Search Results (36)

Non-nutritive sweeteners (NNSs) are consumed to reduce intake by providing a sweet taste with little to no energy. Despite regulatory approval and extensive use, uncertainty remains about their long-term role in weight management and health, and about whether exposure to sweet taste itself, independent of energy, influences these outcomes. This narrative review synthesizes evidence from three recent European consortia: SWEET, SWITCH and Sweet Tooth, which together provide complementary data from acute, short- and long-term randomized controlled trials. The studies examined the effects of NNSs and dietary sweet taste exposure on body weight, health-related biomarkers, sweet taste preference, and eating behavior. Across studies, replacing sugars with NNSs appeared to support weight loss maintenance, while NNS consumption and dietary sweet taste exposure showed no adverse changes in body weight, glucoregulatory and endocrine biomarkers, cardiometabolic risk factors, gut microbiota, or liver enzymes. Likewise, neither NNS use nor different dietary sweet taste exposure altered sweet taste liking, appetite sensation, energy intake, or food choice. However, interpretation should consider the characteristics of the included studies, including selected populations, intervention context, outcome heterogeneity, and the fact that several behavioral and biomarker outcomes were secondary or exploratory. Overall, the reviewed evidence suggests that replacing sugar intake with NNSs may support weight management strategies, while differences in habitual dietary sweet taste exposure per se appear largely neutral with respect to health-related biomarkers and sweet taste preferences. Full article

Data suggest that both pancreatic and intestinally produced glucagon-like peptide-1 (GLP-1) increases in response to inflammation. Here, we set out to determine the tissue-specific function of increased GLP-1 during inflammatory stimuli. Using our innovative mouse model of tissue-specific Gcg (the gene that encodes GLP-1) expression, we explored the function of GLP-1 under severe inflammatory conditions induced by lipopolysaccharide (LPS) administration in lean and obese mice. High-fat diet (HFD) increased the LPS-induced suppression of feeding and increased the plasma levels of pro-inflammatory cytokines and GLP-1. Both pancreatic and intestinal Gcg expression contribute to LPS-induced increases in GLP-1, but Gcg was not necessary for the glucoregulatory or suppressed feeding responses to LPS. While Gcg was not necessary for systemic cytokine increases with LPS in either chow- or HFD-fed mice, whole-body Gcg-null animals had increased macrophage accumulation and an increased expression of genes reflecting pro-inflammatory signaling in the pancreas. We then performed flow cytometry on the pancreas from mice expressing a fluorescent marker on the GLP-1 receptor (GLP-1R). In response to LPS, we found that pancreatic CD64+/CD11b+ macrophages expressed the GLP-1R. We conclude that under severe inflammatory conditions, pancreatic production of GLP-1 functions in an immunological rather than a metabolic role to directly regulate local macrophage accumulation. Full article

Background/Objectives: Chronic low-grade inflammation is associated with insulin resistance and poor glycemic control, leading to the development of type 2 diabetes mellitus (T2DM). The present study investigated the effect of regular mango intake on inflammation and insulin sensitivity in participants with overweight or obesity and chronic low-grade inflammation. Methods: A human clinical study was performed using a randomized, controlled, two-arm, parallel design with a 2 h oral glucose tolerance test (OGTT) administered before and after 4 weeks (4 W) of mango or control product intake (1 cup/twice a day). Fasting and time course blood sampling for 2 h post-OGTT were analyzed for effects on plasma metabolic and inflammation endpoints using analysis of covariance and repeated-measure approaches (SAS 9.4). Results: Forty-eight adults (37.6 ± 2.8 years, 30.5 ± 4.1 BMI kg/m²) completed the study. Markers of inflammation (IL-6, TNFα, hs-CRP) were not different at the end of 4 W (p > 0.05). The intervention did not significantly influence fasting glucose concentrations; however, insulin was significantly lowered with the mango compared to the control intervention (8.2 ± 1.2 vs. 15.3 ± 1.2 µIU/mL respectively, p = 0.05). Furthermore, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), along with the disposition index (DI), was significantly improved in the mango compared to the control interventions (HOMA-IR, 2.28 ± 1.19 vs. 4.67 ± 1.21, p = 0.03; DI, 2.76 ± 1.02 vs. 5.37 ± 1.03, p = 0.04). Mean insulin concentrations were also significantly lower at W4 compared to W0 after the OGTT in the mango vs. control intervention (intervention × week effect, p = 0.04). Relative expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), a gene regulating endogenous antioxidant defense, was non-significantly increased twofold in the mango intervention (W4 vs. W0). Conclusions: Collectively, the data suggest that mango intake increased insulin sensitivity in individuals with chronic low-grade inflammation, possibly through activating Nrf-2 genes and increasing cellular antioxidant status. The data warrant further research on consuming mango fruit as part of a dietary pattern to address insulin resistance and the mechanisms underpinning the actions of mango intake. Full article

