NFIA regulates granule recruitment and exocytosis in the adult pancreas

SummaryAfter food ingestion, pancreatic cells secrete zymogen and hormone-containing granules to precisely control digestion and blood glucose levels. Identifying regulators of this process is paramount to combatting multiple pancreatic diseases. Here we show that pancreatic deletion of the transcription factor nuclear factor IA (NFIA) leads to hyperglycemia, hypoinsulinemia, and hypolipidemia. Surprisingly, insulin and digestive enzymes are produced in the absence of NFIA, however, they are not secreted properly and instead accumulate inside pancreatic cells. In NFIA-deficient mice we saw a reduction of insulin granules in the ready releasable pool and the first-phase insulin response was impaired. We found that NFIA binds to and activates Rab39b, a Rab GTPase critical for exocytosis. Re-expression of Rab39b in NFIA knockout islets restored glucose-stimulated insulin secretion. In sum, the NFIA-Rab39b axis regulates pancreatic physiology through granule recruitment and docking, linking NFIA to a new process with potential effects in diabetes, pancreatitis, and lipid disorders.

Class II HLA Genotype Association With First-Phase Insulin Response Is Explained by Islet Autoantibodies

Context A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both. Objective To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR. Design, Setting, Participants A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. Main Outcome Measure The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR. Results A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P < 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P < 0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P < 0.0001 and P = 0.0013, respectively). Conclusions The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.

Transgenerational metabolic outcomes associated with uteroplacental insufficiency

Intrauterine growth restriction increases adult metabolic disease risk with evidence to suggest that suboptimal conditions in utero can have transgenerational effects. We determined whether impaired glucose tolerance, reduced insulin secretion, and pancreatic deficits are evident in second-generation (F2) male and female offspring from growth-restricted mothers, in a rat model of uteroplacental insufficiency. Late gestation uteroplacental insufficiency was induced by bilateral uterine vessel ligation (restricted) or sham surgery (control) in Wistar-Kyoto rats. First-generation (F1) control and restricted females were mated with normal males and F2 offspring studied at postnatal day 35 and at 6 and 12 months. F2 glucose tolerance, insulin secretion, and sensitivity were assessed at 6 and 12 months and pancreatic morphology was quantified at all study ages. At 6 months, F2 restricted male offspring exhibited blunted first-phase insulin response (−35%), which was associated with reduced pancreatic β-cell mass (−29%). By contrast, F2 restricted females had increased β-cell mass despite reduced first-phase insulin response (−38%). This was not associated with any changes in plasma estradiol concentrations. Regardless of maternal birth weight, F2 control and restricted males had reduced homeostatic model assessment of insulin resistance and elevated plasma triglyceride concentrations at 6 months and reduced whole-body insulin sensitivity at 6 and 12 months compared with females. We report that low maternal birth weight is associated with reduced first-phase insulin response and gender-specific differences in pancreatic morphology in the F2. Further studies will define the mode(s) of disease transmission, including direct insults to developing gametes, adverse maternal responses to pregnancy, or inherited mechanisms.