scholarly journals Amyloid precursor protein in pancreatic islets

2017 ◽  
Vol 235 (1) ◽  
pp. 49-67 ◽  
Author(s):  
Joshua A Kulas ◽  
Kendra L Puig ◽  
Colin K Combs
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Precursor Protein ◽  
Pancreatic Islets ◽  
Culture Media ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Precursor Protein ◽  
Protein Levels ◽  
Glucose Levels

The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Aβ), a plaque-forming peptide in Alzheimer’s disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well-characterized consequence of type 1 and type 2 diabetes. In this study, we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes. Our data demonstrate the presence of APP within the pancreas, including pancreatic islets in both mouse and human samples. Additionally, we report that the APP/PS1 mouse model of AD overexpresses APP within pancreatic islets, although this did not result in detectable levels of Aβ. We compared whole pancreas and islet culture lysates by Western blot from C57BL/6 (WT), APP−/− and APP/PS1 mice and observed APP-dependent differences in the total protein levels of GLUT4, IDE and BACE2. Immunohistochemistry for BACE2 detected high levels in pancreatic α cells. Additionally, both mouse and human islets processed APP to release sAPP into cell culture media. Moreover, sAPP stimulated insulin but not glucagon secretion from islet cultures. We conclude that APP and its metabolites are capable of influencing the basic physiology of the pancreas, possibly through the release of sAPP acting in an autocrine or paracrine manner.

Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion

2004 ◽  
Vol 286 (6) ◽  
pp. E1023-E1031 ◽  
Author(s):  
Isabelle Leclerc ◽  
Wolfram W. Woltersdorf ◽  
Gabriela da Silva Xavier ◽  
Rebecca L. Rowe ◽  
Sarah E. Cross ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Pancreatic Islets ◽  
Human Islets ◽  
Β Cells ◽  
Min6 Cells ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Metformin, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether metformin or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in AMPK activity inhibit insulin secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761–774, 2003). Here, we explore whether 1) glucose, metformin, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate insulin secretion from human islets. Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with metformin (0.2–1 mM) activated AMPK in both human islets and MIN6 β-cells in parallel with an inhibition of insulin secretion, whereas leptin (10–100 nM) was without effect in MIN6 cells. These studies demonstrate that AMPK activity is subject to regulation by both glucose and metformin in pancreatic islets and clonal β-cells. The inhibitory effects of metformin on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes.

scholarly journals Pathogenetic substantiation and effectiveness of vildagliptin use inpatients with diabetes mellitus type 2

2009 ◽  
Vol 6 (3) ◽  
pp. 16-26 ◽  
Author(s):  
T I Romantsova
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Glucose Levels ◽  
Β Cell Function ◽  
Control Of Diabetes ◽  
Glucagon Like Peptide 1

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. Now it isrecognized that the β-cell failure occurs much earlier and is more severe than previously thought. As a result, earlier and more aggressive new therapy is needed to achiev e better control of diabetes and to prev ent/slow the progressive B-cell failure that already is w ell established in IGT subjects. One approach is to target the incretin mimetic hormone glucagon-like peptide-1 (GLP-1). When blood glucose levels are elevated, GrP-1 stimulates insulin secretion, decreases glucagon secretion, impro ves β-cell function, and slows gastric emptying. GrP-1 production is reduced in patients with type 2 diabetes. Furthermore, GrP-1 is rapidly degraded by the dipeptidyl peptidase 4 (DPP-4) enzyme. Trials have showed, that new inhibitor DPP-4 vildagliptin (Galvus) hav e been demonstrated to significantly reduce HbA lc, fasting and prandial glucose levels when used as monotherapy and in соmbination with traditional agents. Advantages of vildagliptin include few adverse events, low risk of hypoglycemia, neutral effect on body weight, and a once-daily oral dosing regimen. Inaddition, vildagliptin may preserve the decline in β-cell function. Hence, vildagliptin may modify the natural progressive course of diabetes; this however, must be confirmed with longer-term controlled studies

scholarly journals Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion

Diabetologia ◽  
2010 ◽  
Vol 54 (4) ◽  
pp. 819-827 ◽  
Author(s):  
G. da Silva Xavier ◽  
H. Farhan ◽  
H. Kim ◽  
S. Caxaria ◽  
P. Johnson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Protein Kinase ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Pas Domain

Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus

2011 ◽  
Vol 91 (3) ◽  
pp. 795-826 ◽  
Author(s):  
Per Westermark ◽  
Arne Andersson ◽  
Gunilla T. Westermark
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Amyloid Fibrils ◽  
Mammalian Species ◽  
Islet Amyloid Polypeptide ◽  
Glucagon Secretion ◽  
Β Cells ◽  
Islet Amyloid ◽  
Pancreatic Islets Of Langerhans

Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is a regulatory peptide with putative function both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets. It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described. IAPP was discovered through its ability to aggregate into pancreatic islet amyloid deposits, which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats. Aggregated IAPP has cytotoxic properties and is believed to be of critical importance for the loss of β-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of IAPP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.

scholarly journals In pancreatic islets from type 2 diabetes patients, the dampened circadian oscillators lead to reduced insulin and glucagon exocytosis

