scholarly journals A glucose-dependent spatial patterning of exocytosis in human β-cells is disrupted in type 2 diabetes

2019 ◽  
Author(s):  
Jianyang Fu ◽  
John Maringa Githaka ◽  
Xiaoqing Dai ◽  
Gregory Plummer ◽  
Kunimasa Suzuki ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Hot Spots ◽  
Secretory Granules ◽  
Relative Proportion ◽  
List Type ◽  
Spatial Patterning ◽  
Β Cells ◽  
C Terminus ◽  
Insulin Exocytosis

SUMMARYImpaired insulin secretion in type 2 diabetes (T2D) is linked to reduced insulin granule docking, disorganization of the exocytotic site, and an impaired glucose-dependent facilitation of insulin exocytosis. We show in β-cells from 80 human donors that the glucose-dependent amplification of exocytosis is disrupted in T2D. Spatial analyses of granule fusion events, visualized by total internal reflection fluorescence (TIRF) microscopy, demonstrate that these are non-random across the surface of β-cells from donors with no diabetes (ND). The compartmentalization of events occurs within regions defined by concurrent or recent membrane-resident secretory granules. This organization, and the number of membrane-associated granules, is glucose-dependent and notably impaired in T2D β-cells. Mechanistically, multi-channel Kv2.1 clusters contribute to maintaining the density of membrane-resident granules and the number of fusion ‘hot spots’, while SUMOylation sites at the channel N-(K145) and C-terminus (K470) determine the relative proportion of fusion events occurring within these regions. Thus, a glucose-dependent compartmentalization of fusion, regulated in part by a structural role for Kv2.1, is disrupted in β-cells from donors with type 2 diabetes.HIGHLIGHTSExocytosis of secretory granules is non-random across the surface of human β-cells, and this organization is disrupted in type 2 diabetes.Increasing glucose facilitates the spatial compartmentalization of fusion, independent of an overall increase in event frequency.Compartmentalized ‘hot spots’ occur at sites marked by membrane-associated granules, the density of which is regulated in part by a clustered K+ channel (Kv2.1).SUMOylation status of the channel controls the proportion of events that occur within these local regions.

scholarly journals Microtubules and Gαo-signaling modulate the preferential secretion of young insulin secretory granules in islet β cells via independent pathways

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0241939
Author(s):  
Ruiying Hu ◽  
Xiaodong Zhu ◽  
Mingyang Yuan ◽  
Kung-Hsien Ho ◽  
Irina Kaverina ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Plasma Membrane ◽  
Secretory Granules ◽  
Additive Effects ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulation ◽  
High Insulin ◽  
Glucose Stimulated Insulin Secretion

For sustainable function, each pancreatic islet β cell maintains thousands of insulin secretory granules (SGs) at all times. Glucose stimulation induces the secretion of a small portion of these SGs and simultaneously boosts SG biosynthesis to sustain this stock. The failure of these processes, often induced by sustained high-insulin output, results in type 2 diabetes. Intriguingly, young insulin SGs are more likely secreted during glucose-stimulated insulin secretion (GSIS) for unknown reasons, while older SGs tend to lose releasability and be degraded. Here, we examine the roles of microtubule (MT) and Gαo-signaling in regulating the preferential secretion of young versus old SGs. We show that both MT-destabilization and Gαo inactivation results in more SGs localization near plasma membrane (PM) despite higher levels of GSIS and reduced SG biosynthesis. Intriguingly, MT-destabilization or Gαo-inactivation results in higher secretion probabilities of older SGs, while combining both having additive effects on boosting GSIS. Lastly, Gαo inactivation does not detectably destabilize the β-cell MT network. These findings suggest that Gαo and MT can modulate the preferential release of younger insulin SGs via largely parallel pathways.

scholarly journals A glucose-dependent spatial patterning of exocytosis in human β cells is disrupted in type 2 diabetes

