Recent evidences propose the role of cholesterol homeostasis in maintaining the adequate secretory response of insulin from pancreatic beta cells 12. The resultant hyperglycemia is influenced by several co-morbidities like hyperlipidaemia 6, 7, hypercholesterolaemia 8, 9, and elevated plasma triglycerides 10 which contribute to the metabolic signaling that regulate GSIS 11. Although insulin resistance and systemic inflammation contribute to the patho-physiology of the disease 2, 3, 4, pancreatic beta-cell dysfunction and consequent impaired Glucose Stimulated Insulin Secretion (GSIS) is considered to be an essential step for the progression of the disease from pre-diabetic to the diabetic stage 1, 5. 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. 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. 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. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol.
To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol.
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. 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. Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes.
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