2005, 67, 1655–1665. [Google Scholar] [CrossRef] [PubMed]
  44. Boccia, L.; Gamakharia, S.; Coester, B.; Whiting, L.; Lutz, T.A.; Le Foll, C. Amylin brain circuitry. Peptides 2020, 132, 170366. [Google Scholar] [CrossRef] [PubMed]
  45. Coester, B.; Koester-Hegmann, C.; Lutz, T.A.; Le Foll, C. Amylin/Calcitonin Receptor-Mediated Signaling in POMC Neurons Influences Energy Balance and Locomotor Activity in Chow-Fed Male Mice. Diabetes 2020, 69, 1110–1125. [Google Scholar] [CrossRef] [PubMed]
  46. Liberini, C.G.; Boyle, C.N.; Cifani, C.; Venniro, M.; Hope, B.T.; Lutz, T.A. Amylin receptor components and the leptin receptor are co-expressed in single rat area postrema neurons. Eur. J. Neurosci. 2016, 43, 653–661. [Google Scholar] [CrossRef] [Green Version]
  47. Young, A. Inhibition of insulin secretion. Adv. Pharmacol. 2005, 52, 173–192. [Google Scholar]
  48. Young, A. Effects in skeletal muscle. Adv. Pharmacol. 2005, 52, 209–228. [Google Scholar]
  49. Young, A. Effects in fat. Adv. Pharmacol. 2005, 52, 235–238. [Google Scholar]
  50. Bailey, R.J.; Walker, C.S.; Ferner, A.H.; Loomes, K.M.; Prijic, G.; Halim, A.; Whiting, L.; Phillips, A.R.; Hay, D.L. Pharmacological characterization of rat amylin receptors: Implications for the identification of amylin receptor subtypes. Br. J. Pharmacol. 2012, 166, 151–167. [Google Scholar] [CrossRef] [Green Version]
  51. Muff, R.; Born, W.; Fischer, J.A. Calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin: Homologous peptides, separate receptors and overlapping biological actions. Eur. J. Endocrinol. 1995, 133, 17–20. [Google Scholar] [CrossRef] [PubMed]
  52. Kuwasako, K.; Hay, D.L.; Nagata, S.; Murakami, M.; Kitamura, K.; Kato, J. Functions of third extracellular loop and helix 8 of Family B GPCRs complexed with RAMPs and characteristics of their receptor trafficking. Curr. Protein Pept. Sci. 2013, 14, 416–428. [Google Scholar] [CrossRef] [PubMed]
  53. Hay, D.L.; Garelja, M.L.; Poyner, D.R.; Walker, C.S. Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br. J. Pharmacol. 2018, 175, 3–17. [Google Scholar] [CrossRef] [PubMed]
  54. Lee, S.M.; Jeong, Y.; Simms, J.; Warner, M.L.; Poyner, D.R.; Chung, K.Y.; Pioszak, A.A. Calcitonin Receptor N-Glycosylation Enhances Peptide Hormone Affinity by Controlling Receptor Dynamics. J. Mol. Biol. 2020, 432, 1996–2014. [Google Scholar] [CrossRef] [PubMed]
  55. Coester, B.; Pence, S.W.; Arrigoni, S.; Boyle, C.N.; Le Foll, C.; Lutz, T.A. RAMP1 and RAMP3 Differentially Control Amylin’s Effects on Food Intake, Glucose and Energy Balance in Male and Female Mice. Neuroscience 2020, 447, 74–93. [Google Scholar] [CrossRef]
  56. Fernandes-Santos, C.; Zhang, Z.; Morgan, D.A.; Guo, D.F.; Russo, A.F.; Rahmouni, K. Amylin Acts in the Central Nervous System to Increase Sympathetic Nerve Activity. Endocrinology 2013, 154, 2481–2488. [Google Scholar] [CrossRef] [Green Version]
  57. Mollet, A.; Gilg, S.; Riediger, T.; Lutz, T.A. Infusion of the amylin antagonist AC 187 into the area postrema increases food intake in rats. Physiol. Behav. 2004, 81, 149–155. [Google Scholar] [CrossRef]
  58. Grabler, V.; Lutz, T.A. Chronic infusion of the amylin antagonist AC 187 increases feeding in Zucker fa/fa rats but not in lean controls. Physiol. Behav. 2004, 81, 481–488. [Google Scholar] [CrossRef]
  59. Olsson, M.; Herrington, M.K.; Reidelberger, R.D.; Permert, J.; Gebre-Medhin, S.; Arnelo, U. Food intake and meal pattern in IAPP knockout mice with and without infusion of exogenous IAPP. Scand. J. Gastroenterol. 2012, 47, 191–196. [Google Scholar] [CrossRef] [Green Version]
  60. Gingell, J.J.; Rees, T.A.; Hendrikse, E.R.; Siow, A.; Rennison, D.; Scotter, J.; Harris, P.W.R.; Brimble, M.A.; Walker, C.S.; Hay, D.L. Distinct Patterns of Internalization of Different Calcitonin Gene-Related Peptide Receptors. ACS Pharmacol. Transl. Sci. 2020, 3, 296–304. [Google Scholar] [CrossRef]
  61. Boyle, C.N.; Rossier, M.M.; Lutz, T.A. Influence of high-fat feeding, diet-induced obesity, and hyperamylinemia on the sensitivity to acute amylin. Physiol. Behav. 2011, 104, 20–28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Riediger, T.; Schmid, H.A.; Young, A.A.; Simon, E. Pharmacological characterisation of amylin-related peptides activating subfornical organ neurones. Brain Res. 1999, 837, 161–168. [Google Scholar] [CrossRef]
  63. Fletcher, M.M.; Keov, P.; Truong, T.T.; Mennen, G.; Hick, C.A.; Zhao, P.; Furness, S.G.B.; Kruse, T.; Clausen, T.R.; Wootten, D.; et al. AM833 Is a Novel Agonist of Calcitonin Family G Protein-Coupled Receptors: Pharmacological Comparison with Six Selective and Nonselective Agonists. J. Pharmacol. Exp. Ther. 2021, 377, 417–440. [Google Scholar] [CrossRef] [PubMed]
  64. Boyle, C.N.; Lutz, T.A.; le Foll, C. Amylin—Its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity. Mol. Metab. 2018, 8, 203–210. [Google Scholar] [CrossRef]
  65. Foll, L.C.; Lutz, T.A. Systemic and Central Amylin, Amylin Receptor Signaling, and Their Physiological and Pathophysiological Roles in Metabolism. Compr. Physiol. 2020, 10, 811–837. [Google Scholar]
  66. Zakariassen, H.L.; John, L.M.; Lutz, T.A. Central control of energy balance by amylin and calcitonin receptor agonists and their potential for treatment of metabolic diseases. Basic Clin. Pharmacol. Toxicol. 2020, 127, 163–177. [Google Scholar] [CrossRef]
  67. Lutz, T.A. The role of amylin in the control of energy homeostasis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010, 298, 1475–1484. [Google Scholar] [CrossRef] [Green Version]
  68. Lutz, T.A.; Geary, N.; Szabady, M.M.; Del Prete, E.; Scharrer, E. Amylin decreases meal size in rats. Physiol. Behav. 1995, 58, 1197–1202. [Google Scholar] [CrossRef]
