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A glucose-dependent spatial patterning of exocytosis in human ?-cells is disrupted in type 2 diabetes.

ABSTRACT: Impaired 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 ?-cells from 80 human donors that the glucose-dependent amplification of exocytosis is disrupted in T2D. Spatial analyses of granule fusion, visualized by total internal reflection fluorescence (TIRF) microscopy in 24 of these donors, demonstrate that these are non-random across the surface of ?-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 ?-cells. Mechanistically, multi-channel Kv2.1 clusters contribute to maintaining the density of membrane-resident granules and the number of fusion 'hotspots', 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 ?-cells from donors with type 2 diabetes.

SUBMITTER: Fu J

PROVIDER: S-EPMC6629118 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Fu Jianyang J Githaka John Maringa JM Dai Xiaoqing X Plummer Gregory G Suzuki Kunimasa K Spigelman Aliya F AF Bautista Austin A Kim Ryekjang R Greitzer-Antes Dafna D Fox Jocelyn E Manning JEM Gaisano Herbert Y HY MacDonald Patrick E PE

JCI insight 20190514

Impaired 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, visualized by total internal reflection fluorescence (TIRF) microscopy in 24 of these donors, demonstrate that these are non-random across t ...[more]

PMID: 31085831

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Project description:ContextIn healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP's insulinotropic effect is impaired and effects on bone may be reduced.ObjectiveTo investigate GIP's effect on bone biomarkers in patients with T2D.DesignRandomized, double-blinded, crossover study investigating 6 interventions.PatientsTwelve male patients with T2D.InterventionsA primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with "insulin-induced hypoglycemia" (PG lowered to 3 mmol/L), "fasting hyperglycemia" (mean PG ~8 mmol/L), or "aggravated hyperglycemia" (mean PG ~12 mmol/L).Main outcome measuresBone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH.ResultsOn days with insulin-induced hypoglycemia, CTX was suppressed by up to 40 ± 15% during GIP administration compared with 12 ± 11% during placebo infusion (P < 0.0001). On days with fasting hyperglycemia, CTX was suppressed by up to 36 ± 15% during GIP administration, compared with 0 ± 9% during placebo infusion (P < 0.0001). On days with aggravated hyperglycemia, CTX was suppressed by up to 47 ± 23% during GIP administration compared with 10 ± 9% during placebo infusion (P = 0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes.ConclusionsShort-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients.PrécisShort-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.

Dataset Information

A glucose-dependent spatial patterning of exocytosis in human ?-cells is disrupted in type 2 diabetes.

Publications

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

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