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Mechanistic Insights into the Pathogenesis of Type 2 Diabetes

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A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Medical Biology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 52785

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Special Issue Editors

Dr. Magdalene Montgomery

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Guest Editor

Department of Physiology, School of Biomedical Sciences, University of Melbourne, Melbourne 3010, Australia
Interests: type 2 diabetes; lipid metabolism; endocrine signaling; non-alcoholic fatty liver disease, mitochondrial function

Dr. Stacey Keenan

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Guest Editor

Biology of Lipid Metabolism Laboratory, Department of Physiology | Faculty of MDHS, Level 6, West Wing, Medical Building, The University of Melbourne, Victoria 3010, Australia
Interests: insulin resistance; lipid droplet biology; obesity; type 2 diabetes; mitochondrial function; perilipin proteins

Special Issue Information

Dear Colleagues,

Diabetes cost the global economy AUD $537 billion in 2010, or 11.6% of total world healthcare expenditure, and is predicted to be the fourth leading cause of death by 2030 (WHO Health Statistics 2015). Most worrying is the rising prevalence of people with impaired fasting glucose or impaired glucose tolerance (pre-diabetes, estimated prevalence ~40% in 2012), which increases the risk of premature cardiovascular disease and future type 2 diabetes development. Finding ways to prevent the development of type 2 diabetes, as well as ways to manage it, is a major global health challenge of the 21st century.

This Special Issue welcomes submissions of original research articles, reviews and short communications focussing on the mechanisms underlying the pathogenesis of insulin resistance and type 2 diabetes, ranging from obesity- and lipid-induced metabolic dysfunction in peripheral tissues, to central insulin resistance, genetic susceptibility, and aging-associated pathogenesis.

This Issue, collating the newest insights into the pathways that drive the development of insulin resistance, will undoubtedly increase our understanding of the fundamental biology underlying glucose metabolism and insulin action and aid in the generation of more targeted therapies.

Dr. Magdalene Montgomery
Dr. Stacey Keenan
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

insulin resistance
glucose metabolism
type 2 diabetes

Published Papers (11 papers)

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Research

Jump to: Review

17 pages, 2809 KiB

Open AccessArticle

Protection against Glucolipotoxicity by High Density Lipoprotein in Human PANC-1 Hybrid 1.1B4 Pancreatic Beta Cells: The Role of microRNA

by Jamie M.R. Tarlton, Richard J. Lightbody, Steven Patterson and Annette Graham

Biology 2021, 10(3), 218; https://doi.org/10.3390/biology10030218 - 13 Mar 2021

Cited by 5 | Viewed by 2249

Abstract

High-density lipoproteins provide protection against the damaging effects of glucolipotoxicity in beta cells, a factor which sustains insulin secretion and staves off onset of type 2 diabetes mellitus. This study examines epigenetic changes in small non-coding microRNA sequences induced by high density lipoproteins in a human hybrid beta cell model, and tests the impact of delivery of a single sequence in protecting against glucolipotoxicity. Human PANC-1.1B4 cells were used to establish Bmax and Kd for [³H]cholesterol efflux to high density lipoprotein, and minimum concentrations required to protect cell viability and reduce apoptosis to 30mM glucose and 0.25 mM palmitic acid. Microchip array identified the microRNA signature associated with high density lipoprotein treatment, and one sequence, hsa-miR-21-5p, modulated via delivery of a mimic and inhibitor. The results confirm that low concentrations of high-density lipoprotein can protect against glucolipotoxicity, and report the global microRNA profile associated with this lipoprotein; delivery of miR-21-5p mimic altered gene targets, similar to high density lipoprotein, but could not provide sufficient protection against glucolipotoxicity. We conclude that the complex profile of microRNA changes due to HDL treatment may be difficult to replicate using a single microRNA, findings which may inform current drug strategies focused on this approach. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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14 pages, 2370 KiB