  69. Coester, B.; Foll, C.L.; Lutz, T.A. Viral depletion of calcitonin receptors in the area postrema: A proof-of-concept study. Physiol. Behav. 2020, 223, 112992. [Google Scholar] [CrossRef]
  70. Reidelberger, R.D.; Haver, A.C.; Arnelo, U.; Smith, D.D.; Schaffert, C.S.; Permert, J. Amylin receptor blockade stimulates food intake in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004, 287, 568–574. [Google Scholar] [CrossRef] [Green Version]
  71. Young, A. Amylin and the integrated control of nutrient influx. Adv. Pharmacol. 2005, 52, 67–77. [Google Scholar] [PubMed]
  72. Lutz, T.A.; del Prete, E.; Scharrer, E. Reduction of food intake in rats by intraperitoneal injection of low doses of amylin. Physiol. Behav. 1994, 55, 891–895. [Google Scholar] [CrossRef]
  73. Morley, E.J.; Flood, J.F. Amylin decreases food intake in mice. Peptides 1991, 12, 865–869. [Google Scholar] [CrossRef]
  74. Rushing, P.A.; Hagan, M.M.; Seeley, R.J.; Lutz, T.A.; Woods, S.C. Amylin: A novel action in the brain to reduce body weight. Endocrinology 2000, 141, 850–853. [Google Scholar] [CrossRef]
  75. Rushing, P.A.; Hagan, M.M.; Seeley, R.J.; Lutz, T.A.; D’Alessio, D.A.; Air, E.L.; Woods, S.C. Inhibition of central amylin signaling increases food intake and body adiposity in rats. Endocrinology 2001, 142, 5035. [Google Scholar] [CrossRef]
  76. Lutz, T.A.; Senn, M.; Althaus, J.; Del Prete, E.; Ehrensperger, F.; Scharrer, E. Lesion of the area postrema/nucleus of the solitary tract (AP/NTS) attenuates the anorectic effects of amylin and calcitonin gene-related peptide (CGRP) in rats. Peptides 1998, 19, 309–317. [Google Scholar] [CrossRef]
  77. Riediger, T.; Schmid, H.A.; Lutz, T.A.; Simon, E. Amylin and glucose co-activate area postrema neurons of the rat. Neurosci. Lett. 2002, 328, 121–124. [Google Scholar] [CrossRef]
  78. Gedulin, R.B.; Young, A.A. Hypoglycemia overrides amylin-mediated regulation of gastric emptying in rats. Diabetes 1998, 47, 93–97. [Google Scholar] [CrossRef]
  79. Honegger, M.; Lutz, T.A.; Boyle, C.N. Hypoglycemia attenuates acute amylin-induced reduction of food intake in male rats. Physiol. Behav. 2021, 237, 113435. [Google Scholar] [CrossRef]
  80. Riediger, T.; Zuend, D.; Becskei, C.; Lutz, T.A. The anorectic hormone amylin contributes to feeding-related changes of neuronal activity in key structures of the gut-brain axis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004, 286, 114–122. [Google Scholar] [CrossRef] [Green Version]
  81. Lutz, T.A.; Coester, B.; Whiting, L.; Dunn-Meynell, A.A.; Boyle, C.N.; Bouret, S.G.; Levin, B.E.; Le Foll, C. Amylin Selectively Signals Onto POMC Neurons in the Arcuate Nucleus of the Hypothalamus. Diabetes 2018, 67, 805–817. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Braegger, F.E.; Asarian, L.; Dahl, K.; Lutz, T.A.; Boyle, C.N. The role of the area postrema in the anorectic effects of amylin and salmon calcitonin: Behavioral and neuronal phenotyping. Eur. J. Neurosci. 2014, 40, 3055–3066. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Boccia, L.; le Foll, C.; Lutz, T.A. Noradrenaline signaling in the LPBN mediates amylin’s and salmon calcitonin’s hypophagic effect in male rats. FASEB J. 2020, 34, 15448–15461. [Google Scholar] [CrossRef]
  84. Boccia, L.B.; Borner, T.; Ghidewon, M.Y.; Kulka, P.; Piffaretti, C.; Doebley, S.A.; De Jonghe, B.C.; Grill, H.J.; Lutz, T.A.; Le Foll, C. Hypophagia induced by salmon calcitonin, but not by amylin, is partially driven by malaise and is mediated by CGRP neurons. Mol. Metab. 2022, 58, 101444. [Google Scholar] [CrossRef] [PubMed]
  85. Potes, C.S.; Turek, V.F.; Cole, R.L.; Vu, C.; Roland, B.L.; Roth, J.D.; Riediger, T.; Lutz, T.A. Noradrenergic neurons of the area postrema mediate amylin’s hypophagic action. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010, 299, 623–631.e5. [Google Scholar] [CrossRef] [Green Version]
  86. Cheng, W.; Gonzalez, I.; Pan, W.; Tsang, A.H.; Adams, J.; Ndoka, E.; Gordian, D.; Khoury, B.; Roelofs, K.; Evers, S.S.; et al. Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding. Cell Metab. 2020, 31, 301–312.e5. [Google Scholar] [CrossRef] [PubMed]
  87. Carter, M.E.; Soden, M.E.; Zweifel, L.S.; Palmiter, R.D. Genetic identification of a neural circuit that suppresses appetite. Nature 2013, 503, 111–114. [Google Scholar] [CrossRef]
  88. Mietlicki-Baase, G.E.; Hayes, M.R. Amylin activates distributed CNS nuclei to control energy balance. Physiol. Behav. 2014, 136, 39–46. [Google Scholar] [CrossRef] [Green Version]
  89. Mietlicki-Baase, E.G.; McGrath, L.E.; Koch-Laskowski, K.; Krawczyk, J.; Reiner, D.J.; Pham, T.; Nguyen, C.T.N.; Turner, C.A.; Olivos, D.R.; Wimmer, M.E.; et al. Amylin receptor activation in the ventral tegmental area reduces motivated ingestive behavior. Neuropharmacology 2017, 123, 67–79. [Google Scholar] [CrossRef]
  90. Mietlicki-Baase, E.G.; Reiner, D.J.; Cone, J.J.; Olivos, D.R.; McGrath, L.E.; Zimmer, D.J.; Roitman, M.F.; Hayes, M.R. Amylin modulates the mesolimbic dopamine system to control energy balance. Neuropsychopharmacology 2015, 40, 372–385. [Google Scholar] [CrossRef] [Green Version]
  91. Whiting, L.; McCutcheon, J.E.; Boyle, C.N.; Roitman, M.F.; Lutz, T.A. The area postrema (AP) and the parabrachial nucleus (PBN) are important sites for salmon calcitonin (sCT) to decrease evoked phasic dopamine release in the nucleus accumbens (NAc). Physiol. Behav. 2017, 176, 9–16. [Google Scholar] [CrossRef] [PubMed]
  92. Zakariassen, H.L.; John, L.M.; Lykkesfeldt, J.; Raun, K.; Glendorf, T.; Schaffer, L.; Lundh, S.; Secher, A.; Lutz, T.A.; Le Foll, C. Salmon calcitonin distributes into the arcuate nucleus to a subset of NPY neurons in mice. Neuropharmacology 2020, 167, 107987. [Google Scholar] [CrossRef] [PubMed]