Objectives: This article compares metabolic, pancreatic, and gut-derived hormone responses to isomaltulose ingestion, before versus during submaximal sustained exercise, in adults with type 1 diabetes (T1D) using automated insulin delivery systems. Methods: In a randomized, cross-over trial, eight participants with T1D being treated with automated insulin pumps (five females, age: 47 ± 16 years, BMI: 27.5 ± 3.8 kg·m², diabetes duration: 23 ± 11 years, HbA1c: 8.3 ± 0.9 [67.5 ± 9.5]% [mmol/mol]) attended the laboratory on two separate occasions and consumed an isocaloric amount of isomaltulose as either (1) a single serving (0.75g CHO·kg⁻¹ BM) with a 25% reduction in bolus insulin 90 min before 45 min of cycling (PEC) or (2) three separate isocaloric servings (0.25g CHO·kg⁻¹ BM each) without bolus insulin during exercise (DEC). Plasma glucose (PG), gut incretins (GLP-1 and GIP), pancreatic glucagon, exogenous insulin, and whole-body fuel oxidation rates were determined. Data were treated via a two-way repeated measures ANOVA, with p ≤ 0.05 accepted as significant. Results: PG concentrations throughout exercise were higher and less variable with DEC compared to PEC. The exercise-induced change in PG was directionally divergent between trials (PEC: ∆ − 3.2 ± 1.2 mmol/L vs. DEC: ∆ + 1.7 ± 1.5 mmol/L, p < 0.001), changing at a rate of −0.07 ± 0.03 mmol/L/min with PEC and +0.04 ± 0.03 mmol/L/min with DEC (p < 0.001 between conditions). Throughout the exercise period, GLP-1, GIP, glucagon, and total insulin concentrations were lower with DEC (all p ≤ 0.02). The oxidation rates of carbohydrates were lower (p = 0.009) and of lipids were greater (p = 0.014) with DEC compared to PEC. Conclusions: The consumption of smaller servings of isomaltulose during, rather than as a single isocaloric serving before, submaximal sustained exercise provided (i) a better glycemic protective effect, (ii) a lesser push on pancreatic and gut-mediated glucoregulatory hormones, and (iii) a lower reliance on whole-body carbohydrate oxidation. Such information serves to remind us of the potential importance of nutrition for modulating the metabolic fate of an acute bout of exercise and may help inform best practice guidelines for exercise management in the T1D-sphere. Full article

Obesity is a costly and ongoing health complication in the United States and globally. Bioactive-rich foods, especially those providing polyphenols, represent an emerging and attractive strategy to address this issue. Berry-derived anthocyanins and their metabolites are of particular interest for their bioactive effects, including weight maintenance and protection from metabolic aberrations. Earlier findings from small clinical trials suggest modulation of substrate oxidation and glucose tolerance with mediation of prospective benefits attributable to the gut microbiota, but mixed results suggest appropriate anthocyanin dosing poses a challenge. The objective of this randomized, placebo-controlled study was to determine if anthocyanin-dense elderberry juice (EBJ) reproduces glucoregulatory and substrate oxidation effects observed with other berries and if this is mediated by the gut microbiota. Overweight or obese adults (BMI > 25 kg/m²) without chronic illnesses were randomized to a 5-week crossover study protocol with two 1-week periods of twice-daily EBJ or placebo (PL) separated by a washout period. Each treatment period included 4 days of controlled feeding with a 40% fat diet to allow for comparison of measurements in fecal microbiota, meal tolerance testing (MTT), and indirect calorimetry between test beverages. Eighteen study volunteers completed the study. At the phylum level, EBJ significantly increased Firmicutes and Actinobacteria, and decreased Bacteroidetes. At the genus level, EBJ increased Faecalibacterium, Ruminococcaceae, and Bifidobacterium and decreased Bacteroides and lactic acid-producing bacteria, indicating a positive response to EBJ. Supporting the changes to the microbiota, the EBJ treatment significantly reduced blood glucose following the MTT. Fat oxidation also increased significantly both during the MTT and 30 min of moderate physical activity with the EBJ treatment. Our findings confirm the bioactivity of EBJ-sourced anthocyanins on outcomes related to gut health and obesity. Follow-up investigation is needed to confirm our findings and to test for longer durations. Full article

