Research

Motivation 

Type 2 diabetes affects approximately 10% of the U.S. adult population, with an additional 84.1 million people living with prediabetes. The proper functioning of pancreatic islets is crucial for maintaining whole-body glucose homeostasis. When the β-cells within these islets fail to release sufficient insulin, the risk of developing Type 2 diabetes significantly increases. Impairments in cellular processes that reduce insulin secretion are due to fewer fusion-competent insulin granules reaching the plasma membrane. This key event occurs before the clinical onset of Type 2 diabetes. Therefore, understanding how β-cells modulate and reduce the fusion of insulin granules in healthy and diseased states is essential for identifying mechanisms underlying insulin secretion. This knowledge could be leveraged to develop new treatments and preventive strategies for Type 2 diabetes. Our research focuses on uncovering these mechanisms, particularly how they are altered by obesity and the pathophysiology of Type 2 diabetes, with the goal of enhancing insulin secretion as a therapeutic approach.

Adipose tissues play a critical role in maintaining lipid and glucose balance. Increased adiposity, which contributes to obesity, is strongly linked to the development of Type 2 diabetes. Consequently, identifying and characterizing the signaling pathways that reduce adiposity is essential for lowering the risk of Type 2 diabetes.

Project 1: The role of the Tomosyn family of proteins in regulating insulin granule fusion complexes to control insulin secretion and glucose homeostasis

​Left, Tomosyn-1 is expressed in human islet β-cells. Right (Top) Primary domain architecture of Tomosyn-1. VLD is a vamp-like domain. Right (Bottom) Working Model. Tomosyn-1 prevents the fusion of insulin granules to the PM, reducing insulin secretion. We propose that it prevents the formation of the SNARE complexes (i.e., binding of syntaxins to Vamp2/8 and Snap25) required for the fusion of insulin granules. Tomosyn-1 exists in an active or inactive state, depending on whether it is unphosphorylated or phosphorylated. In an unphosphorylated state, Tomosyn-1 inhibits the formation of the SNARE complex, whereas phosphorylation of Tomosyn-1 decreases its inhibitory function. We propose that phosphorylated Tomosyn-1 1) undergoes protein degradation via E3 ubiquitin ligase Hrd1, leading to an increase in insulin secretion, and 2) reduces binding with the SNARE protein, facilitating SNARE-mediated insulin secretion.

We identified a mutation in the Tomosyn-2 gene and demonstrated that it is causative for the diabetogenic phenotype observed in certain inbred strains of mice. This discovery, along with the characterization of Tomosyn-2, was published in PLOS Genetics, Diabetes, and The Journal of Biological Chemistry. Our work garnered significant attention and was featured in over 50 national and international media outlets, including Science Daily and Associated Press. Currently, we are investigating how Tomosyn-2 inhibits insulin secretion, leading to impaired glucose tolerance in both healthy and pathophysiological states of Type 2 diabetes.

A related family member, Tomosyn-1, is expressed in β-cells and is critical in regulating insulin secretion and overall glucose metabolism. We demonstrated that the insulin granule membrane protein synaptotagmin-9 (Syt9) interacts with Tomosyn-1 and the plasma membrane protein syntaxin1A to form an inhibitory complex that modulates insulin secretion. This work was published in the FASEB Journal. Our lab has developed Tomosyn-1^Floxed and Tomosyn-2^Floxed mouse models to specifically investigate the role of these proteins in β-cells and their impact on whole-body glucose homeostasis in both healthy and the pathophysiology of obesity and Type 2 diabetes. Unraveling the role of Tomosyn proteins will offer new insights into the regulation of insulin secretion and how insulin secretion is compromised in Type 2 diabetes.

Project 2: Autocrine/paracrine inhibitory feedback regulation of insulin secretion in β-cells

Left, C1ql3 is expressed in human islet β-cells. Right, the model showing GLP1-cAMP increases insulin secretion by activating the signaling transduction (short-term) pathway that enhances the formation of insulin granule fusion complex (A) and gene expression (long-term) (B). A working model shows that C1ql3 signals in an autocrine/paracrine manner by binding to its receptor BAI3 to regulate insulin secretion by inhibiting cAMP signaling.The adjoining figure is adapted from Bhatnagar et al., Compr Physiol. 2023 Jun 26; 13(3): 5023–5049.

The CTRP family members (adiponectin, C1q/Tnf5, and C1q/Tnf1) regulate whole-body energy metabolism. We discovered a novel C1ql3 secreted protein signaling pathway that specifically inhibits cyclic adenosine monophosphate (cAMP)–stimulated insulin secretion from mouse and human islet β-cells. Our data show that C1ql3 functions by a BAI3 adhesion GPCR in an autocrine manner, modulating the cAMP signaling in β-cells to inhibit insulin secretion. The initial characterization of the C1ql3-BAI3 signaling pathway was published in JBC and Scientific Reports. We have now generated and validated C1ql3^Floxed and BAI3^KOmouse models. Currently, we are using these mice to elucidate the role of C1ql3/BAI3 in β-cells in Type 2 Diabetes. Pharmacological activators of cAMP are used for Type 2 Diabetes therapeutics. Thus, the specificity of C1ql3-BAI3 for cAMP signaling makes it an attractive therapeutic drug target for improving insulin secretion in Type 2 Diabetes. This pathway has led us to pursue the undescribed role of C1ql 1-4 secreted proteins and BAI (1-3) G-protein receptors in islet function.

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