Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells.

Suman Asalla,Shravan Babu Girada,Partha Pratim Ghosh,Utpal Bhadra,A Ibrahim,Manika Pal Bhadra,Anupama Row,Srinivas Oruganti,Prasenjit Mitra,Swetha Pavani Rao,Bhaskar Kandagatla,Ramya S Kuna,Shasi Vardhan Kalivendi,Debabrata Chowdhury

doi:10.1038/srep27513

Abstract

Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation.

Highlights

Type 2 diabetes accounts for the majority of the cases of diabetes and is characterized by insulin resistance and pancreatic beta cell dysfunction[1] resulting in the alteration of glucose homeostasis
FS stands for fasting blood sugar; IN: insulin; TGL: Triglycerides; Total Cholesterol (TC): Total cholesterol, low density lipoprotein (LDL): Low Density Lipoproteins; HDL: High density Lipoproteins and FH: Family History
Impairment of Glucose Stimulated Insulin Secretion (GSIS) due to cholesterol accumulation in pancreatic beta cells has been described in various mouse models[13,15] as well as in patients harboring autosomal recessive mutations in ABCA1 gene[14]

Summary

Introduction

Type 2 diabetes accounts for the majority of the cases of diabetes and is characterized by insulin resistance and pancreatic beta cell dysfunction[1] resulting in the alteration of glucose homeostasis. Patients suffering from Tangier disease, caused by the deficiency of ABCA1, have attenuated GSIS reflecting on the importance of cholesterol efflux from pancreatic beta cells for the maintenance of proper insulin secretory response[14]. The tissue specific knock out of ATP-binding cassette transporter G1 (ABCG1), the protein which alters the intracellular cholesterol distribution, has been shown to impair GSIS in pancreatic beta cells[15]. Hao et al had developed genetically engineered mouse model where increase in the serum cholesterol without any alteration of serum free fatty acids has been shown to attenuate GSIS8. These data indicate the importance of proper intracellular cholesterol distribution in regulating pancreatic beta-cell function. We provide evidences that pre-treatment with the small molecule M1 stimulates cellular respiration, restores the mitochondrial function and stimulates GSIS which was abolished in cholesterol treated pancreatic beta cells

Methods

Results

Conclusion