  93. Eiden, S.; Daniel, C.; Steinbrueck, A.; Schmidt, I.; Simon, E. Salmon calcitonin—A potent inhibitor of food intake in states of impaired leptin signalling in laboratory rodents. J. Physiol. 2002, 541, 1041–1048. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Osto, M.; Wielinga, P.Y.; Alder, B.; Walser, N.; Lutz, T.A. Modulation of the satiating effect of amylin by central ghrelin, leptin and insulin. Physiol. Behav. 2007, 91, 566–572. [Google Scholar] [CrossRef]
  95. Duffy, S.; Lutz, T.A.; Boyle, C.N. Rodent models of leptin receptor deficiency are less sensitive to amylin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2018, 315, r856–r865. [Google Scholar] [CrossRef]
  96. Chan, J.L.; Roth, J.D.; Weyer, C. It takes two to tango: Combined amylin/leptin agonism as a potential approach to obesity drug development. J. Investig. Med. 2009, 57, 777–783. [Google Scholar] [CrossRef]
  97. Roth, J.D.; Roland, B.L.; Cole, R.L.; Trevaskis, J.L.; Weyer, C.; Koda, J.E.; Anderson, C.M.; Parkes, D.G.; Baron, A.D. Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies. Proc. Natl. Acad. Sci. USA 2008, 105, 7257–7262. [Google Scholar] [CrossRef] [Green Version]
  98. Roth, J.D.; Trevaskis, J.L.; Turek, V.F.; Parkes, D.G. “Weighing in” on synergy: Preclinical research on neurohormonal anti-obesity combinations. Brain Res. 2010, 1350, 86–94. [Google Scholar] [CrossRef]
  99. Trevaskis, J.L.; Coffey, T.; Cole, R.; Lei, C.; Wittmer, C.; Walsh, B.; Weyer, C.; Koda, J.; Baron, A.D.; Parkes, D.G.; et al. Amylin-mediated restoration of leptin responsiveness in diet-induced obesity: Magnitude and mechanisms. Endocrinology 2008, 149, 5679–5687. [Google Scholar] [CrossRef] [Green Version]
  100. Trevaskis, J.L.; Lei, C.; Koda, J.E.; Weyer, C.; Parkes, D.G.; Roth, J.D. Interaction of leptin and amylin in the long-term maintenance of weight loss in diet-induced obese rats. Obesity 2010, 18, 21–26. [Google Scholar] [CrossRef]
  101. Trevaskis, J.L.; Parkes, D.G.; Roth, J.D. Insights into amylin-leptin synergy. Trends Endocrinol. Metab. 2010, 21, 473–479. [Google Scholar] [CrossRef] [PubMed]
  102. Trevaskis, J.L.; Wittmer, C.; Athanacio, J.R.; Griffin, P.S.; Parkes, D.G.; Roth, J.D. Amylin/leptin synergy is absent in extreme obesity and not restored by calorie restriction-induced weight loss in rats. Obes. Sci. Pract. 2016, 2, 385–391. [Google Scholar] [CrossRef] [PubMed]
  103. Turek, V.F.; Trevaskis, J.L.; Levin, B.E.; Dunn-Meynell, A.A.; Irani, B.; Gu, G.; Wittmer, C.; Griffin, P.S.; Vu, C.; Parkes, D.G.; et al. Mechanisms of amylin/leptin synergy in rodent models. Endocrinology 2010, 151, 143–152. [Google Scholar] [CrossRef] [PubMed]
  104. Irani, B.G.; Dunn-Meynell, A.A.; Levin, B.E. Altered hypothalamic leptin, insulin and melanocortin binding associated with moderate fat diet and predisposition to obesity. Endocrinology 2007, 148, 310–316. [Google Scholar] [CrossRef] [Green Version]
  105. Dunn-Meynell, A.A.; Le Foll, C.; Johnson, M.D.; Lutz, T.A.; Hayes, M.R.; Levin, B.E. Endogenous VMH amylin signaling is required for full leptin signaling and protection from diet-induced obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2016, 310, 355–365. [Google Scholar] [CrossRef]
  106. Sexton, P.M.; Paxinos, G.; Kenney, M.A.; Wookey, P.J.; Beaumont, K. In vitro autoradiographic localization of amylin binding sites in rat brain. Neuroscience 1994, 62, 553–567. [Google Scholar] [CrossRef]
  107. Christopoulos, G.; Paxinos, G.; Huang, X.F.; Beaumont, K.; Toga, A.W.; Sexton, P.M. Comparative distribution of receptors for amylin and the related peptides calcitonin gene related peptide and calcitonin in rat and monkey brain. Can. J. Physiol. Pharmacol. 1995, 73, 1037–1041. [Google Scholar] [CrossRef]
  108. Mietlicki-Baase, E.G.; Rupprecht, L.E.; Olivos, D.R.; Zimmer, D.J.; Alter, M.D.; Pierce, R.C.; Schmidt, H.D.; Hayes, M.R. Amylin receptor signaling in the ventral tegmental area is physiologically relevant for the control of food intake. Neuropsychopharmacology 2013, 38, 1685–1697. [Google Scholar] [CrossRef] [Green Version]
  109. Le Foll, C.; Johnson, M.D.; Dunn-Meynell, A.A.; Boyle, C.N.; Lutz, T.A.; Levin, B.E. Amylin-induced central IL-6 production enhances ventromedial hypothalamic leptin signaling. Diabetes 2015, 64, 1621–1631. [Google Scholar] [CrossRef] [Green Version]
  110. Larsen, L.; Le Foll, C.; Dunn-Meynell, A.A.; Levin, B.E. IL-6 Ameliorates Defective Leptin Sensitivity in DIO Ventromedial Hypothalamic Nucleus Neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2016, 311, R764–R770. [Google Scholar] [CrossRef] [Green Version]
  111. Irani, B.G.; Le Foll, C.; Dunn-Meynell, A.A.; Levin, B.E. Ventromedial nucleus neurons are less sensitive to leptin excitation in rats bred to develop diet-induced obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009, 296, 521–527. [Google Scholar] [CrossRef] [PubMed]
  112. Rahmouni, K.; Fath, M.A.; Seo, S.; Thedens, D.R.; Berry, C.J.; Weiss, R.; Nishimura, D.Y.; Sheffield, V.C. Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J. Clin. Investig. 2008, 118, 1458–1467. [Google Scholar] [CrossRef] [PubMed]
  113. Seo, S.; Guo, D.F.; Bugge, K.; Morgan, D.A.; Rahmouni, K.; Sheffield, V.C. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum. Mol. Genet. 2009, 18, 1323–1331. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Coester, B.; Lutz, T.A.; le Foll, C. Mouse Microglial Calcitonin Receptor Knockout Impairs Hypothalamic Amylin Neuronal pSTAT3 Signaling but Lacks Major Metabolic Consequences. Metabolites 2022, 12, 51. [Google Scholar] [CrossRef]
