Exocytosis mechanisms underlying insulin release and glucose uptake: conserved roles for Munc18c and syntaxin 4

Type 2 diabetes has been coined “a two-hit disease,” as it involves specific defects of glucose-stimulated insulin secretion from the pancreatic beta cells in addition to defects in peripheral tissue insulin action required for glucose uptake. Both of these processes, insulin secretion and glucose uptake, are mediated by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein core complexes composed of syntaxin, SNAP-23/25, and VAMP proteins. The SNARE core complex is regulated by the Sec1/Munc18 (SM) family of proteins, which selectively bind to their cognate syntaxin isoforms with high affinity. The process of insulin secretion uses multiple Munc18-syntaxin isoform pairs, whereas insulin action in the peripheral tissues appears to use only the Munc18c-syntaxin 4 pair. Importantly, recent reports have linked obesity and Type 2 diabetes in humans with changes in protein levels and single nucleotide polymorphisms (SNPs) of Munc18 and syntaxin isoforms relevant to these exocytotic processes, although the molecular mechanisms underlying the observed phenotypes remain incomplete ( 5 , 104 , 144 ). Given the conservation of these proteins in two seemingly disparate processes and the need to design and implement novel and more effective clinical interventions, it will be vitally important to delineate the mechanisms governing these conserved SNARE-mediated exocytosis events. Thus, we provide here an up-to-date historical review of advancements in defining the roles and molecular mechanisms of Munc18-syntaxin complexes in the pathophysiology of Type 2 diabetes.

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Effects of Magnesium Deficiency on Mechanisms of Insulin Resistance in Type 2 Diabetes: Focusing on the Processes of Insulin Secretion and Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms20061351 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1351 ◽

Cited By ~ 22

Author(s):

Krasimir Kostov

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Pancreatic Beta Cells ◽

Molecular Mechanisms ◽

Glucose Utilization ◽

Magnesium Deficiency ◽

Target Cells ◽

Periodic Monitoring

Magnesium (Mg2+) is an essential mineral for human health and plays an important role in the regulation of glucose homeostasis and insulin actions. Despite the widespread clinical evidences for the association of Mg2+ deficiency (MgD) and type 2 diabetes mellitus (T2D), molecular mechanisms by which Mg2+ contributes to insulin resistance (IR) are still under discussion. Mg2+ regulates electrical activity and insulin secretion in pancreatic beta-cells. Intracellular Mg2+ concentrations are critical for the phosphorylation of the insulin receptor and other downstream signal kinases of the target cells. Low Mg2+ levels result in a defective tyrosine kinase activity, post-receptor impairment in insulin action, altered cellular glucose transport, and decreased cellular glucose utilization, which promotes peripheral IR in T2D. MgD triggers chronic systemic inflammation that also potentiates IR. People with T2D may end up in a vicious circle in which MgD increases IR and IR causes MgD, that requires periodic monitoring of serum Mg2+ levels.

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The impact of dietary protein restriction on insulin secretion and action

Proceedings of The Nutrition Society ◽

10.1017/s0029665199000841 ◽

1999 ◽

Vol 58 (3) ◽

pp. 647-653 ◽

Cited By ~ 6

Author(s):

Mark J. Holness

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Insulin Action ◽

Synergistic Effects ◽

Protein Restriction ◽

Dependent Diabetes Mellitus ◽

Organ Systems ◽

The Impact

The goal of this review is to develop the hypothesis, and review the evidence, that protein restriction, through synergistic effects on multiple organ systems predisposes to loss of normal regulation of fuel homeostasis that plays the central role in the development of type 2 (non-insulin-dependent) diabetes mellitus. The ability of insulin to regulate glucose production and disposal varies between individuals. These differences, together with the various compensatory mechanisms that are invoked to attempt to normalize fuel homeostasis, are of fundamental importance in the development and clinical course of type 2 diabetes mellitus. Protein deprivation impacts on both insulin secretion and insulin action. These effects may persist even when a diet containing adequate protein is presented subsequently. Data are presented that suggest that protein restriction results in an impaired ability of pancreatic β-cells to compensate adequately for the defect in insulin action in insulin-resistant individuals. This persistent impairment of insulin secretion resulting from protein restriction predisposes to loss of glucoregulatory control and impaired insulin action after the subsequent imposition of a diabetogenic challenge. This inability to maintain the degree of compensatory hyperinsulinaemia necessary to prevent loss of glucose tolerance may have relevance to the increased incidence of diabetes on changing from a nutritionally-poor diet to a Western diet, and to the hypothesis that some cases of type 2 diabetes in adulthood may be related to poor early nutrition.

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Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle

AJP Advances in Physiology Education ◽

10.1152/advan.00080.2014 ◽

2014 ◽

Vol 38 (4) ◽

pp. 308-314 ◽

Cited By ~ 95

Author(s):

Kristin I. Stanford ◽

Laurie J. Goodyear

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Molecular Mechanisms ◽

Glucose Transporter ◽

Whole Body ◽

Metabolic Genes ◽

Increase Glucose Uptake ◽

Glucose Transporter Proteins

Exercise is a well-established tool to prevent and combat type 2 diabetes. Exercise improves whole body metabolic health in people with type 2 diabetes, and adaptations to skeletal muscle are essential for this improvement. An acute bout of exercise increases skeletal muscle glucose uptake, while chronic exercise training improves mitochondrial function, increases mitochondrial biogenesis, and increases the expression of glucose transporter proteins and numerous metabolic genes. This review focuses on the molecular mechanisms that mediate the effects of exercise to increase glucose uptake in skeletal muscle.