Open AccessArticle

Differential Effects of Empagliflozin on Microvascular Complications in Murine Models of Type 1 and Type 2 Diabetes

by Stephanie A. Eid, Phillipe D. O’Brien, Lucy M. Hinder, John M. Hayes, Faye E. Mendelson, Hongyu Zhang, Lixia Zeng, Katharina Kretzler, Samanthi Narayanan, Steven F. Abcouwer, Frank C. Brosius III, Subramaniam Pennathur, Masha G. Savelieff and Eva L. Feldman

Biology 2020, 9(11), 347; https://doi.org/10.3390/biology9110347 - 22 Oct 2020

Cited by 23 | Viewed by 3197

Abstract

Microvascular complications account for the significant morbidity associated with diabetes. Despite tight glycemic control, disease risk remains especially in type 2 diabetes (T2D) patients and no therapy fully prevents nerve, retinal, or renal damage in type 1 diabetes (T1D) or T2D. Therefore, new antidiabetic drug classes are being evaluated for the treatment of microvascular complications. We investigated the effect of empagliflozin (EMPA), an inhibitor of the sodium/glucose cotransporter 2 (SGLT2), on diabetic neuropathy (DPN), retinopathy (DR), and kidney disease (DKD) in streptozotocin-induced T1D and db/db T2D mouse models. EMPA lowered blood glycemia in T1D and T2D models. However, it did not ameliorate any microvascular complications in the T2D model, which was unexpected, given the protective effect of SGLT2 inhibitors on DKD progression in T2D subjects. Although EMPA did not improve DKD in the T1D model, it had a potential modest effect on DR measures and favorably impacted DPN as well as systemic oxidative stress. These results support the concept that glucose-centric treatments are more effective for DPN in T1D versus T2D. This is the first study that provides an evaluation of EMPA treatment on all microvascular complications in a side-by-side comparison in T1D and T2D models. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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16 pages, 1645 KiB

Open AccessArticle

Short-Term Effects of Early Menopause on Adiposity, Fatty Acids Profile and Insulin Sensitivity of a Swine Model of Female Obesity

by Ana Heras-Molina, José Luis Pesantez-Pacheco, Marta Vazquez-Gomez, Consolacion Garcia-Contreras, Susana Astiz, Beatriz Isabel and Antonio Gonzalez-Bulnes

Biology 2020, 9(9), 284; https://doi.org/10.3390/biology9090284 - 11 Sep 2020

Cited by 2 | Viewed by 2248

Abstract

Menopause strongly increases incidence and consequences of obesity and non-communicable diseases in women, with recent research suggesting a very early onset of changes in lipid accumulation, dyslipidemia, and insulin resistance. However, there is a lack of adequate preclinical models for its study. The present trial evaluated the usefulness of an alternative method to surgical ovariectomy, the administration of two doses of a GnRH analogue-protein conjugate (Vacsincel^®), for inducing ovarian inactivity in sows used as preclinical models of obesity and menopause. All the sows treated with the compound developed ovarian stoppage after the second dose and, when exposed to obesogenic diets during the following three months, showed changes in the patterns of fat deposition, in the fatty acids profiles at the different tissues and in the plasma concentrations of fructosamine, urea, β-hydroxibutirate, and haptoglobin when compared to obese fed with the same diet but maintaining ovarian activity. Altogether, these results indicate that menopause early augments the deleterious effects induced by overfeeding and obesity on metabolic traits, paving the way for future research on physiopathology of these conditions and possible therapeutic targets using the swine model. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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13 pages, 1473 KiB

Open AccessArticle

Increased Plasma Levels of Adenylate Cyclase 8 and cAMP Are Associated with Obesity and Type 2 Diabetes: Results from a Cross-Sectional Study

by Samy M. Abdel-Halim, Ashraf Al Madhoun, Rasheeba Nizam, Motasem Melhem, Preethi Cherian, Irina Al-Khairi, Dania Haddad, Mohamed Abu-Farha, Jehad Abubaker, Milad S. Bitar and Fahd Al-Mulla