  115. Moore, C.X.; Cooper, G.J. Co-secretion of amylin and insulin from cultured islet beta-cells: Modulation by nutrient secretagogues, islet hormones and hypoglycemic agents. Biochem. Biophys. Res. Commun. 1991, 179, 1–9. [Google Scholar] [CrossRef]
  116. Scherbaum, W.A. The role of amylin in the physiology of glycemic control. Exp. Clin. Endocrinol. Diabetes 1998, 106, 97–102. [Google Scholar] [CrossRef] [Green Version]
  117. Young, A.A.; Gedulin, B.R.; Rink, T.J. Dose-responses for the slowing of gastric emptying in a rodent model by glucagon-like peptide (7-36) NH2, amylin, cholecystokinin, and other possible regulators of nutrient uptake. Metabolism 1996, 45, 1–3. [Google Scholar] [CrossRef]
  118. Kong, M.F.; King, P.; Macdonald, I.A.; Stubbs, T.A.; Perkins, A.C.; Blackshaw, P.E.; Moyses, C.; Tattersall, R.B. Infusion of pramlintide, a human amylin analogue, delays gastric emptying in men with IDDM. Diabetologia 1997, 40, 82–88. [Google Scholar] [CrossRef] [Green Version]
  119. Gedulin, B.R.; Rink, T.J.; Young, A.A. Dose-response for glucagonostatic effect of amylin in rats. Metabolism 1997, 46, 67–70. [Google Scholar] [CrossRef]
  120. Chance, W.T.; Balasubramaniam, A.; Zhang, F.S.; Wimalawansa, S.J.; Fischer, J.E. Anorexia following the intrahypothalamic administration of amylin. Brain Res. 1991, 539, 352–354. [Google Scholar] [CrossRef]
  121. Wielinga, P.Y.; Lowenstein, C.; Muff, S.; Munz, M.; Woods, S.C.; Lutz, T.A. Central amylin acts as an adiposity signal to control body weight and energy expenditure. Physiol. Behav. 2010, 101, 45–52. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Roth, J.D.; Hughes, H.; Kendall, E.; Baron, A.D.; Anderson, C.M. Antiobesity effects of the beta-cell hormone amylin in diet-induced obese rats: Effects on food intake, body weight, composition, energy expenditure, and gene expression. Endocrinology 2006, 147, 5855–5864. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Wang, Z.L.; Bennet, W.M.; Ghatei, M.A.; Byfield, P.G.; Smith, D.M.; Bloom, S.R. Influence of islet amyloid polypeptide and the 8-37 fragment of islet amyloid polypeptide on insulin release from perifused rat islets. Diabetes 1993, 42, 330–335. [Google Scholar] [CrossRef] [PubMed]
  124. Young, A.A.; Wang, M.W.; Gedulin, B.; Rink, T.J.; Pittner, R.; Beaumont, K. Diabetogenic effects of salmon calcitonin are attributable to amylin-like activity. Metabolism 1995, 44, 1581–1589. [Google Scholar] [CrossRef]
  125. Young, A.A.; Mott, D.M.; Stone, K.; Cooper, G.J. Amylin activates glycogen phosphorylase in the isolated soleus muscle of the rat. FEBS Lett. 1991, 281, 149–151. [Google Scholar] [CrossRef]
  126. Kolterman, O.G.; Gottlieb, A.; Moyses, C.; Colburn, W. Reduction of postprandial hyperglycemia in subjects with IDDM by intravenous infusion of AC137, a human amylin analogue. Diabetes Care 1995, 18, 1179–1182. [Google Scholar] [CrossRef]
  127. Young, A.A.; Gedulin, B.; Vine, W.; Percy, A.; Rink, T.J. Gastric emptying is accelerated in diabetic BB rats and is slowed by subcutaneous injections of amylin. Diabetologia 1995, 38, 642–648. [Google Scholar] [CrossRef]
  128. Edwards, G.L.; Gedulin, B.R.; Jodka, C.; Dilts, R.P.; Miller, C.C.; Young, A. Area postrem (AP)-lesions block the regulation of gastric emptying by amylin. Neurogastroenterol. Motil. 1998, 10, 26. [Google Scholar]
  129. Jodka, C.M.; Green, D.; Young, A.; Gedulin, B. Amylin modulation of gastric emptying in rats depends upon an intact vagus. Diabetes 1996, 45, A235. [Google Scholar]
  130. Young, A. Inhibition of gastric emptying. Adv. Pharmacol. 2005, 52, 99–121. [Google Scholar]
  131. Woods, S.C.; Lutz, T.A.; Geary, N.; Langhans, W. Pancreatic signals controlling food intake; insulin, glucagon and amylin. Philos. Trans. R. Soc. B Biol. Sci. 2006, 361, 1219–1235. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Geary, N.; Langhans, W.; Scharrer, E. Metabolic concomitants of glucagon-induced suppression of feeding in the rat. Am. J. Physiol. 1981, 241, 330–335. [Google Scholar] [CrossRef] [PubMed]
  133. Langhans, W.; Zeiger, U.; Scharrer, E.; Geary, N. Stimulation of feeding in rats by intraperitoneal injection of antibodies to glucagon. Science 1982, 218, 894–896. [Google Scholar] [CrossRef] [PubMed]
  134. Young, A. Inhibition of glucagon secretion. Adv. Pharmacol. 2005, 52, 151–171. [Google Scholar] [PubMed]
  135. Silvestre, R.A.; Rodriguez-Gallardo, J.; Jodka, C.; Parkes, D.G.; Pittner, R.A.; Young, A.A.; Marco, J. Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas. Am. J. Physiol. Endocrinol. Metab. 2001, 280, 443–449. [Google Scholar] [CrossRef] [PubMed]
  136. Gedulin, B.R.; Jodka, C.M.; Herrmann, K.; Young, A.A. Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC187. Regul. Pept. 2006, 137, 121–127. [Google Scholar] [CrossRef]
  137. Hartter, E.; Svoboda, T.; Ludvik, B.; Schuller, M.; Lell, B.; Kuenburg, E.; Brunnbauer, M.; Woloszczuk, W.; Prager, R. Basal and stimulated plasma levels of pancreatic amylin indicate its co-secretion with insulin in humans. Diabetologia 1991, 34, 52–54. [Google Scholar] [CrossRef]
  138. Enoki, S.; Mitsukawa, T.; Takemura, J.; Nakazato, M.; Aburaya, J.; Toshimori, H.; Matsukara, S. Plasma islet amyloid polypeptide levels in obesity, impaired glucose tolerance and non-insulin-dependent diabetes mellitus. Diabetes Res. Clin. Pract. 1992, 15, 97–102. [Google Scholar] [CrossRef]
  139. Ludvik, B.; Lell, B.; Hartter, E.; Schnack, C.; Prager, R. Decrease of stimulated amylin release precedes impairment of insulin secretion in type II diabetes. Diabetes 1991, 40, 1615–1619. [Google Scholar] [CrossRef]
  140. Butler, P.C.; Chou, J.; Carter, W.B.; Wang, Y.N.; Bu, B.H.; Chang, D.; Chang, J.K.; Rizza, R.A. Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans. Diabetes 1990, 39, 752–756. [Google Scholar] [CrossRef] [Green Version]