2020 ◽  
Vol 117 (5) ◽  
pp. 2484-2495 ◽  
Author(s):  
Volodymyr Petrenko ◽  
Nikhil R. Gandasi ◽  
Daniel Sage ◽  
Anders Tengholm ◽  
Sebastian Barg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Islet Cell ◽  
Glucagon Secretion ◽  
Molecular Clocks ◽  
Clock Proteins ◽  
Temporal Profiles

Circadian clocks operative in pancreatic islets participate in the regulation of insulin secretion in humans and, if compromised, in the development of type 2 diabetes (T2D) in rodents. Here we demonstrate that human islet α- and β-cells that bear attenuated clocks exhibit strongly disrupted insulin and glucagon granule docking and exocytosis. To examine whether compromised clocks play a role in the pathogenesis of T2D in humans, we quantified parameters of molecular clocks operative in human T2D islets at population, single islet, and single islet cell levels. Strikingly, our experiments reveal that islets from T2D patients contain clocks with diminished circadian amplitudes and reduced in vitro synchronization capacity compared to their nondiabetic counterparts. Moreover, our data suggest that islet clocks orchestrate temporal profiles of insulin and glucagon secretion in a physiological context. This regulation was disrupted in T2D subjects, implying a role for the islet cell-autonomous clocks in T2D progression. Finally, Nobiletin, an agonist of the core-clock proteins RORα/γ, boosted both circadian amplitude of T2D islet clocks and insulin secretion by these islets. Our study emphasizes a link between the circadian clockwork and T2D and proposes that clock modulators hold promise as putative therapeutic agents for this frequent disorder.

scholarly journals Human glucagon expression is under the control of miR-320a

Endocrinology ◽  
2020 ◽  
Author(s):  
Seongho Jo ◽  
Guanlan Xu ◽  
Gu Jing ◽  
Junqin Chen ◽  
Anath Shalev
Keyword(s):  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Luciferase Reporter ◽  
Potential Binding ◽  
Mrna And Protein Expression ◽  
Reporter Assays ◽  
First Time

Abstract Increased glucagon is a hallmark of diabetes and leads to worsening of the hyperglycemia, but the molecular mechanisms causing it are still unknown. We therefore investigated the possibility that microRNAs might be involved in the regulation of glucagon. Indeed, analysis of the glucagon 3’UTR revealed potential binding sites for miR-320a and using luciferase reporter assays we found that miR-320a directly targets the 3’UTRs of human and rodent glucagon. In addition, endogenous glucagon mRNA and protein expression as well as glucagon secretion were reduced in response to miR-320a overexpression, whereas inhibition of miR-320a upregulated glucagon expression. Interestingly, miR-320a expression was decreased by high glucose and this was associated with an increase in glucagon expression in human islets and mouse αTC1-6 cells. Moreover, miR-320a overexpression completely blunted these effects. Importantly, miR-320a was also significantly downregulated in human islets of subjects with type 2 diabetes and this was accompanied by increased glucagon expression. Thus, our data suggest that glucose-induced downregulation of miR-320a may contribute to the paradoxical increase in glucagon observed in type 2 diabetes and reveal for the first time that glucagon expression is under the control by a microRNA providing novel insight into the abnormal regulation of glucagon in diabetes.

scholarly journals Antidiabetic Activity of a Highly Potent and Selective Nonpeptide Somatostatin Receptor Subtype-2 Agonist

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4664-4673 ◽  
Author(s):  
Mathias Z. Strowski ◽  
Doreen E. Cashen ◽  
Elizabeth T. Birzin ◽  
Lihu Yang ◽  
Vandana Singh ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Somatostatin Receptor ◽  
Glucagon Secretion ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Glucose Levels ◽  
Somatostatin Receptor Subtypes ◽  
Novel Approach

Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst1–sst5) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst2, whereas B cells express sst5. In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst2-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst2-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst2-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst2 selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst2-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.

scholarly journals Inhibition of the malate–aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion

2015 ◽  
Vol 468 (1) ◽  
pp. 49-63 ◽  
Author(s):  
Jelena A. Stamenkovic ◽  
Lotta E. Andersson ◽  
Alice E. Adriaenssens ◽  
Annika Bagge ◽  
Vladimir V. Sharoyko ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucagon Secretion ◽  
Nutrient Sensing ◽  
Β Cells ◽  
Mouse Pancreatic Islets ◽  
Glucagon And Insulin ◽  
Malate Aspartate Shuttle

Secretion of both glucagon and insulin is perturbed in Type 2 diabetes (T2D). In the present study, we identify a difference in mitochondrial shuttling between α- and β-cells that adjusts nutrient sensing and which potentially could be employed to specifically target secretion of either hormone.

scholarly journals GPR40 protein levels are crucial to the regulation of stimulated hormone secretion in pancreatic islets. Lessons from spontaneous obesity-prone and non-obese type 2 diabetes in rats

2013 ◽  
Vol 381 (1-2) ◽  
pp. 150-159 ◽  
Author(s):  
Sandra Meidute Abaraviciene ◽  
Sarheed J. Muhammed ◽  
Stefan Amisten ◽  
Ingmar Lundquist ◽  
Albert Salehi
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Hormone Secretion ◽  
Protein Levels
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