Targeted Genetic Inactivation of N-Acetylglucosaminyltransferase-IVa Impairs Insulin Secretion from Pancreatic β Cells and Evokes Type 2 Diabetes

2010 ◽  
pp. 205-222 ◽  
Author(s):  
Kazuaki Ohtsubo
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Genetic Inactivation

scholarly journals Teucrium polium: Potential Drug Source for Type 2 Diabetes Mellitus

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 128
Author(s):  
Yaser Albadr ◽  
Andrew Crowe ◽  
Rima Caccetta
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Teucrium Polium

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.

scholarly journals Angiotensin(1–7) activates MAS-1 and upregulates CFTR to promote insulin secretion in pancreatic β-cells: the association with type 2 diabetes

2021 ◽  
Author(s):  
Xue-Lian Zhang ◽  
Xinyi Zhao ◽  
Yong Wu ◽  
Wen-qing Huang ◽  
Jun-jiang Chen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Human Blood ◽  
Human Subjects ◽  
Blood Levels ◽  
Intracellular Camp ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Stimulated Insulin Secretion

Objective: The beneficial effect of angiotensin(1–7), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how angiotensin(1–7) or MAS-1 affects insulin secretion remains elusive and whether endogenous level of angiotensin(1–7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of CFTR, a cAMP-activated Cl- channel, in regulation of insulin secretion. Here, we tested possible involvement of CFTR in mediating angiotensin(1–7)’s effect on insulin secretion and measured the level of angiotensin(1–7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes. Methods: Angiotensin(1–7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, western blotting as well as insulin ELISA in a pancreatic β cell line, RINm5F. Human blood samples were collected from 333 individuals with (n=197) and without (n=136) type 2 diabetes. Angiotensin(1–7), MAS-1 and CFTR level in the human blood were determined by ELISA. Results: In RINm5F cells, angiotensin(1–7) induced intracellular cAMP increase, CREB activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not angiotensin(1–7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2-diabetic but not non-diabetic subjects. Conclusion: These results suggested MAS-1 and CFTR as key players in mediating angiotensin(1–7)-promoted insulin secretion in pancreatic β cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.

Novel roles of SUMO in pancreatic β-cells: thinking outside the nucleus

2012 ◽  
Vol 90 (6) ◽  
pp. 765-770 ◽  
Author(s):  
Jocelyn E. Manning Fox ◽  
Catherine Hajmrle ◽  
Patrick E. MacDonald
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Endocrine Pancreas ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cellular Processes ◽  
Wide Range ◽  
Cell Gene

The endocrine pancreas is critically important in the regulation of energy metabolism, with defective insulin secretion from pancreatic islet β-cells a major contributing factor to the development of type 2 diabetes. Small ubiquitin-like modifier (SUMO) proteins have been demonstrated to covalently modify a wide range of target proteins, mediating a broad range of cellular processes. While the effects of SUMOylation on β-cell gene transcription have been previously reviewed, recent reports indicate roles for SUMO outside of the nucleus. In this review we shall focus on the reported non-nuclear roles of SUMOylation in the regulation of β-cells, including SUMOylation as a novel signaling pathway in the acute regulation of insulin secretion.

scholarly journals Protein Phosphatase 1 (PP-1)-Dependent Inhibition of Insulin Secretion by Leptin in INS-1 Pancreatic β-Cells and Human Pancreatic Islets

Endocrinology ◽  
2011 ◽  
Vol 152 (5) ◽  
pp. 1800-1808 ◽  
Author(s):  
Peter Kuehnen ◽  
Katharina Laubner ◽  
Klemens Raile ◽  
Christof Schöfl ◽  
Franz Jakob ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Enzyme Activity ◽  
Insulin Secretion ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Β Cells ◽  
Pancreatic Β Cells