Biology 2020, 9(9), 244; https://doi.org/10.3390/biology9090244 - 24 Aug 2020

Cited by 13 | Viewed by 3066

Abstract

Adenylate cyclases (ADCYs) catalyze the conversion of ATP to cAMP, an important co-factor in energy homeostasis. Giving ADCYs role in obesity, diabetes and inflammation, we questioned whether calcium-stimulated ADCY isoforms may be variably detectable in human plasma. We report the results of a cross-sectional study assessing circulating levels of functional ADCY1, −3 and −8 in patients with T2D vs. non-diabetic (ND) controls in association with obesity. ADCY1 levels exhibited no significant change between ND and T2D groups. ADCY3 levels were lower in obese individuals, albeit not statistically significantly. In contrast, ADCY8 plasma levels were significantly higher in obese and T2D patients compared to controls (p = 0.001) and patients with T2D only (p = 0.039). ADCY8 levels correlated positively with body mass index and Hb1Ac levels. Parallel to the increased ADCY8 levels, significantly higher cAMP levels were observed in patients with T2D compared with ND controls, and further elevated in obese individuals, irrespective of T2D status. Additionally, cAMP levels positively correlated with fasting plasma glucose levels. In conclusion, the current cross-sectional study demonstrated elevated levels of circulating plasma ADCY8 and cAMP in obesity and T2D. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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17 pages, 1377 KiB

Open AccessArticle

Artificial Neural Networks Model for Predicting Type 2 Diabetes Mellitus Based on VDR Gene FokI Polymorphism, Lipid Profile and Demographic Data

by Ma’mon M. Hatmal, Salim M. Abderrahman, Wajeha Nimer, Zaynab Al-Eisawi, Hamzeh J. Al-Ameer, Mohammad A. I. Al-Hatamleh, Rohimah Mohamud and Walhan Alshaer

Biology 2020, 9(8), 222; https://doi.org/10.3390/biology9080222 - 13 Aug 2020

Cited by 14 | Viewed by 3640

Abstract

Type 2 diabetes mellitus (T2DM) is a multifactorial disease associated with many genetic polymorphisms; among them is the FokI polymorphism in the vitamin D receptor (VDR) gene. In this case-control study, samples from 82 T2DM patients and 82 healthy controls were examined to investigate the association of the FokI polymorphism and lipid profile with T2DM in the Jordanian population. DNA was extracted from blood and genotyped for the FokI polymorphism by polymerase chain reaction (PCR) and DNA sequencing. Lipid profile and fasting blood sugar were also measured. There were significant differences in high-density lipoprotein (HDL) cholesterol and triglyceride levels between T2DM and control samples. Frequencies of the FokI polymorphism (CC, CT and TT) were determined in T2DM and control samples and were not significantly different. Furthermore, there was no significant association between the FokI polymorphism and T2DM or lipid profile. A feed-forward neural network (FNN) was used as a computational platform to predict the persons with diabetes based on the FokI polymorphism, lipid profile, gender and age. The accuracy of prediction reached 88% when all parameters were included, 81% when the FokI polymorphism was excluded, and 72% when lipids were only included. This is the first study investigating the association of the VDR gene FokI polymorphism with T2DM in the Jordanian population, and it showed negative association. Diabetes was predicted with high accuracy based on medical data using an FNN. This highlights the great value of incorporating neural network tools into large medical databases and the ability to predict patient susceptibility to diabetes. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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18 pages, 2847 KiB

Open AccessArticle

Exercise Ameliorates Insulin Resistance of Type 2 Diabetes through Motivating Short-Chain Fatty Acid-Mediated Skeletal Muscle Cell Autophagy

