The traditional view of insulin release machinery in pancreatic ? cells relies essentially on the influx of Ca2+ from the extracellular medium, eventually leading to insulin secretion. The mechanisms involved in Ca2+ mobilization from the major intracellular storage compartment, which in metazoan cells is represented by the endoplasmic reticulum (ER), remain less understood. The main intracellular Ca2+ release channels are Inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs). The role of RyR in the pathophysiology of type 2 diabetes mellitus (T2DM) has been recently clarified, demonstrating that RyR is crucial in glucose-stimulated insulin secretion. Instead, the exact role of ? cell IP3R in T2DM is poorly understood and remains a glaring knowledge gap in the metabolic field. Three isoforms of IP3R have been identified in mammals (IP3R1-3); their expression pattern is overlapping and functionally redundant. Pancreatic ? cells express all IP3R isoforms, and their levels are upregulated by chronic glucose stimulation. We hypothesize that IP3Rs play a key role in the pathophysiology of T2DM. In the present proposal, we will test this hypothesis in vivo, ex vivo, and in vitro using state-of-the-art models including both genetic and pharmacologic tools. Scientific premise and rationale: Genome-based studies in humans have demonstrated that gain-of-function mutations in genes encoding for IP3Rs are linked to perturbations in glucose homeostasis and enhanced susceptibility to diet-induced diabetes; similarly, genetic mapping identified IP3Rs as a risk factor for T2DM; however, these associations have not been functionally explained. Moreover, controversial findings have been reported when attempting to examine the actual role of IP3Rs in ? cells. We have robust preliminary data showing that IP3Rs are significantly upregulated in islets from T2DM patients compared with non-diabetic individuals; similarly, we detected a marked upregulation of IP3Rs in islets from mice fed high-fat diet (HFD) and db/db mice compared with non-diabetic littermates fed standard chow. On these grounds, we will explore the following specific aims:
Aim 1 will define in vivo the functional role of ? cell IP3Rs in the pathogenesis of T2DM, characterizing the metabolic phenotype of a novel, ? cell-specific, animal model, whereas Aim 2 will identify the molecular mechanisms linking IP3Rs to pancreatic ? cell (dys)function in T2DM, focusing on mitochondrial fitness and autophagy. Importantly, although the ER-mitochondrial interface is known to be a primary site for autophagosome formation, the exact role of IP3Rs in autophagy and mitophagy remain extremely debated. We will conduct assays in mice, in islets, and in ? cells; human islet studies are included to investigate potential similarities and differences between murine and human ? cells. We also designed rescue studies to verify if the proposed mechanisms are necessary and sufficient to mediate the effects of IP3Rs in ? cells. The planned experiments are highly relevant, with a high degree of conceptual and technical innovation; indeed, our studies will provide an unbiased assessment of the functional role of ? cell IP3Rs and define previously unrecognized pathways linking IP3Rs, mitochondrial dysfunction, and autophagy/mitophagy in the pathophysiology of T2DM.

Public Health Relevance

The prevalence of diabetes is dramatically increasing, affecting more than 7.5 billion people worldwide, with a significant economic burden, quantified in >$327 billion/year only in the United States, where 1 out of 3 adults has prediabetes. This is the first investigation into the mechanistic role of a major intracellular calcium release channel within the pancreatic beta cell in the pathogenesis of diabetes, using a novel and specific murine model. Our studies, relevant to public health and to the NIH mission to discover basic mechanisms underlying human disease, suggest an unprecedented role for this channel in the pathophysiology of diabetes via a pathway that involves the regulation of mitochondrial quality control.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Wang, Xujing
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
United States
Zip Code