  141. Westermark, P.; Wilander, E.; Westermark, G.T.; Johnson, K.H. Islet amyloid polypeptide-like immunoreactivity in the islet B cells of type 2 (non-insulin-dependent) diabetic and non-diabetic individuals. Diabetologia 1987, 30, 887–892. [Google Scholar] [CrossRef]
  142. Janson, J.; Soeller, W.C.; Roche, P.C.; Nelson, R.T.; Torchia, A.J.; Kreutter, D.K.; Butler, P.C. Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc. Natl. Acad. Sci. USA 1996, 93, 7283–7288. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Pieber, T.R.; Roitelman, J.; Lee, Y.; Luskey, K.L.; Stein, D.T. Direct plasma radioimmunoassay for rat amylin-(1-37): Concentrations with acquired and genetic obesity. Am. J. Physiol. 1994, 267, E156–E164. [Google Scholar] [CrossRef] [PubMed]
  144. Pieber, T.R.; Stein, D.T.; Ogawa, A.; Alam, T.; Ohneda, M.; McCorkle, K.; Chen, L.; McGarry, J.D.; Unger, R.H. Amylin-insulin relationships in insulin resistance with and without diabetic hyperglycemia. Am. J. Physiol. 1993, 265, E446–E453. [Google Scholar] [CrossRef] [PubMed]
  145. Leckstrom, A.; Ostenson, C.G.; Efendic, S.; Arnelo, U.; Permert, J.; Lundquist, I.; Westermark, P. Increased storage and secretion of islet amyloid polypeptide relative to insulin in the spontaneously diabetic GK rat. Pancreas 1996, 13, 259–267. [Google Scholar] [CrossRef] [PubMed]
  146. Mulder, H.; Ahren, B.; Sundler, F. Islet amyloid polypeptide (amylin) and insulin are differentially expressed in chronic diabetes induced by streptozotocin in rats. Diabetologia 1996, 39, 649–657. [Google Scholar] [CrossRef] [PubMed]
  147. Lee, Y.; Berglund, E.D.; Wang, M.Y.; Fu, X.; Yu, X.; Charron, M.J.; Burgess, S.C.; Unger, R.H. Metabolic manifestations of insulin deficiency do not occur without glucagon action. Proc. Natl. Acad. Sci. USA 2012, 109, 14972–14976. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  148. Wang, M.Y.; Yan, H.; Shi, Z.; Evans, M.R.; Yu, X.; Lee, Y.; Chen, S.; Williams, A.; Philippe, J.; Roth, M.G.; et al. Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway. Proc. Natl. Acad. Sci. USA 2015, 112, 2503–2508. [Google Scholar] [CrossRef] [Green Version]
  149. Levetan, C.; Want, L.L.; Weyer, C.; Strobel, S.A.; Crean, J.; Wang, Y.; Maggs, D.G.; Kolterman, O.G.; Chandran, M.; Mudaliar, S.R.; et al. Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 2003, 26, 1–8. [Google Scholar] [CrossRef] [Green Version]
  150. Nyholm, B.; Orskov, L.; Hove, K.Y.; Gravholt, C.H.; Møller, N.; Alberti, K.G.; Moyses, C.; Kolterman, O.; Schmitz, O. The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus. Metabolism 1999, 48, 935–941. [Google Scholar] [CrossRef]
  151. Fineman, M.; Weyer, C.; Maggs, D.G.; Strobel, S.; Kolterman, O.G. The human amylin analog, pramlintide, reduces postprandial hyperglucagonemia in patients with type 2 diabetes mellitus. Horm. Metab. Res. 2002, 34, 504–508. [Google Scholar] [CrossRef]
  152. Fineman, M.S.; Koda, J.E.; Shen, L.Z.; Strobel, S.A.; Maggs, D.G.; Weyer, C.; Kolterman, O.G. The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia in patients with type 1 diabetes. Metabolism 2002, 51, 636–641. [Google Scholar] [CrossRef] [PubMed]
  153. Nyholm, B.; Møller, N.; Gravholt, C.H.; Orskov, L.; Mengel, A.; Bryan, G.; Moyses, C.; Alberti, K.G.; Schmitz, O. Acute effects of the human amylin analog AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabolism in patients with insulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 1996, 81, 1083–1089. [Google Scholar] [PubMed]
  154. Kautzky-Willer, A.; Thomaseth, K.; Ludvik, B.; Nowotny, P.; Rabensteiner, D.; Waldhausl, W.; Pacini, G.; Prager, R. Elevated islet amyloid pancreatic polypeptide and proinsulin in lean gestational diabetes. Diabetes 1997, 46, 607–614. [Google Scholar] [CrossRef] [PubMed]
  155. Boyle, C.N.; Le Foll, C. Amylin and Leptin interaction: Role During Pregnancy, Lactation and Neonatal Development. Neuroscience 2019, 447, 136–147. [Google Scholar] [CrossRef] [PubMed]
  156. Leuthardt, A.S.; Bayer, J.; Monné Rodríguez, J.M.; Boyle, C.N. Influence of High Energy Diet and Polygenic Predisposition for Obesity on Postpartum Health in Rat Dams. Front. Physiol. 2022, 12, 772707. [Google Scholar] [CrossRef]
  157. Gurlo, T.; Kim, S.; Butler, A.E.; Liu, C.; Pei, L.; Rosenberger, M.; Butler, P.C. Pregnancy in human IAPP transgenic mice recapitulates beta cell stress in type 2 diabetes. Diabetologia 2019, 62, 1000–1010. [Google Scholar] [CrossRef] [Green Version]
  158. Becerril, S.; Frühbeck, G. Cagrilintide plus semaglutide for obesity management. Lancet 2021, 397, 1687–1689. [Google Scholar] [CrossRef]
  159. Kruse, T.; Hansen, J.L.; Dahl, K.; Schäffer, L.; Sensfuss, U.; Poulsen, C.; Schlein, M.; Hansen, A.M.K.; Jeppesen, C.B.; Dornonville de la Cour, C.; et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. J. Med. Chem. 2021, 64, 11183–11194. [Google Scholar] [CrossRef]
  160. Lutz, T.A. Roles of amylin in satiation, adiposity and brain development. Forum Nutr. 2010, 63, 64–74. [Google Scholar]
  161. Gloy, V.L.; Lutz, T.A.; Langhans, W.; Geary, N.; Hillebrand, J.J. Basal plasma levels of insulin, leptin, ghrelin, and amylin do not signal adiposity in rats recovering from forced overweight. Endocrinology 2010, 151, 4280–4288. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. Gorski, J.N.; Dunn-Meynell, A.A.; Levin, B.E. Maternal obesity increases hypothalamic leptin receptor expression and sensitivity in juvenile obesity-prone rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007, 292, 1782–1791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Johnson, M.D.; Bouret, S.G.; Dunn-Meynell, A.A.; Boyle, C.N.; Lutz, T.A.; Levin, B.E. Early postnatal amylin treatment enhances hypothalamic leptin signaling and neural development in the selectively bred diet-induced obese rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2016, 311, r1032–r1044. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Levin, B.E.; Dunn-Meynell, A.A.; Ricci, M.R.; Cummings, D.E. Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats. Am. J. Physiol. 2003, 285, E949–E957. [Google Scholar] [CrossRef] [PubMed]