Nut-based products are a good source of high-quality plant protein in addition to mono- and polyunsaturated fatty acids, and may aid low-glycaemic dietary strategies important for the prevention of type 2 diabetes (T2D). In particular, they may be advantageous in populations susceptible to dysglycaemia, such as Asian Chinese. The present study aimed to compare effects of a higher-protein nut bar (HP-NB, also higher in total fibre and unsaturated fats, comprising mixed almonds and peanuts) vs. an isoenergetic higher-carbohydrate cereal bar (HC-CB) within the diet of 101 Chinese adults with overweight and normo- or hyperglycaemia. Ectopic pancreas and liver fat were characterised using magnetic resonance imaging and spectroscopy (MRI/S) as a secondary outcome. Participants were randomized to receive HP-NB or HC-CB daily as a 1 MJ light meal or snack replacement, in addition to healthy eating advice. Anthropometry and clinical indicators of T2D risk were assessed fasted and during an oral glucose tolerance test (OGTT), pre- and post-intervention. No significant difference was observed between diet groups for body weight, body mass index, waist or hip circumference, blood pressure, glucoregulatory markers, lipid profile or inflammatory markers over 12 weeks (all, p > 0.05). No difference was observed between glycaemic subgroups or those with normal versus high ectopic organ fat. Although HP-NB can attenuate postprandial glycaemia following a meal, no effects were observed for either fasting or glucose-mediated outcomes following longer-term inclusion in the habitual diet of Chinese adults with overweight, including at-risk subgroups. Full article

Metabolic disorders are increasingly prevalent conditions that manifest pathophysiologically along a continuum. Among reported metabolic risk factors, elevated fasting serum glucose (FSG) levels have shown the most substantial increase in risk exposure. Ultimately leading to insulin resistance (IR), this condition is associated with notable deteriorations in the prognostic outlook for major diseases, including neurodegenerative diseases, cancer risk, and mortality related to cardiovascular disease. Tackling metabolic dysfunction, with a focus on prevention, is a critically important aspect for human health. In this study, an investigation into the potential antidiabetic properties of a salmon protein hydrolysate (SPH) was conducted, focusing on its potential dipeptidyl peptidase-IV (DPP-IV) inhibition and direct glucose uptake in vitro. Characterization of the SPH utilized a bioassay-guided fractionation approach to identify potent glucoregulatory peptide fractions. Low-molecular-weight (MW) fractions prepared by membrane filtration (MWCO = 3 kDa) showed significant DPP-IV inhibition (IC₅₀ = 1.01 ± 0.12 mg/mL) and glucose uptake in vitro (p ≤ 0.0001 at 1 mg/mL). Further fractionation of the lowest MW fractions (<3 kDa) derived from the permeate resulted in three peptide subfractions. The subfraction with the lowest molecular weight demonstrated the most significant glucose uptake activity (p ≤ 0.0001), maintaining its potency even at a dilution of 1:500 (p ≤ 0.01). Full article

Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer’s, Parkinson’s, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin’s mechanisms of action and potential therapeutic benefits for neurodegenerative disorders. A comprehensive search of electronic databases, including PubMed, MEDLINE, Embase, and Cochrane library, focused on key phrases such as “metformin”, “neuroprotection”, and “neurodegenerative diseases”, with data up to September 2023. Recent research on metformin’s glucoregulatory mechanisms reveals new molecular targets, including the activation of the LKB1–AMPK signaling pathway, which is crucial for chronic administration of metformin. The pleiotropic impact may involve other stress kinases that are acutely activated. The precise role of respiratory chain complexes (I and IV), of the mitochondrial targets, or of the lysosomes in metformin effects remains to be established by further research. Research on extrahepatic targets like the gut and microbiota, as well as its antioxidant and immunomodulatory properties, is crucial for understanding neurodegenerative disorders. Experimental data on animal models shows promising results, but clinical studies are inconclusive. Understanding the molecular targets and mechanisms of its effects could help design clinical trials to explore and, hopefully, prove its therapeutic effects in neurodegenerative conditions. Full article

Intraduodenal quinine, in the dose of 600 mg, stimulates glucagon-like peptide-1 (GLP-1), cholecystokinin and insulin; slows gastric emptying (GE); and lowers post-meal glucose in men. Oral sensitivity to bitter substances may be greater in women than men. We, accordingly, evaluated the dose-related effects of quinine on GE, and the glycaemic responses to, a mixed-nutrient drink in females, and compared the effects of the higher dose with those in males. A total of 13 female and 13 male healthy volunteers received quinine-hydrochloride (600 mg (‘QHCl-600’) or 300 mg (‘QHCl-300’, females only) or control (‘C’), intraduodenally (10 mL bolus) 30 min before a drink (500 kcal, 74 g carbohydrates). Plasma glucose, insulin, C-peptide, GLP-1, glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin were measured at baseline, for 30 min after quinine alone, and then for 2 h post-drink. GE was measured by ¹³C-acetate breath-test. QHCl-600 alone stimulated insulin, C-peptide and GLP-1 secretion compared to C. Post-drink, QHCl-600 reduced plasma glucose, stimulated C-peptide and GLP-1, and increased the C-peptide/glucose ratio and oral disposition index, while cholecystokinin and GIP were less, in females and males. QHCl-600 also slowed GE compared to C in males and compared to QHCl-300 in females (p < 0.05). QHCl-300 reduced post-meal glucose concentrations and increased the C-peptide/glucose ratio, compared to C (p < 0.05). Magnitudes of glucose lowering and increase in C-peptide/glucose ratio by QHCl-600 were greater in females than males (p < 0.05). We conclude that quinine modulates glucoregulatory functions, associated with glucose lowering in healthy males and females. However, glucose lowering appears to be greater in females than males, without apparent differential effects on GI functions. Full article

The mechanisms behind reported decreases in plasma insulin and glucagon during hemodialysis (HD) are not clear. Here, we investigated these mechanisms during HD treatment and the characteristics of insulin and glucagon removal when using two super high-flux membranes. In an experimental study, clearance, adsorption rates, and reduction rates of insulin and glucagon were investigated when using cellulose triacetate (CTA) and polysulfone (PS) membranes in a closed circuit using bovine blood. In a clinical study, 20 diabetes patients with end-stage kidney disease who were stable on HD were randomly selected for two HD sessions with two different membranes. At 1 h after the initiation of HD, insulin and glucagon clearance were measured, and the reduction rates were also investigated. In the experimental study, the PS membrane showed significantly higher clearance, adsorption rates, and reduction rates of insulin and glucagon compared with the CTA membrane. Although glucagon was detected in the ultrafiltration fluids in both membranes, insulin was absent in the PS membrane. In the clinical study, both membranes showed significant reductions in plasma insulin and glucagon at each time point. The PS membrane showed significantly higher insulin clearance and reduction rates compared with the CTA membrane. The two membranes showed no significant difference in glucagon clearance, but the glucagon reduction rate was significantly higher with the PS membrane. Our findings show that HD with the two super high-flux membranes used removes significant amounts of glucoregulatory peptide hormones from plasma in patients with diabetes and end-stage kidney disease, potentially affecting their glucose metabolism. Full article

