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Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes.

ABSTRACT: Loss of first-phase insulin secretion is an early sign of developing type 2 diabetes (T2D). Ca2+ entry through voltage-gated L-type Ca2+ channels triggers exocytosis of insulin-containing granules in pancreatic ? cells and is required for the postprandial spike in insulin secretion. Using high-resolution microscopy, we have identified a subset of docked insulin granules in human ? cells and rat-derived clonal insulin 1 (INS1) cells for which localized Ca2+ influx triggers exocytosis with high probability and minimal latency. This immediately releasable pool (IRP) of granules, identified both structurally and functionally, was absent in ? cells from human T2D donors and in INS1 cells cultured in fatty acids that mimic the diabetic state. Upon arrival at the plasma membrane, IRP granules slowly associated with 15 to 20 L-type channels. We determined that recruitment depended on a direct interaction with the synaptic protein Munc13, because expression of the II-III loop of the channel, the C2 domain of Munc13-1, or of Munc13-1 with a mutated C2 domain all disrupted L-type channel clustering at granules and ablated fast exocytosis. Thus, rapid insulin secretion requires Munc13-mediated recruitment of L-type Ca2+ channels in close proximity to insulin granules. Loss of this organization underlies disturbed insulin secretion kinetics in T2D.

SUBMITTER: Gandasi NR

PROVIDER: S-EPMC5451232 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes.

Gandasi Nikhil R NR Yin Peng P Riz Michela M Chibalina Margarita V MV Cortese Giuliana G Lund Per-Eric PE Matveev Victor V Rorsman Patrik P Sherman Arthur A Pedersen Morten G MG Barg Sebastian S

The Journal of clinical investigation 20170508 6

Loss of first-phase insulin secretion is an early sign of developing type 2 diabetes (T2D). Ca2+ entry through voltage-gated L-type Ca2+ channels triggers exocytosis of insulin-containing granules in pancreatic β cells and is required for the postprandial spike in insulin secretion. Using high-resolution microscopy, we have identified a subset of docked insulin granules in human β cells and rat-derived clonal insulin 1 (INS1) cells for which localized Ca2+ influx triggers exocytosis with high pr ...[more]

PMID: 28481223

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Project description:TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In individuals with type 1 diabetes, these variants are associated with a higher C-peptide AUC, a lower glucose AUC during an OGTT, single autoantibody positivity near diagnosis, particularly in individuals older than 12 years of age, and a lower frequency of type 1 diabetes-associated HLA genotypes. Based on initial observations from clinical cohorts, we tested the hypothesis that type 2 diabetes-predisposing TCF7L2 genetic variants are associated with a higher percentage of residual insulin-containing cells (ICI%) in pancreases of donors with type 1 diabetes, by examining genomic data and pancreatic tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) programme. We analysed nPOD donors with type 1 diabetes (n=110; mean±SD age at type 1 diabetes onset 12.2±7.9 years, mean±SD diabetes duration 15.3±13.7 years, 53% male, 80% non-Hispanic White, 12.7% African American, 7.3% Hispanic) using data pertaining to residual beta cell number; quantified islets containing insulin-positive beta cells in pancreatic tissue sections; and expressed these values as a percentage of the total number of islets from each donor (mean ± SD ICI% 9.8±21.5, range 0-92.2). Donors with a high ICI% (≥5) (n=30; 27%) vs a low ICI% (<5) (n=80; 73%) were older at onset (15.3±6.9 vs 11.1±8 years, p=0.013), had a shorter diabetes duration at donor tissue procurement (7.0±7.4 vs 18.5±14.3 years, p<0.001), a higher African ancestry score (0.2±0.3 vs 0.1±0.2, p=0.043) and a lower European ancestry score (0.7±0.3 vs 0.9±0.3, p=0.023). After adjustment for age of onset (p=0.105), diabetes duration (p<0.001), BMI z score (p=0.145), sex (p=0.351) and African American race (p=0.053), donors with the TCF7L2 rs7903146 T allele (TC or TT, 45.5%) were 2.93 times (95% CI 1.02, 8.47) more likely to have a high ICI% than those without it (CC) (p=0.047). Overall, these data support the presence of a type 1 diabetes endotype associated with a genetic factor that predisposes to type 2 diabetes, with donors in this category exhibiting less severe beta cell loss. It is possible that in these individuals the disease pathogenesis may include mechanisms associated with type 2 diabetes and thus this may provide an explanation for the poor response to immunotherapies to prevent type 1 diabetes or its progression in a subset of individuals. If so, strategies that target both type 1 diabetes and type 2 diabetes-associated factors when they are present may increase the success of prevention and treatment in these individuals.

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Dataset Information

Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes.

Publications

Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes.

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