  165. Levin, B.E.; Dunn-Meynell, A.A.; Banks, W.A. Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling prior to obesity onset. Am. J. Physiol. 2004, 286, R143–R150. [Google Scholar]
  166. Bouret, S.G.; Gorski, J.N.; Patterson, C.M.; Chen, S.; Levin, B.E.; Simerly, R.B. Hypothalamic neural projections are permanently disrupted in diet-induced obese rats. Cell Metab. 2008, 7, 179–185. [Google Scholar] [CrossRef] [Green Version]
  167. Gonzalez, I.E.; Ramirez-Matias, J.; Lu, C.; Pan, W.; Zhu, A.; Myers, M.G.; Olson, D.P. Paraventricular Calcitonin Receptor-Expressing Neurons Modulate Energy Homeostasis in Male Mice. Endocrinology 2021, 162, bqab072. [Google Scholar] [CrossRef]
  168. Pan, W.; Adams, J.M.; Allison, M.B.; Patterson, C.; Flak, J.N.; Jones, J.; Strohbehn, G.; Trevaskis, J.; Rhodes, C.J.; Olson, D.P.; et al. Essential Role for Hypothalamic Calcitonin Receptor—Expressing Neurons in the Control of Food Intake by Leptin. Endocrinology 2018, 159, 1860–1872. [Google Scholar] [CrossRef] [Green Version]
  169. De Souza, C.T.; Araujo, E.P.; Bordin, S.; Ashimine, R.; Zollner, R.L.; Boschero, A.C.; Saad, M.J.; Velloso, L.A. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 2005, 146, 4192–4199. [Google Scholar] [CrossRef] [Green Version]
  170. Thaler, J.P.; Yi, C.X.; Schur, E.A.; Guyenet, S.J.; Hwang, B.H.; Dietrich, M.O.; Zhao, X.; Sarruf, D.A.; Izgur, V.; Maravilla, K.R.; et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Investig. 2012, 122, 153–162. [Google Scholar] [CrossRef] [Green Version]
  171. Lee, D.; Thaler, J.P.; Berkseth, K.E.; Melhorn, S.J.; Schwartz, M.W.; Schur, E.A. Longer T2 relaxation time is a marker of hypothalamic gliosis in mice with diet-induced obesity. Am. J. Physiol. Endocrinol. Metab. 2013, 304, E1245–E1250. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  172. Zhang, X.; Zhang, G.; Zhang, H.; Karin, M.; Bai, H.; Cai, D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 2008, 135, 61–73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  173. Nannipieri, M.; Baldi, S.; Mari, A.; Colligiani, D.; Guarino, D.; Camastra, S.; Barsotti, E.; Berta, R.; Moriconi, D.; Bellini, R.; et al. Roux-en-Y gastric bypass and sleeve gastrectomy: Mechanisms of diabetes remission and role of gut hormones. J. Clin. Endocrinol. Metab. 2013, 98, 4391–4399. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Bose, M.; Machineni, S.; Oliván, B.; Teixeira, J.; McGinty, J.J.; Bawa, B.; Koshy, N.; Colarusso, A.; Laferrère, B. Superior appetite hormone profile after equivalent weight loss by gastric bypass compared to gastric banding. Obesity 2010, 18, 1085–1091. [Google Scholar] [CrossRef] [Green Version]
  175. Tharakan, G.; Behary, P.; Wewer Albrechtsen, N.J.; Chahal, H.; Kenkre, J.; Miras, A.D.; Ahmed, A.R.; Holst, J.J.; Bloom, S.R.; Tan, T. Roles of increased glycaemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass. Eur. J. Endocrinol. 2017, 177, 455–464. [Google Scholar] [CrossRef]
  176. Shin, A.C.; Zheng, H.; Townsend, R.L.; Sigalet, D.L.; Berthoud, H.R. Meal-induced hormone responses in a rat model of Roux-en-Y gastric bypass surgery. Endocrinology 2010, 151, 1588–1597. [Google Scholar] [CrossRef] [Green Version]
  177. Patti, M.E.; Goldfine, A.B. Hypoglycaemia following gastric bypass surgery—Diabetes remission in the extreme? Diabetologia 2010, 53, 2276–2279. [Google Scholar] [CrossRef] [Green Version]
  178. Kefurt, R.; Langer, F.B.; Schindler, K.; Shakeri-Leidenmuhler, S.; Ludvik, B.; Prager, G. Hypoglycemia after Roux-En-Y gastric bypass: Detection rates of continuous glucose monitoring (CGM) versus mixed meal test. Surg. Obes. Relat. Dis. 2015, 11, 564–569. [Google Scholar] [CrossRef]
  179. Goldfine, A.B.; Mun, E.C.; Devine, E.; Bernier, R.; Baz-Hecht, M.; Jones, D.B.; Schneider, B.E.; Holst, J.J.; Patti, M.E. Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. J. Clin. Endocrinol. Metab. 2007, 92, 4678–4685. [Google Scholar] [CrossRef] [Green Version]
  180. Goldfine, A.B.; Patti, M.E. How common is hypoglycemia after gastric bypass? Obesity 2016, 24, 1210–1211. [Google Scholar] [CrossRef] [Green Version]
  181. Patti, M.E.; Goldfine, A.B. Hypoglycemia after gastric bypass: The dark side of GLP-1. Gastroenterology 2014, 146, 605–608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  182. Salehi, M.; Vella, A.; McLaughlin, T.; Patti, M.E. Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies. J. Clin. Endocrinol. Metab. 2018, 103, 2815–2826. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  183. Sheehan, A.; Goldfine, A.; Bajwa, M.; Wolfs, D.; Kozuka, C.; Piper, J.; Fowler, K.; Patti, M.E. Pramlintide for Post-Bariatric Hypoglycemia. Diabetes Obes. Metab. 2022, preprint. [Google Scholar]
  184. Christoffersen, B.O.; Sanchez-Delgado, G.; John, L.M.; Ryan, D.H.; Raun, K.; Ravussin, E. Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss. Obesity 2022, 30, 841–857. [Google Scholar] [CrossRef]
  185. Lutz, T.A.; Meyer, U. Amylin at the interface between metabolic and neurodegenerative disorders. Front. Neurosci. 2015, 9, 216. [Google Scholar] [CrossRef]
  186. Mietlicki-Baase, E.G. Amylin in Alzheimer’s disease: Pathological peptide or potential treatment? Neuropharmacology 2018, 136, 287–297. [Google Scholar] [CrossRef]
