👤 Harshal Deshmukh

Insulin secretory granule (ISG) maturation is a crucial aspect of insulin secretion and glucose homeostasis. The regulation of this maturation remains poorly understood, especially how secretory stimuli affect ISG maturity and subcellular localization. In this study, we used soft X-ray tomography (SXT) to quantitatively map ISG morphology, density, and location in single INS-1E and mouse pancreatic β cells under the effect of various secretory stimuli. We found that the activation of glucokinase (GK), gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide-1 receptor (GLP-1R), and G protein-coupled receptor 40 (GPR40) promotes ISG maturation. Each stimulus induces unique structural remodeling in ISGs, by altering size and density, depending on the specific signaling cascades activated. These distinct ISG subpopulations mobilize and redistribute in the cell, altering the overall cellular structural organization. Our results provide insight into how current diabetes and obesity therapies impact ISG maturation and may inform the development of future treatments that target maturation specifically. Show less

Insulin secretory granule (ISG) maturation is a crucial aspect of insulin secretion and glucose homeostasis. The regulation of this maturation remains poorly understood, especially how secretory stimuli affect ISG maturity and subcellular localization. In this study, we used soft X-tomography (SXT) to quantitatively map ISG morphology, density, and location in single INS-1E and mouse pancreatic β-cells under the effect of various secretory stimuli. We found that the activation of glucokinase (GK), gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide-1 receptor (GLP-1R), and G-protein coupled receptor 40 (GPR40) promote ISG maturation. Each stimulus induces unique structural remodeling in ISGs, by altering size and density, depending on the specific signaling cascades activated. These distinct ISG subpopulations mobilize and redistribute in the cell altering overall cellular structural organization. Our results provide insight into how current diabetes and obesity therapies impact ISG maturation and may inform the development of future treatments that target maturation specifically. Show less

Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity. To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies. We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models. Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 × 10-9) and rs9368219 in the CDKAL1 (P value = 3.15 × 10-9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity. We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity. Show less

Triple-negative breast cancer (TNBC) tumors are composed of a heterogeneous population containing both cancer cells and cancer stem cells (CSCs). These CSCs are generated through an epithelial-to-mesenchymal transition (EMT), thus making it pertinent to identify the unique EMT-molecular targets that regulate this phenomenon. In the present study, we performed in silico analysis of microarray data from luminal, Her2 Thus, the molecular investigation for the gene regulatory framework in the present study identified MMPs, a downstream effector in the SNAI1-mediated EMT regulation. Show less

Diabesity and its related cardio-hepato-renal complications are of absolute concern globally. Last decade has witnessed a growing interest in the scientific community in investigating novel pharmaco-therapies employing the pancreatic hormone, glucagon. Canonically, this polypeptide hormone is known for its use in rescue treatment for hypoglycaemic shocks owing to its involvement in the counter-regulatory feedback mechanism. However, substantial studies in the recent past elucidated the pleiotropic effects of glucagon in diabesity and related complications like non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). Thus, the dual nature of this peptide has sparked the search for drugs that can modify glucagon signalling to combat hypoglycaemia or diabesity. Thus far, researchers have explored various pharmacological approaches to utilise this peptide in imminent modern therapies. The research endeavours in this segment led to explorations of stable glucagon formulations/analogues, glucagon receptor antagonism, glucagon receptor agonism, and incretin poly-agonism as new strategies for the management of hypoglycaemia or diabesity. This 'three-dimensional' research on glucagon resulted in the discovery of various drug candidates that proficiently modify glucagon signalling. Currently, several emerging glucagon-based therapies are under pre-clinical and clinical development. We sought to summarise the recent progress to comprehend glucagon-mediated pleiotropic effects, provide an overview of drug candidates currently being developed and future perspectives in this research domain. Show less

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. Show less