scholarly journals The Role of cAMP in Beta Cell Stimulus–Secretion and Intercellular Coupling

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1658
Author(s):  
Andraž Stožer ◽  
Eva Paradiž Leitgeb ◽  
Viljem Pohorec ◽  
Jurij Dolenšek ◽  
Lidija Križančić Bombek ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Beta Cells ◽  
Molecular Mechanisms ◽  
Gastric Inhibitory Polypeptide ◽  
Nucleotide Exchange ◽  
Intercellular Coupling ◽  
Pharmacological Management ◽  
Secondary Messenger ◽  
Glucagon Like Peptide 1 ◽  
The Impact

Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The molecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus–secretion coupling cascade, ranging from the proximal regulation of ion channel activity to the central Ca2+ signal and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the relevance for the whole organism and translation to humans.

scholarly journals The Role of cAMP in Beta Cell Stimulus-Secretion and Inter-cellular Coupling

2021 ◽  
Author(s):  
Andraž Stožer ◽  
Eva Paradiž Leitgeb ◽  
Viljem Pohorec ◽  
Jurij Dolenšek ◽  
Lidija Križančić Bombek ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Beta Cells ◽  
Gastric Inhibitory Polypeptide ◽  
Nucleotide Exchange ◽  
Pharmacological Management ◽  
Downstream Signaling ◽  
Secondary Messenger ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
The Impact

Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The mo-lecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus-secretion coupling cascade, ranging from the proximal regula-tion of ion channel activity, to the central Ca2+ signal, and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the rele-vance for the whole organism and translation to humans.

scholarly journals New Aspects of Cellular Cholesterol Regulation on Blood Glucose Control—Review and Perspective on the Impact of Statin Medications on Metabolic Health

2017 ◽  
Vol 13 (02) ◽  
pp. 63
Author(s):  
Brian A Grice ◽  
Jeffrey S Elmendorf ◽  
◽  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Glucose Metabolism ◽  
Pancreatic Beta Cells ◽  
Insulin Action ◽  
Cholesterol Metabolism ◽  
Blood Glucose Control ◽  
Metabolic Health ◽  
Cellular Cholesterol ◽  
The Impact

Cholesterol is an essential component of cell membranes, and during the past several years, diabetes researchers have found that membrane cholesterol levels in adipocytes, skeletal muscle fibers and pancreatic beta cells influence insulin action and insulin secretion. Consequently, it is thought that dysregulated cell cholesterol homeostasis could represent a determinant of type 2 diabetes (T2D). Recent clinical findings compellingly add to this notion by finding increased T2D susceptibility in individuals with alterations in a variety of cholesterol metabolism genes. While it remains imperfectly understood how statins influence glucose metabolism, the fact that they display an influence on blood glucose levels and diabetes susceptibility seems to intensify the emerging importance of understanding cellular cholesterol in glucose metabolism. Taking this into account, this review first presents cell system and animal model findings that demonstrate the negative impact of cellular cholesterol accumulation or diminution on insulin action and insulin secretion. With this framework, a description of how changes in cholesterol metabolism genes are associated with T2D susceptibility will be presented. In addition, the connection between statins and T2D risk will be reviewed with expanded information on pitavastatin, a newer statin medication that displays actions favoring metabolic health.

Pharmacological Management of Diabetic Nephropathy

2020 ◽  
Vol 18 (2) ◽  
pp. 139-147 ◽  
Author(s):  
Vasilios Papademetriou ◽  
Sofia Alataki ◽  
Konstantinos Stavropoulos ◽  
Christodoulos Papadopoulos ◽  
Kostas Bakogiannis ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Renin Angiotensin System ◽  
Lipid Lowering ◽  
Pharmacological Management ◽  
Drug Classes ◽  
Sodium Glucose Cotransporter ◽  
Glucagon Like Peptide 1 ◽  
Lipid Lowering Agents ◽  
The Impact ◽  
Ras Inhibitors