by Ling Yang, Haiqi Lin, Wentao Lin and Xiaoyang Xu

Biology 2020, 9(8), 203; https://doi.org/10.3390/biology9080203 - 3 Aug 2020

Cited by 35 | Viewed by 5019

Abstract

Background: Exercise can ameliorate type II diabetes mellitus (T2DM) by regulating intestinal flora metabolites. However, the detailed mechanism needs to be further explored. Methods: A T2DM model using mice was established by feeding them a high-fat diet and giving them subsequent streptozocin injections. Fasting blood glucose and serum insulin were determined by blood glucose meter and radioimmunoassay, respectively. Intestinal flora was measured by 16sRNA sequencing. SCFA content was measured by gas chromatography (GC) or enzyme-linked immunosorbent assay (ELISA). A fluorescently labeled 2-deoxyglucose (2-NBDG) kit was employed to detect glucose uptake capacity, and western blot was utilized to explore the signaling pathway of insulin resistance and cell autophagy. Results: In the T2DM model, along with a reduction in insulin resistance (IR), exercise reversed the decline of intestinal Bacteroidetes and the increase of Firmicutes. For metabolites of Bacteroides, exercise restored the decline in total intestinal and plasma short-chain fatty acids (SCFAs) in T2DM mice. However, the administration of GLPG0974—the inhibitor of G protein-coupled receptor 43 (GPR43), which is the receptor of SCFAs—abolished exercise-mediated alleviation in IR in vivo and acetate-mediated reduction of skeletal muscle IR (SMIR) in vitro. Mechanistically, exercise induced skeletal muscle cell autophagy, thereby ameliorating SMIR, which was neutralized by GLPG0974 exposure. Conclusions: Exercise-mediated SCFAs-upregulation may ameliorate insulin resistance (IR) through increasing autophagy of skeletal muscle cells by binding to GPR43. This study provides a theoretical basis for targeting gut bacterial metabolites to prevent T2DM. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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Review

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16 pages, 1343 KiB

Open AccessReview

Teucrium polium: Potential Drug Source for Type 2 Diabetes Mellitus

by Yaser Albadr, Andrew Crowe and Rima Caccetta

Biology 2022, 11(1), 128; https://doi.org/10.3390/biology11010128 - 13 Jan 2022

Cited by 4 | Viewed by 3010

Abstract

The prevalence of type 2 diabetes mellitus is rising globally and this disease is proposed to be the next pandemic after COVID-19. Although the cause of type 2 diabetes mellitus is unknown, it is believed to involve a complex array of genetic defects that affect metabolic pathways which eventually lead to hyperglycaemia. This hyperglycaemia arises from an inability of the insulin-sensitive cells to sufficiently respond to the secreted insulin, which eventually results in the inadequate secretion of insulin from pancreatic β-cells. Several treatments, utilising a variety of mechanisms, are available for type 2 diabetes mellitus. However, more medications are needed to assist with the optimal management of the different stages of the disease in patients of varying ages with the diverse combinations of other medications co-administered. Throughout modern history, some lead constituents from ancient medicinal plants have been investigated extensively and helped in developing synthetic antidiabetic drugs, such as metformin. Teucrium polium L. (Tp) is a herb that has a folk reputation for its antidiabetic potential. Previous studies indicate that Tp extracts significantly decrease blood glucose levels r and induce insulin secretion from pancreatic β-cells in vitro. Nonetheless, the constituent/s responsible for this action have not yet been elucidated. The effects appear to be, at least in part, attributable to the presence of selected flavonoids (apigenin, quercetin, and rutin). This review aims to examine the reported glucose-lowering effect of the herb, with a keen focus on insulin secretion, specifically related to type 2 diabetes mellitus. An analysis of the contribution of the key constituent flavonoids of Tp extracts will also be discussed. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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27 pages, 1579 KiB

Open AccessEditor’s ChoiceReview

Macronutrient Determinants of Obesity, Insulin Resistance and Metabolic Health

by Jibran A. Wali, Samantha M. Solon-Biet, Therese Freire and Amanda E. Brandon

Biology 2021, 10(4), 336; https://doi.org/10.3390/biology10040336 - 16 Apr 2021

Cited by 18 | Viewed by 6737

Abstract

Obesity caused by the overconsumption of calories has increased to epidemic proportions. Insulin resistance is often associated with an increased adiposity and is a precipitating factor in the development of cardiovascular disease, type 2 diabetes, and altered metabolic health. Of the various factors contributing to metabolic impairments, nutrition is the major modifiable factor that can be targeted to counter the rising prevalence of obesity and metabolic diseases. However, the macronutrient composition of a nutritionally balanced “healthy diet” are unclear, and so far, no tested dietary intervention has been successful in achieving long-term compliance and reductions in body weight and associated beneficial health outcomes. In the current review, we briefly describe the role of the three major macronutrients, carbohydrates, fats, and proteins, and their role in metabolic health, and provide mechanistic insights. We also discuss how an integrated multi-dimensional approach to nutritional science could help in reconciling apparently conflicting findings. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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21 pages, 1755 KiB