JCI Insight ◽  
2019 ◽  
Vol 4 (12) ◽  
Author(s):  
Jianyang Fu ◽  
John Maringa Githaka ◽  
Xiaoqing Dai ◽  
Gregory Plummer ◽  
Kunimasa Suzuki ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Spatial Patterning ◽  
Β Cells

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 Inside the Insulin Secretory Granule

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 515
Author(s):  
Mark Germanos ◽  
Andy Gao ◽  
Matthew Taper ◽  
Belinda Yau ◽  
Melkam A. Kebede
Keyword(s):  
Secretory Granules ◽  
Β Cells ◽  
Β Cell ◽  
Proinsulin Processing ◽  
Membrane Bound ◽  
Golgi Network ◽  
Insulin Secretory Granule ◽  
Insulin Storage ◽  
Cellular Stimulation

The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. Insulin is synthesized in the endoplasmic reticulum (ER) as a biologically inactive precursor, proinsulin, along with several other proteins that will also become members of the insulin SG. Their coordinated synthesis enables synchronized transit through the ER and Golgi apparatus for congregation at the trans-Golgi network, the initiating site of SG biogenesis. Here, proinsulin and its constituents enter the SG where conditions are optimized for proinsulin processing into insulin and subsequent insulin storage. A healthy β-cell is continually generating SGs to supply insulin in vast excess to what is secreted. Conversely, in type 2 diabetes (T2D), the inability of failing β-cells to secrete may be due to the limited biosynthesis of new insulin. Factors that drive the formation and maturation of SGs and thus the production of insulin are therefore critical for systemic glucose control. Here, we detail the formative hours of the insulin SG from the luminal perspective. We do this by mapping the journey of individual members of the SG as they contribute to its genesis.

scholarly journals Antibodies Against the C-Terminus of ApoA-1 Are Inversely Associated with Cholesterol Efflux Capacity and HDL Metabolism in Subjects with and without Type 2 Diabetes Mellitus

2019 ◽  
Vol 20 (3) ◽  
pp. 732 ◽  
Author(s):  
Robin Dullaart ◽  
Sabrina Pagano ◽  
Frank Perton ◽  
Nicolas Vuilleumier
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Apolipoprotein B ◽  
Cholesterol Efflux ◽  
Hdl Cholesterol ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cholesterol Efflux Capacity ◽  
C Terminus

Background: We determined relationships of cholesterol efflux capacity (CEC), plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) with anti-c-terminus apoA-1 (Ac-terAA1) and anti-apolipoprotein (apo)-1 (AAA1) autoantibodies in subjects with and without Type 2 diabetes mellitus (T2D). Methods: In 75 T2D subjects and 75 nondiabetic subjects, Ac-terAA1 and AAA1 plasma levels were measured by enzyme-linked immunosorbent assay. CEC was measured as [3H]-cholesterol efflux from human cultured fibroblasts to diluted individual subject plasma. Plasma EST and CET were assayed by isotope methods. Results: Ac-terAA1 and AAA1 levels and were similar between T2D and control subjects. Univariate regression analysis (n = 150) demonstrated that Ac-terAA1 levels were inversely correlated with CEC, EST, CET, total cholesterol, non-HDL cholesterol, triglycerides and apolipoprotein B, (p < 0.05 to p < 0.01), but not with glucose and HbA1c. In separate multivariable linear regression models, CEC, EST and CET were inversely associated with Ac-terAA1 levels independently of age, sex, T2D and drug use (β = −0.186, p = 0.026; β = −0.261, p < 0.001; and β = −0.321, p < 0.001; respectively). These associations were lost after additional adjustment for non-HDL cholesterol and triglycerides. No associations were observed for AAA1. Conclusions: CEC, plasma EST and CET are inversely associated with Ac-terAA1 autoantibodies, conceivably attributable to an inverse relationship of these autoantibodies with apolipoprotein B-containing lipoproteins.