  187. Grizzanti, J.; Corrigan, R.; Servizi, S.; Casadesus, G. Amylin Signaling in Diabetes and Alzheimer’s Disease: Therapy or Pathology? J. Neurol. Neuromedicine 2019, 4, 12–16. [Google Scholar] [CrossRef] [Green Version]
  188. Young, A.A.; Vine, W.; Gedulin, B.R.; Pittner, R.; Janes, S.; Gaeta, L.S.L.; Percy, A.J.; Moore, C.X.; Koda, J.E.; Rink, T.J.; et al. Preclinical pharmacology of pramlintide in the rat: Comparisons with human and rat amylin. Drug Dev. Res. 1996, 37, 231–248. [Google Scholar] [CrossRef]
  189. Ryan, G.J.; Jobe, L.J.; Martin, R. Pramlintide in the treatment of type 1 and type 2 diabetes mellitus. Clin. Ther. 2005, 27, 1500–1512. [Google Scholar] [CrossRef]
  190. Hollander, P.; Maggs, D.G.; Ruggles, J.A.; Fineman, M.; Shen, L.; Kolterman, O.G.; Weyer, C. Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. Obes. Res. 2004, 12, 661–668. [Google Scholar] [CrossRef] [Green Version]
  191. Thompson, R.G.; Peterson, J.; Gottlieb, A.; Mullane, J. Effects of pramlintide, an analog of human amylin, on plasma glucose profiles in patients with IDDM: Results of a multicenter trial. Diabetes 1997, 46, 632–636. [Google Scholar] [CrossRef] [PubMed]
  192. Weyer, C.; Maggs, D.G.; Young, A.A.; Kolterman, O.G. Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: A physiological approach toward improved metabolic control. Curr. Pharm. Des. 2001, 7, 1353–1373. [Google Scholar] [CrossRef] [PubMed]
  193. Riddle, M.; Frias, J.; Zhang, B.; Maier, H.; Brown, C.; Lutz, K.; Kolterman, O. Pramlintide improved glycemic control and reduced weight in patients with type 2 diabetes using basal insulin. Diabetes Care 2007, 30, 2794–2799. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  194. Thompson, R.G.; Pearson, L.; Kolterman, O.G. Effects of 4 weeks’ administration of pramlintide, a human amylin analogue, on glycaemia control in patients with IDDM: Effects on plasma glucose profiles and serum fructosamine concentrations. Diabetologia 1997, 40, 1278–1285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  195. Chapman, I.; Parker, B.; Doran, S.; Feinle-Bisset, C.; Wishart, J.; Strobel, S.; Wang, Y.; Burns, C.; Lush, C.; Weyer, C.; et al. Effect of pramlintide on satiety and food intake in obese subjects and subjects with type 2 diabetes. Diabetologia 2005, 48, 838–848. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  196. Heise, T.; Heinemann, L.; Heller, S.; Weyer, C.; Wang, Y.; Strobel, S.; Kolterman, O.; Maggs, D. Effect of pramlintide on symptom, catecholamine, and glucagon responses to hypoglycemia in healthy subjects. Metabolism 2004, 53, 1227–1232. [Google Scholar] [CrossRef]
  197. Ryan, G.; Briscoe, T.A.; Jobe, L. Review of pramlintide as adjunctive therapy in treatment of type 1 and type 2 diabetes. Drug Des. Dev. Ther. 2009, 2, 203–214. [Google Scholar] [CrossRef] [Green Version]
  198. Srivastava, G.; Apovian, C. Future Pharmacotherapy for Obesity: New Anti-obesity Drugs on the Horizon. Curr. Obes. Rep. 2018, 7, 147–161. [Google Scholar] [CrossRef]
  199. Younk, L.M.; Mikeladze, M.; Davis, S.N. Pramlintide and the treatment of diabetes: A review of the data since its introduction. Expert Opin. Pharmacother. 2011, 12, 1439–1451. [Google Scholar] [CrossRef]
  200. Riddle, M.C.; Nahra, R.; Han, J.; Castle, J.; Hanavan, K.; Hompesch, M.; Huffman, D.; Strange, P.; Ohman, P. Control of Postprandial Hyperglycemia in Type 1 Diabetes by 24-Hour Fixed-Dose Coadministration of Pramlintide and Regular Human Insulin: A Randomized, Two-Way Crossover Study. Diabetes Care 2018, 41, 2346–2352. [Google Scholar] [CrossRef] [Green Version]
  201. Riddle, M.C.; Yuen, K.C.; de Bruin, T.W.; Herrmann, K.; Xu, J.; Ohman, P.; Kolterman, O.G. Fixed ratio dosing of pramlintide with regular insulin before a standard meal in patients with type 1 diabetes. Diabetes Obes. Metab. 2015, 17, 904–907. [Google Scholar] [CrossRef] [PubMed]
  202. Maikawa, C.L.; Smith, A.A.A.; Zou, L.; Roth, G.A.; Gale, E.C.; Stapleton, L.M.; Baker, S.W.; Mann, J.L.; Yu, A.C.; Correa, S.; et al. A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs. Nat. Biomed. Eng. 2020, 4, 507–517. [Google Scholar] [CrossRef] [PubMed]
  203. Maianti, J.P.; McFedries, A.; Foda, Z.H.; Kleiner, R.E.; Du, X.Q.; Leissring, M.A.; Tang, W.J.; Charron, M.J.; Seeliger, M.A.; Saghatelian, A.; et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature 2014, 511, 94–98. [Google Scholar] [CrossRef] [Green Version]
  204. Aronne, L.; Fujioka, K.; Aroda, V.; Chen, K.; Halseth, A.; Kesty, N.C.; Burns, C.; Lush, C.W.; Weyer, C. Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: A phase 2, randomized, placebo-controlled, dose-escalation study. J. Clin. Endocrinol. Metab. 2007, 92, 2977–2983. [Google Scholar] [CrossRef] [PubMed]
  205. Mack, C.M.; Soares, C.J.; Wilson, J.K.; Athanacio, J.R.; Turek, V.F.; Trevaskis, J.L.; Roth, J.D.; Smith, P.A.; Gedulin, B.; Jodka, C.M.; et al. Davalintide (AC2307), a novel amylin-mimetic peptide: Enhanced pharmacological properties over native amylin to reduce food intake and body weight. Int. J. Obes. 2010, 34, 385–395. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  206. Mack, C.M.; Smith, P.A.; Athanacio, J.R.; Xu, K.; Wilson, J.K.; Reynolds, J.M.; Jodka, C.M.; Lu, M.G.; Parkes, D.G. Glucoregulatory effects and prolonged duration of action of davalintide: A novel amylinomimetic peptide. Diabetes Obes. Metab. 2011, 13, 1105–1113. [Google Scholar] [CrossRef]
  207. Guerreiro, L.H.; Guterres, M.F.; Melo-Ferreira, B.; Erthal, L.C.; Rosa Mda, S.; Lourenco, D.; Tinoco, P.; Lima, L.M. Preparation and characterization of PEGylated amylin. AAPS PharmSciTech 2013, 14, 1083–1097. [Google Scholar] [CrossRef] [Green Version]