Open AccessEditor’s ChoiceReview

Emerging Roles of Metallothioneins in Beta Cell Pathophysiology: Beyond and above Metal Homeostasis and Antioxidant Response

by Mohammed Bensellam, D. Ross Laybutt and Jean-Christophe Jonas

Biology 2021, 10(3), 176; https://doi.org/10.3390/biology10030176 - 26 Feb 2021

Cited by 8 | Viewed by 3549

Abstract

Metallothioneins (MTs) are low molecular weight, cysteine-rich, metal-binding proteins whose precise biological roles have not been fully characterized. Existing evidence implicated MTs in heavy metal detoxification, metal ion homeostasis and antioxidant defense. MTs were thus categorized as protective effectors that contribute to cellular homeostasis and survival. This view has, however, been challenged by emerging evidence in different medical fields revealing novel pathophysiological roles of MTs, including inflammatory bowel disease, neurodegenerative disorders, carcinogenesis and diabetes. In the present focused review, we discuss the evidence for the role of MTs in pancreatic beta-cell biology and insulin secretion. We highlight the pattern of specific isoforms of MT gene expression in rodents and human beta-cells. We then discuss the mechanisms involved in the regulation of MTs in islets under physiological and pathological conditions, particularly type 2 diabetes, and analyze the evidence revealing adaptive and negative roles of MTs in beta-cells and the potential mechanisms involved. Finally, we underscore the unsettled questions in the field and propose some future research directions. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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18 pages, 6424 KiB

Open AccessReview

Oxidative Stress and Inflammation in Renal and Cardiovascular Complications of Diabetes

by Amelia Charlton, Jessica Garzarella, Karin A. M. Jandeleit-Dahm and Jay C. Jha

Biology 2021, 10(1), 18; https://doi.org/10.3390/biology10010018 - 30 Dec 2020

Cited by 83 | Viewed by 7042

Abstract

Oxidative stress and inflammation are considered major drivers in the pathogenesis of diabetic complications, including renal and cardiovascular disease. A symbiotic relationship also appears to exist between oxidative stress and inflammation. Several emerging therapies target these crucial pathways, to alleviate the burden of the aforementioned diseases. Oxidative stress refers to an imbalance between reactive oxygen species (ROS) and antioxidant defenses, a pathological state which not only leads to direct cellular damage but also an inflammatory cascade that further perpetuates tissue injury. Emerging therapeutic strategies tackle these pathways in a variety of ways, from increasing antioxidant defenses (antioxidants and Nrf2 activators) to reducing ROS production (NADPH oxidase inhibitors and XO inhibitors) or inhibiting the associated inflammatory pathways (NLRP3 inflammasome inhibitors, lipoxins, GLP-1 receptor agonists, and AT-1 receptor antagonists). This review summarizes the mechanisms by which oxidative stress and inflammation contribute to and perpetuate diabetes associated renal and cardiovascular disease along with the therapeutic strategies which target these pathways to provide reno and cardiovascular protection in the setting of diabetes. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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20 pages, 1285 KiB

Open AccessReview

Incretin Hormones and Type 2 Diabetes—Mechanistic Insights and Therapeutic Approaches

by Geke Aline Boer and Jens Juul Holst

Biology 2020, 9(12), 473; https://doi.org/10.3390/biology9120473 - 16 Dec 2020

Cited by 53 | Viewed by 12061

Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes. Full article

(This article belongs to the Special Issue Mechanistic Insights into the Pathogenesis of Type 2 Diabetes)

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