Genes of Type 2 Diabetes in β Cells

2006 ◽  
Vol 35 (2) ◽  
pp. 357-369 ◽  
Author(s):  
Mirko Trajkovski ◽  
Hassan Mziaut ◽  
Peter E. Schwarz ◽  
Michele Solimena
Keyword(s):  
Type 2 Diabetes ◽  
Β Cells

scholarly journals Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation

2004 ◽  
Vol 377 (3) ◽  
pp. 709-716 ◽  
Author(s):  
Emma T. A. S. JAIKARAN ◽  
Melanie R. NILSSON ◽  
Anne CLARK
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Fibrils ◽  
Secretory Granules ◽  
Pancreatic Beta Cell ◽  
Islet Amyloid Polypeptide ◽  
Fibril Formation ◽  
Islet Amyloid ◽  
Β Sheet

Islet amyloid polypeptide (IAPP), or ‘amylin’, is co-stored with insulin in secretory granules of pancreatic islet β-cells. In Type 2 diabetes, IAPP converts into a β-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Granule components, including insulin, inhibit spontaneous IAPP fibril formation in vitro. To determine the mechanism of this inhibition, molecular interactions of insulin with human IAPP (hIAPP), rat IAPP (rIAPP) and other peptides were examined using surface plasmon resonance (BIAcore), CD and transmission electron microscopy (EM). hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. rIAPP and insulin, but not pro-insulin, bound to hIAPP. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In the presence of insulin, hIAPP did not spontaneously develop β-sheet secondary structure or form fibrils. Insulin interacted with pre-formed IAPP fibrils in a regular repeating pattern, as demonstrated by immunoEM, suggesting that the binding sites for insulin remain exposed in hIAPP fibrils. Since rIAPP and hIAPP form complexes with insulin (and each other), this could explain the lack of amyloid fibrils in transgenic mice expressing hIAPP. It is likely that IAPP fibrillogenesis is inhibited in secretory granules (where the hIAPP concentration is in the millimolar range) by heteromolecular complex formation with insulin. Alterations in the proportions of insulin and IAPP in granules could disrupt the stability of the peptide. The increase in the proportion of unprocessed pro-insulin produced in Type 2 diabetes could be a major factor in destabilization of hIAPP and induction of fibril formation.

scholarly journals Increased vimentin in human α- and β-cells in type 2 diabetes

2017 ◽  
Vol 233 (3) ◽  
pp. 217-227 ◽  
Author(s):  
Maaike M Roefs ◽  
Françoise Carlotti ◽  
Katherine Jones ◽  
Hannah Wills ◽  
Alexander Hamilton ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Epithelial To Mesenchymal Transition ◽  
Islet Cells ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Mesenchymal Transition ◽  
Cell Expression

Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (β-cells) in the human ND group (1.43% total α-cells, 0.98% total β-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells; P < 0.05). Vimentin-positive β-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive β-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and β-cell dysfunction in T2DM.

scholarly journals Lack of association between UBE2E2 gene polymorphism (rs7612463) and type 2 diabetes mellitus in a Saudi population.

2014 ◽  
Vol 61 (4) ◽  
Author(s):  
Khalid Khalaf Alharbi ◽  
Imran Ali Khan ◽  
Yazeed A Al-Sheikh ◽  
Fawiziah Khalaf Alharbi ◽  
Fahad Khalaf Alharbi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Case Control Study ◽  
Saudi Population ◽  
Β Cells ◽  
Pcr Rflp ◽  
Ubiquitin Conjugating Enzyme ◽  
Control Study

The ubiquitin-conjugating enzyme E2E 2 (UBE2E2) gene plays an important role in insulin synthe-sis and secretion under conditions in which stress to the endoplasmic reticu-lum is increased in β-cells. In this case-control study, we have selected rs7612462 polymorphism within UBE2E2 gene to identify in a Saudi population the type 2 diabetes mellitus (T2DM) subjects. In total, 376 subjects with T2DM and 380 controls were enrolled in this study. We have collected 5 mL of peripheral blood from each participant for biochemical and molecular analyses. PCR-RFLP was used to generate genotypes at rs7612462 in all of the study subjects. Clinical data and anthropometric measurements of the patients were significantly different from those of the controls (p

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