Leptin inhibits insulin secretion from pancreatic β-cells, and in turn, insulin stimulates leptin biosynthesis and secretion from adipose tissue. Dysfunction of this adipoinsular feedback loop has been proposed to be involved in the development of hyperinsulinemia and type 2 diabetes mellitus. At the molecular level, leptin acts through various pathways, which in combination confer inhibitory effects on insulin biosynthesis and secretion. The aim of this study was to identify molecular mechanisms of leptin action on insulin secretion in pancreatic β-cells. To identify novel leptin-regulated genes, we performed subtraction PCR in INS-1 β-cells. Regulated expression of identified genes was confirmed by RT-PCR and Northern and Western blotting. Furthermore, functional impact on β-cell function was characterized by insulin-secretion assays, intracellular Ca2+ concentration measurements, and enzyme activity assays. PP-1α, the catalytic subunit of protein phosphatase 1 (PP-1), was identified as a novel gene down-regulated by leptin in INS-1 pancreatic β-cells. Expression of PP-1α was verified in human pancreatic sections. PP-1α mRNA and protein expression is down-regulated by leptin, which culminates in reduction of PP-1 enzyme activity in β-cells. In addition, glucose-induced insulin secretion was inhibited by nuclear inhibitor of PP-1 and calyculin A, which was in part mediated by a reduction of PP-1-dependent calcium influx into INS-1 β-cells. These results identify a novel molecular pathway by which leptin confers inhibitory action on insulin secretion, and impaired PP-1 inhibition by leptin may be involved in dysfunction of the adipoinsular axis during the development of hyperinsulinemia and type 2 diabetes mellitus.

Abstract 34: Apolipoprotein A-I Increases Insulin Secretion from β-cells via a Protein Kinase A Dependent Mechanism

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Blake J Cochran ◽  
Kerry-Anne Rye
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Adenyl Cyclase ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Kinase A ◽  
Dependent Mechanism

Introduction: The progression to hyperglycaemia in type 2 diabetes is marked by β-cell insulin secretory dysfunction and cell loss. We have previously demonstrated that apolipoprotein (apo) A-I, the major protein constituent of high density lipoproteins (HDL) increases insulin expression and secretion from β-cells. Clinical data also suggests that pharmacological elevation of HDL levels is associated with improved glycemic control in patients with type 2 diabetes. With the current interest in HDL raising therapeutics, defining the mechanism by which apoA-I acts on insulin secretion is of importance. Objective: To elucidate the cell signalling events responsible for increasing insulin secretion from pancreatic β-cells treated with lipid-free apoA-I. Methods: Ins-1E (rat insulinoma) cells were pre-treated for 30 min with the Protein kinase A (PKA) specific inhibitor H89 (20 μM), soluble and transmembrane adenyl cyclase specific inhibitors (KH7, 30 μM and 2’5’ dideoxyadenosine, 50 μM, respectively) or vehicle control, then incubated for 1 h with lipid-free apoA-I (final concentration 1 mg/mL) under both basal (2.8 mM) and high (25 mM) glucose conditions. The insulin concentration in the culture supernatants was determined by radioimmunoassay and the cells were either lysed for protein analysis by western blotting or treated with 0.1 M HCl for determining cAMP by enzyme immunoassay. Results: Incubation of Ins-1E cells with apoA-I increased insulin secretion up to 3-fold. This increase was no longer apparent when the cells were pre-treated with H89. Incubation with apoA-I increased cAMP accumulation in Ins-1E cells 2.5-fold. This increase was totally inhibited when the cells were pre-incubated with 2’5’ dideoxyadenosine but not by KH7, indicating that transmembrane adenyl cyclase(s) are responsible for this response. ApoA-I also activated the small GTPase Cdc42, which may link cell surface apoA-I receptors with transmembrane adenyl cyclases. Conclusion: ApoA-I increases insulin secretion from pancreatic β-cells via a PKA-dependent mechanism involving transmembrane, but not soluble, adenyl cyclases and possibly Cdc42. This provides a possible explanation of the clinical observations that increased HDL may be beneficial in type 2 diabetes.

scholarly journals Circulating LncRNAs Analysis in Patients with Type 2 Diabetes Reveals Novel Genes Influencing Glucose Metabolism and Islet β-Cell Function

2018 ◽  
Vol 46 (1) ◽  
pp. 335-350 ◽  
Author(s):  
Yuting Ruan ◽  
Nie Lin ◽  
Qiang Ma ◽  
Rongping Chen ◽  
Zhen Zhang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Diabetic Patients ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Min6 Cells ◽  
Β Cell Function