Introduction:Diabetes mellitus (DM) is one of the most common diseases worldwide. Its adverse effects on several body organs, have made treatment of DM a priority. One of the most serious complications of DM is diabetic nephropathy (DN).Objective:The aim of this review is to critically discuss available data on the pharmacological management of DN.Objective:A comprehensive review of the literature was performed to identify studies assessing the impact of several drug classes on DN.Results:Several studies have been conducted in order to find a novel and effective treatment of DN. So far, the cornerstone therapy of DN consists of renin-angiotensin system (RAS) inhibitors, agents that decrease the synthesis of intrarenal angiotensin II or block its receptors. Their antiproteinuric and antihypertensive effects can not only decelerate the progress of DN but prevent its onset as well. Novel antidiabetic drugs, such as sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide- 1 receptor agonists (GLP-1 RA), are promising agents in the therapy of DN, due to their positive effect on renal and cardiovascular adverse events. From lipid-lowering agents, atorvastatin improves DN up to stage 3 and substantially reduces CVD.Conclusion:RAS inhibitors, SGLT-2i and GLP-1 agonists were found to be beneficial for the treatment of DN. Larger renal trials are needed in order to incorporate these drugs into the first line treatment of DN.

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

2010 ◽  
Vol 298 (3) ◽  
pp. R517-R531 ◽  
Author(s):  
Jenna L. Jewell ◽  
Eunjin Oh ◽  
Debbie C. Thurmond
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Uptake ◽  
Pancreatic Beta Cells ◽  
Insulin Action ◽  
Molecular Mechanisms ◽  
Receptor Protein ◽  
Peripheral Tissues ◽  
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.

scholarly journals Dietary Eriodictyol Alleviates Adiposity, Hepatic Steatosis, Insulin Resistance, and Inflammation in Diet-Induced Obese Mice

2019 ◽  
Vol 20 (5) ◽  
pp. 1227 ◽  
Author(s):  
Eun-Young Kwon ◽  
Myung-Sook Choi
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Molecular Mechanisms ◽  
Gastric Inhibitory Polypeptide ◽  
Normal Diet ◽  
Acid Oxidation ◽  
Obese Mice ◽  
Metabolic Disturbances ◽  
Glucagon Like Peptide 1 ◽  
Hepatic Fatty Acid Oxidation

The present study aimed to investigate the molecular mechanisms underlying the anti-obesity effect of flavonoid eriodictyol (ED) supplementation in mice fed with a high-fat diet (HFD). C57BL/6N mice were fed with normal diet (ND), HFD (40 kcal% fat), or HFD + 0.005% (w/w) ED for 16 weeks. In HFD-induced obese mice, dietary ED supplementation significantly alleviated dyslipidemia and adiposity by downregulating the expression of lipogenesis-related genes in white adipose tissue (WAT), while enhancing fecal lipid excretion. ED additionally improved hepatic steatosis and decreased the production of pro-inflammatory cytokines by downregulating the expression of hepatic enzymes and the genes involved in lipogenesis and upregulating the expression of hepatic fatty acid oxidation-related enzymes and genes. In addition, ED improved insulin resistance (IR) by suppressing hepatic gluconeogenesis, enhancing glucose utilization, and modulating the production and release of two incretin hormones, namely gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Taken together, the current findings indicated that ED can protect against diet-induced obesity and related metabolic disturbances, including dyslipidemia, inflammation, fatty liver disease, and IR in diet-induced obese mice.

Effects of secretagogues on insulin biosynthesis and secretion in polyamine-depleted pancreatic beta-cells

1996 ◽  
Vol 270 (4) ◽  
pp. C1105-C1110 ◽  
Author(s):  
A. Sjoholm
Keyword(s):  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Pancreatic Beta Cells ◽  
Insulin Biosynthesis ◽  
Insulin Production ◽  
Cationic Amino Acid ◽  
Kinase C ◽  
The Impact