Bariatric surgery and pharmacology treatments increase circulating glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), in turn promoting satiety and body weight (BW) loss. However, the utility of GLP-1 and PYY in predicting appetite response during dietary interventions remains unsubstantiated. This study investigated whether the decrease in hunger observed following low energy diet (LED)-induced weight loss was associated with increased circulating ‘satiety peptides’, and/or associated changes in glucose, glucoregulatory peptides or amino acids (AAs). In total, 121 women with obesity underwent an 8-week LED intervention, of which 32 completed an appetite assessment via a preload challenge at both Week 0 and Week 8, and are reported here. Visual analogue scales (VAS) were administered to assess appetite-related responses, and blood samples were collected over 210 min post-preload. The area under the curve (AUC_0-210), incremental AUC (iAUC_0-210), and change from Week 0 to Week 8 (∆) were calculated. Multiple linear regression was used to test the association between VAS–appetite responses and blood biomarkers. Mean (±SEM) BW loss was 8.4 ± 0.5 kg (−8%). Unexpectedly, the decrease in ∆AUC_0-210 hunger was best associated with decreased ∆AUC_0-210 GLP-1, GIP, and valine (p < 0.05, all), and increased ∆AUC_0-210 glycine and proline (p < 0.05, both). The majority of associations remained significant after adjusting for BW and fat-free mass loss. There was no evidence that changes in circulating GLP-1 or PYY were predictive of changes in appetite-related responses. The modelling suggested that other putative blood biomarkers of appetite, such as AAs, should be further investigated in future larger longitudinal dietary studies. Full article

Nesfatin-1 and nesfatin-1-like peptide (Nlp) are derived from precursors nucleobindin-2 and -1, two calcium and DNA binding proteins, respectively. Both peptides exhibit hormone-like actions in mammals and fish. These functions include insulinotropic effects of nesfatin-1 and Nlp seen in mice and their growth hormone suppressive actions reported in goldfish. We hypothesized that nesfatin-1 and Nlp are insulin stimulatory (in adipose tissue) and modulate growth hormone and insulin-like growth factors and glucose transporters in goldfish. To test this, goldfish were intraperitoneally injected with either nesfatin-1 or Nlp (50 ng/g BW) or saline alone (control) and sampled at one-hour post-injection (in vivo study). In a separate study, tissue samples were collected and were incubated with either nesfatin-1 or Nlp for one or six hours (in vitro study). Transcript (mRNA) abundance data from the adipose tissue suggest that both nesfatin-1 and Nlp significantly upregulate the abundance of preproinsulin, insulin receptors, and pcsk1 and pcsk2 mRNAs. Meanwhile, the abundance of preproglucagon mRNA in the adipose tissue was significantly downregulated in both in vivo and in vitro studies. These results agree with the insulinotropic and glucagonostatic roles for nesfatin-1 and Nlp reported in rodents. The transcript abundance of growth regulators (igf1, igf2a, and ghra) and glucose transporters (slc2a2 and slc5a1) were upregulated in the muscle, while an opposite effect on these mRNAs was found in the liver of goldfish following nesfatin-1 and Nlp administration. Our results suggest that both nesfatin-1 and Nlp have tissue-specific regulatory roles on growth and glucoregulatory elements in the liver and muscle of goldfish. This agrees with our previous studies that showed a suppressive action of nesfatin-1 on growth hormone in goldfish liver. The results presented here provide strong supportive/confirmatory evidence for tissue-specific insulinotropic and gluco- and growth-regulatory actions of nesfatin-1 and Nlp in goldfish. Full article