Background/Aims: The islet is an important endocrine organ to secrete insulin to regulate the metabolism of glucose and maintain the stability of blood glucose. Long noncoding RNAs (lncRNAs) are involved in a variety of biological functions and play key roles in many diseases, including type 2 diabetes (T2D). The aim of this study was to determine whether lncRNA-p3134 is associated with glucose metabolism and insulin signaling in pancreatic β cells. Methods: LncRNA microarray technology was used to identify the differentially expressed circulating lncRNAs in T2D patients. RT-PCR analyses were performed to determine the expression of lncRNA-p3134 in 30 pairs of diabetic and non-diabetic patients. The correlation of lncRNA-p3134 to clinical data from T2D patients was analyzed. LncRNA-p3134 was overexpressed in Min6 cells and db/db mice by adenovirus-mediated technology. CCK-8, TUNEL, Western blot, glucose-stimulated insulin secretion (GSIS), ELISAs and immunochemistry were performed to determine the effect of lncRNA-p3134 on proliferation, apoptosis and insulin secretion both in vitro and vivo. Results: The circulating level of lncRNA-p3134 was higher in diabetic patients than in non-diabetic controls and was correlated with fasting blood glucose and HOMA-β levels. The lncRNA-p3134 had risen by 4 times in serum exosomes but nearly unchanged in exosome-free samples. The secretion of lncRNA-p3134 was dynamically modulated by glucose in both Min6 cells and isolated mouse islet cells. LncRNA-p3134 positively regulate GSIS through promoting of key regulators (Pdx-1, MafA, GLUT2 and Tcf7l2) in β cells. In addition, the overexpression of lncRNA-p3134 resulted in a decreased apoptosis ratio and partially reversed the glucotoxicity effects on GSIS function in Min6 cells. The restoration of insulin synthesis and secretion the increase of the insulin positive cells areas by upregulation of lncRNA-p3134 in db/db mice confirmed the compensatory role of lncRNA-p3134 to preserve β-cell function. Furthermore, a protective effect of lncRNA-p3134 on GSIS by positive modulation of PI3K/Akt/mTOR signaling was also confirmed. After blocking the PI3K/AKT signals with their specific inhibitor, the effect of overexpressed lncRNA-p3134 on insulin secretion was obviously attenuated. Conclusion: Taken together, the results of this study provide new insights into lncRNA-p3134 regulation in pancreatic β cells and provide a better understanding of novel mechanism of glucose homeostasis.

scholarly journals Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

2021 ◽  
Vol 22 (3) ◽  
pp. 1059
Author(s):  
Bodo C. Melnik
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Dopaminergic Neurons ◽  
Vagal Nerve ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
The Brain

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D.

scholarly journals RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes

2021 ◽  
Author(s):  
John T Walker ◽  
Diane C Saunders ◽  
Vivek Rai ◽  
Chunhua Dai ◽  
Peter Orchard ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Association Studies ◽  
Critical Role ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Β Cells ◽  
Β Cell ◽  
Gene Regulatory

A hallmark of type 2 diabetes (T2D), a major cause of world-wide morbidity and mortality, is dysfunction of insulin-producing pancreatic islet β cells. T2D genome-wide association studies (GWAS) have identified hundreds of signals, mostly in the non-coding genome and overlapping β cell regulatory elements, but translating these into biological mechanisms has been challenging. To identify early disease-driving events, we performed single cell spatial proteomics, sorted cell transcriptomics, and assessed islet physiology on pancreatic tissue from short-duration T2D and control donors. Here, through integrative analyses of these diverse modalities, we show that multiple gene regulatory modules are associated with early-stage T2D β cell-intrinsic defects. One notable example is the transcription factor RFX6, which we show is a highly connected β cell hub gene that is reduced in T2D and governs a gene regulatory network associated with insulin secretion defects and T2D GWAS variants. We validated the critical role of RFX6 in β cells through direct perturbation in primary human islets followed by physiological and single nucleus multiome profiling, which showed reduced dynamic insulin secretion and large-scale changes in the β cell transcriptome and chromatin accessibility landscape. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs, and individuals and thus we anticipate this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits with GWAS data.

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