To extend previous observations on the importance of polyamines for glucose-stimulated insulinogenesis (N. Welsh and A Sjoholm. Polyamines and insulin production in isolated mouse pancreatic islets. Biochem. J. 252: 701-707, 1988), the impact of other secretagogues on insulin secretion of islets partially depleted in polyamines by selective inhibitors of L-ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase was monitored. Glucose-sensitive, but not basal, insulin release was partially abolished in polyamine-deficient islets. Qualitatively similar impairments in insulin secretion were recorded when such islets were stimulated with nonglucidic nutrients (alpha-ketoisocaproic acid + L-glutamine), a cationic amino acid (L-arginine), activators of phospholipase C (carbachol) or protein kinase C (12-O-tetradecanoylphorbol 13-acetate), an adenosine 1', 5'-cyclic monophosphate-raising agent (forskolin), or a hypoglycemic sulfonylurea (glibenclamide). Additionally, glucose-responsive (pro)insulin biosynthesis was preferentially impeded in polyamine-deficient islets. It is concluded that polyamines act as permissive or stimulatory factors in insulin production and release. In addition, they seemingly do not act in an inhibitory manner on phospholipase C, protein kinase C, or Ca2+ flux into these islets, in contrast to reports in which insulinoma and other cells were used.

Differential effects of cytokines on long-term mitogenic and secretory responses of fetal rat pancreatic beta-cells

1992 ◽  
Vol 263 (1) ◽  
pp. C114-C120 ◽  
Author(s):  
A. Sjoholm
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Dna Synthesis ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Dependent Diabetes Mellitus ◽  
Camp Content ◽  
Fetal Rat ◽  
The Impact

It has been proposed that certain cytokines secreted by islet-infiltrating leukocytes may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in beta-cell destruction. In the present study, the impact of various cytokines on replication and long-term insulin secretion by pancreatic beta-cells was investigated. To this end, fetal rat pancreatic islets containing a high fraction of beta-cells were exposed in culture for 1-3 days to interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interferon-alpha (IFN-alpha), and interleukin-6 (IL-6) at different concentrations. It was found that IL-1 beta markedly decreased beta-cell DNA synthesis during the first day of exposure, an effect that vanished after 2 days and was turned into a potent and dose-dependent stimulation by 3 days of exposure. At this latter time point, IL-1 beta also amplified the mitogenicity of growth hormone (GH) and 16.7 mM glucose. In contrast, basal as well as glucose- and GH-stimulated insulin secretion was consistently suppressed by IL-1 beta from days 1-3. IL-1 beta also lowered the islet adenosine 3',5'-cyclic monophosphate (cAMP) content at all time points studied. However, addition of the stimulatory cAMP analogue Sp-diastereomer of adenosine 3',5'-cyclic monophosphothioate or pertussis toxin, which themselves enhanced DNA synthesis and insulin secretion, failed to prevent the inhibitory actions of IL-1 beta on these parameters, making it unlikely that a decrease in cAMP is an important event in transduction of the inhibitory effects of the cytokine.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Evaluation of Pancreatic and Extra Pancreatic Effects of Branched Amino Acids

2019 ◽  
Vol 26 (2) ◽  
pp. 199-209 ◽  
Author(s):  
Moath Alqaraleh ◽  
Violet Kasabri ◽  
Sundus H. Al alawi ◽  
Nihad Al-Othman
Keyword(s):  
Amino Acids ◽  
Insulin Secretion ◽  
Pancreatic Beta Cells ◽  
Β Cell ◽  
Min6 Cell ◽  
Glucagon Like Peptide 1 ◽  
Inhibitory Potential ◽  
Branched Chain ◽  
Branched Amino Acids ◽  
Dose Dependent

Abstract Background and aims: Leucine, Isoleucine, and Valine collectively known as Branched-chain amino acids (BCAAs), can be closely associated with metabolic dysregulates and with insulin resistance. We aimed to explore the role of BCAAs as potential treatment option for diabetes. Material and method: Bioassay the effect of BCAAs on MIN6 cell line on insulin secretion and pancreatic beta cells expansion, then were checked for inhibitory potential of pancreatic amylase, glucosidase and lipase as alternative approach for diabetes treatment. Results: BCAAs significantly enhance insulin secretion parallel to L-alanine efficacy. Furthermore, BCAAs obtain a dose dependent β-cell proliferation similar to glucagon-like peptide-1. Moreover, these acids could restore the secretory function of MIN6 β-cell despite stressful gluco-lipo-toxicity; separately or combined. Moreover, BCAAs exerted a dose dependent dual inhibition of amylase, glucosidase and lipase. Conclusions: Our current findings suggest that BCAAs supplementation may have a potential therapeutic effect against diabetes as insulin releasing agent and as specific inhibitors for both-amylase/α-amyloglucoside and lipase

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