Type 2 diabetes (T2D) is a challenging health concern worldwide. A lifestyle intervention to treat T2D is difficult to adhere, and the effectiveness of approved medications such as metformin, thiazolidinediones (TZDs), and sulfonylureas are suboptimal. On the other hand, bariatric procedures such as Roux-en-Y gastric bypass (RYGB) are being recognized for their remarkable ability to achieve diabetes remission, although the underlying mechanism is not clear. Recent evidence points to branched-chain amino acids (BCAAs) as a potential contributor to glucose impairment and insulin resistance. RYGB has been shown to effectively lower plasma BCAAs in insulin-resistant or T2D patients that may help improve glycemic control, but the underlying mechanism for BCAA reduction is not understood. Hence, we attempted to explore the mechanism by which RYGB reduces BCAAs. To this end, we randomized diet-induced obese (DIO) mice into three groups that underwent either sham or RYGB surgery or food restriction to match the weight of RYGB mice. We also included regular chow-diet-fed healthy mice as an additional control group. Here, we show that compared to sham surgery, RYGB in DIO mice markedly lowered serum BCAAs most likely by rescuing BCAA breakdown in both liver and white adipose tissues. Importantly, the restored BCAA metabolism following RYGB was independent of caloric intake. Fasting insulin and HOMA-IR were decreased as expected, and serum valine was strongly associated with insulin resistance. While gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are postulated to mediate various surgery-induced metabolic benefits, mice lacking these hormonal signals (GLP-1R/Y2R double KO) were still able to effectively lower plasma BCAAs and improve glucose tolerance, similar to mice with intact GLP-1 and PYY signaling. On the other hand, mice deficient in fibroblast growth factor 21 (FGF21), another candidate hormone implicated in enhanced glucoregulatory action following RYGB, failed to decrease plasma BCAAs and normalize hepatic BCAA degradation following surgery. This is the first study using an animal model to successfully recapitulate the RYGB-led reduction of circulating BCAAs observed in humans. Our findings unmasked a critical role of FGF21 in mediating the rescue of BCAA metabolism following surgery. It would be interesting to explore the possibility of whether RYGB-induced improvement in glucose homeostasis is partly through decreased BCAAs. Full article

Type 2 diabetes mellitus is a chronic metabolic disease, characterized by persistent hyperglycemia, the prevalence of which is on the rise worldwide. Fermented soybean products (FSP) are rich in diverse functional ingredients which have been shown to exhibit therapeutic properties in alleviating hyperglycemia. This review summarizes the hypoglycemic actions of FSP from the perspective of different target-related molecular signaling mechanisms in vitro, in vivo and clinical trials. FSP can ameliorate glucose metabolism disorder by functioning as carbohydrate digestive enzyme inhibitors, facilitating glucose transporter 4 translocation, accelerating muscular glucose utilization, inhibiting hepatic gluconeogenesis, ameliorating pancreatic dysfunction, relieving adipose tissue inflammation, and improving gut microbiota disorder. Sufficiently recognizing and exploiting the hypoglycemic activity of traditional fermented soybean foods could provide a new strategy in the development of the food fermentation industry. Full article

The enzyme aromatase is expressed at high levels in the ventromedial hypothalamic nucleus (VMN), a principal component of the brain gluco-regulatory network. Current research utilized selective gene knockdown tools to investigate the premise that VMN neuroestradiol controls glucostasis. Intra-VMN aromatase siRNA administration decreased baseline aromatase protein expression and tissue estradiol concentrations and either reversed or attenuated the hypoglycemic regulation of these profiles in a VMN segment-specific manner. Aromatase gene repression down-regulated protein biomarkers for gluco-stimulatory (nitric oxide; NO) and -inhibitory (gamma-aminobutyric acid; GABA) neurochemical transmitters. Insulin-induced hypoglycemia (IIH) up- or down-regulated neuronal nitric oxide synthase (nNOS) and glutamate decarboxylase_65/67 (GAD), respectively, throughout the VMN. Interestingly, IIH caused divergent changes in tissue aromatase and estradiol levels in rostral (diminished) versus middle and caudal (elevated) VMN. Aromatase knockdown prevented hypoglycemic nNOS augmentation in VMN middle and caudal segments, but abolished the GAD inhibitory response to IIH throughout this nucleus. VMN nitrergic and GABAergic neurons monitor stimulus-specific glycogen breakdown. Here, glycogen synthase (GS) and phosphorylase brain- (GPbb; AMP-sensitive) and muscle- (GPmm; noradrenergic –responsive) type isoform responses to aromatase siRNA were evaluated. Aromatase repression reduced GPbb and GPmm content in euglycemic controls and prevented hypoglycemic regulation of GPmm but not GPbb expression while reversing glycogen accumulation. Aromatase siRNA elevated baseline glucagon and corticosterone secretion and abolished hypoglycemic hyperglucagonemia and hypercorticosteronemia. Outcomes document the involvement of VMN neuroestradiol signaling in brain control of glucose homeostasis. Aromatase regulation of VMN gluco-regulatory signaling of hypoglycemia-associated energy imbalance may entail, in part, control of GP variant-mediated glycogen disassembly. Full article