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Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng

Journal of Endocrinology ◽

10.1677/joe-09-0026 ◽

2009 ◽

Vol 203 (1) ◽

pp. 65-74 ◽

Cited By ~ 25

Author(s):

Yun Wang ◽

Patsy M Nishina ◽

Jürgen K Naggert

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Glucose Uptake ◽

Molecular Mechanisms ◽

Glucose Transporter ◽

Cytokine Signaling ◽

Mrna Levels ◽

Insulin Resistant

The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low-IRS1 levels are often observed in human T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.

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Impact of 9 Days of Bed Rest on Hepatic and Peripheral Insulin Action, Insulin Secretion, and Whole-Body Lipolysis in Healthy Young Male Offspring of Patients With Type 2 Diabetes

Diabetes ◽

10.2337/db09-0369 ◽

2009 ◽

Vol 58 (12) ◽

pp. 2749-2756 ◽

Cited By ~ 63

Author(s):

Amra C. Alibegovic ◽

Lise Højbjerre ◽

Mette P. Sonne ◽

Gerrit van Hall ◽

Bente Stallknecht ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Insulin Action ◽

Young Male ◽

Bed Rest ◽

Male Offspring ◽

Whole Body

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Genetic framework of type 2 diabetes mellitus

Diabetes Mellitus ◽

10.14341/dm2013411-16 ◽

2013 ◽

Vol 16 (4) ◽

pp. 11-16 ◽

Cited By ~ 3

Author(s):

Irina Arkad'evna Bondar' ◽

Olesya Yur'evna Shabel'nikova

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Secretion ◽

Molecular Mechanisms

More than 100 genes associated with the risk of type 2 diabetes mellitus (T2DM) are now established. Most of them affect insulin secretion, adipogenesis and insulin resistance, but the exact molecular mechanisms determining their involvement in the pathogenesis of T2DM are not understood completely.

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Insulin secretion and insulin action in Taiwanese with type 2 diabetes

Diabetes Research and Clinical Practice ◽

10.1016/s0168-8227(88)80031-7 ◽

1988 ◽

Vol 4 (4) ◽

pp. 289-293 ◽

Cited By ~ 6

Author(s):

D.C. Shen ◽

S.W. Kuo ◽

L.R. Shian ◽

M.T. Fuh ◽

D.A. Wu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Insulin Action

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Disruption of circadian insulin secretion is associated with reduced glucose uptake in first-degree relatives of patients with type 2 diabetes

Diabetes ◽

10.2337/diabetes.48.11.2182 ◽

1999 ◽

Vol 48 (11) ◽

pp. 2182-2188 ◽

Cited By ~ 69

Author(s):

G. Boden ◽

X. Chen ◽

M. Polansky

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Uptake ◽

First Degree Relatives

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Recovery of human type 2 diabetes beta cell function associates with transcriptomic signatures that point to novel therapeutic targets

10.21203/rs.3.rs-871924/v1 ◽

2021 ◽

Author(s):

Mara Suleiman ◽

Xiaoyan Yi ◽

Emanuele Bosi ◽

Frederic Burdet ◽

Carmela De Luca ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Beta Cell ◽

Beta Cell Function ◽

Molecular Mechanisms ◽

Cell Function ◽

Therapeutic Targets ◽

Glucose Stimulated Insulin Secretion ◽

Novel Therapeutic

Abstract Remission of type 2 diabetes (T2D) may occur after very low-calorie diets or bariatric surgery, and is associated with improved pancreatic beta cell function. Here, we evaluated if T2D beta cell dysfunction can be rescued ex-vivo and which are the molecular mechanisms involved. Islets from 19 T2D donors were studied after isolation (“basal”) and following culture at 5.5 or 11.1 mmol/l glucose (“cultured”). We evaluated glucose-stimulated insulin secretion (GSIS) and transcriptomes by RNA sequencing, correlated insulin secretion changes (“cultured” vs “basal”) to global gene expression, and searched for potential therapeutic gene targets and compounds that mimic gene signatures of recovered beta cell function in T2D islets. GSIS improved in 12 out of 19 islet preparations from T2D donors after culture at 5.5 mmol/l glucose (insulin stimulation index increased from 1.4±0.1 to 2.3±0.2, p<0.01), mainly due to greater insulin response to high glucose. No improvement was seen in islets cultured at 11.1 mmol/l glucose. Functional improvement was accompanied by changes in expression of 438 genes, many of which involved in functional and inflammatory processes. Of them, 123 were significantly correlated with changes in glucose-stimulated insulin secretion. Drug repurposing and target identification analyses for beta cell functional recovery predicted several chemical (including Src inhibitors and anti-inflammatory drugs) and genetic hits in pathways such as chemokine, MAPK, ERBB signaling, and autophagy. In conclusion, defective insulin secretion in T2D can be rescued, at least in part, by a “non-diabetic” milieu, demonstrating important T2D beta cell functional plasticity. This recovery associates with specific transcriptomic traits, pointing to known as well as novel therapeutic targets to induce T2D remission.

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