  208. Kowalczyk, R.; Brimble, M.A.; Tomabechi, Y.; Fairbanks, A.J.; Fletcher, M.; Hay, D.L. Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: Structure-activity relationships for amylin receptor agonism. Org. Biomol. Chem. 2014, 12, 8142–8151. [Google Scholar] [CrossRef]
  209. Andreassen, K.V.; Feigh, M.; Hjuler, S.T.; Gydesen, S.; Henriksen, J.E.; Beck-Nielsen, H.; Christiansen, C.; Karsdal, M.A.; Henriksen, K. A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats. Am. J. Physiol. Endocrinol. Metab. 2014, 307, 24–33. [Google Scholar] [CrossRef] [Green Version]
  210. Gydesen, S.; Andreassen, K.V.; Hjuler, S.T.; Christensen, J.M.; Karsdal, M.A.; Henriksen, K. KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight. Am. J. Physiol. Endocrinol. Metab. 2016, 310, 821–827. [Google Scholar] [CrossRef] [Green Version]
  211. Larsen, A.T.; Sonne, N.; Andreassen, K.V.; Karsdal, M.A.; Henriksen, K. The Calcitonin Receptor Plays a Major Role in Glucose Regulation as a Function of Dual Amylin and Calcitonin Receptor Agonist Therapy. J. Pharmacol. Exp. Ther. 2020, 374, 74–83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  212. Hjuler, S.T.; Andreassen, K.V.; Gydesen, S.; Karsdal, M.A.; Henriksen, K. KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration. Eur. J. Pharmacol. 2015, 762, 229–238. [Google Scholar] [CrossRef] [PubMed]
  213. Hjuler, S.T.; Gydesen, S.; Andreassen, K.V.; Pedersen, S.L.; Hellgren, L.I.; Karsdal, M.A.; Henriksen, K. The dual amylin- and calcitonin-receptor agonist KBP-042 increases insulin sensitivity and induces weight loss in rats with obesity. Obesity 2016, 24, 1712–1722. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  214. Lutz, T.A.; Tschudy, S.; Rushing, P.A.; Scharrer, E. Amylin receptors mediate the anorectic action of salmon calcitonin (sCT). Peptides 2000, 21, 233–238. [Google Scholar] [CrossRef]
  215. Andreassen, K.V.; Larsen, A.T.; Sonne, N.; Mohamed, K.E.; Karsdal, M.A.; Henriksen, K. KBP-066A, a long-acting dual amylin and calcitonin receptor agonist, induces weight loss and improves glycemic control in obese and diabetic rats. Mol. Metab. 2021, 53, 101282. [Google Scholar] [CrossRef]
  216. Gydesen, S.; Hjuler, S.T.; Freving, Z.; Andreassen, K.V.; Sonne, N.; Hellgren, L.I.; Karsdal, M.A.; Henriksen, K. A novel dual amylin and calcitonin receptor agonist, KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference. Br. J. Pharmacol. 2017, 174, 591–602. [Google Scholar] [CrossRef] [Green Version]
  217. Henriksen, K.; Broekhuizen, K.; de Boon, W.M.I.; Karsdal, M.A.; Bihlet, A.R.; Christiansen, C.; Dillingh, M.R.; de Kam, M.; Kumar, R.; Burggraaf, J.; et al. Safety, tolerability and pharmacokinetic characterisation of DACRA KBP-042 in healthy male subjects. Br. J. Clin. Pharmacol. 2021, 87, 4786–4796. [Google Scholar] [CrossRef]
  218. Arrigoni, S.; le Foll, C.; Cabak, A.; Lundh, S.; Raun, K.; John, L.M.; Lutz, T.A. A selective role for receptor activity-modifying proteins in subchronic action of the amylin selective receptor agonist NN1213 compared with salmon calcitonin on body weight and food intake in male mice. Eur. J. Neurosci. 2021, 54, 4863–4876. [Google Scholar] [CrossRef]
  219. Bartelt, A.; Jeschke, A.; Muller, B.; Gaziano, I.; Morales, M.; Yorgan, T.; Heckt, T.; Heine, M.; Gagel, R.F.; Emeson, R.B.; et al. Differential effects of Calca-derived peptides in male mice with diet-induced obesity. PLoS ONE 2017, 12, e0180547. [Google Scholar] [CrossRef]
  220. Nakamura, M.; Nomura, S.; Yamakawa, T.; Kono, R.; Maeno, A.; Ozaki, T.; Ito, A.; Uzawa, T.; Utsunomiya, H.; Kakudo, K. Endogenous calcitonin regulates lipid and glucose metabolism in diet-induced obesity mice. Sci. Rep. 2018, 8, 17001. [Google Scholar] [CrossRef]
  221. David, J.M.; Lau, C.W.; McFarlane, J.; Erichsen, L.; Francisco, A.M.; Le Roux, C.; McGowan, B.; Pedersen, S.D.; Pietiläinen, K.; Rubino, D.M.; et al. Efficacy and Safety of AM833 for Weight Loss: A Dose-finding Trial in Adults With Overweight/Obesity. In Proceedings of the Obesity Week, Atlanta, GA, USA, 2–6 November 2020. [Google Scholar]
  222. Thomas Kruse, K.D.; Schäffer, L.; Hansen, J.L.; Poulsen, C.; Hansen, A.M.K.; de la Cour, C.D.D.; Clausen, T.R.; Raun, K. AM833—Development of a Long-acting Amylin Analogue. In Proceedings of the Obesity Week, Atlanta, GA, USA, 2–6 November 2020. [Google Scholar]
  223. Enebo, L.B.; Berthelsen, K.K.; Kankam, M.; Lund, M.T.; Rubino, D.M.; Satylganova, A.; Lau, D.C.W. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: A randomised, controlled, phase 1b trial. Lancet 2021, 397, 1736–1748. [Google Scholar] [CrossRef]
  224. Kirsten Dahl, J.L.H.; Skyggebjerg, R.B.; John, L.M.; Hansen, A.M.K.; de la Cour, C.D.D.; Plesner, A.; Clausen, T.R.; Jeppesen, C.B.; Hjøllund, K.R.; Li, F.; et al. Preclinical Weight Loss Efficacy of AM833 in Animal Models of Obesity. In Proceedings of the Obesity Week, Atlanta, GA, USA, 2–6 November 2020. [Google Scholar]
  225. Gamakharia, S.; Le Foll, C.; Rist, W.; Baader-Pagler, T.; Baljuls, A.; Lutz, T.A. The calcitonin receptor is the main mediator of LAAMA’s body weight lowering effects in male mice. Eur. J. Pharmacol. 2021, 908, 174352. [Google Scholar] [CrossRef] [PubMed]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Boyle, C.N.; Zheng, Y.; Lutz, T.A. Mediators of Amylin Action in Metabolic Control. J. Clin. Med. 2022, 11, 2207.

AMA Style

Boyle CN, Zheng Y, Lutz TA. Mediators of Amylin Action in Metabolic Control. Journal of Clinical Medicine. 2022; 11(8):2207.

Chicago/Turabian Style

Boyle, Christina N., Yi Zheng, and Thomas A. Lutz. 2022. "Mediators of Amylin Action in Metabolic Control" Journal of Clinical Medicine 11, no. 8: 2207.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop