Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells.
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.
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telengana, 500046, India.|Dept. of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, Telangana, 500046, India.
Suman
S
Asalla
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telengana, 500046, India.
Shravan Babu
SB
Girada
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telengana, 500046, India.
Ramya S
RS
Kuna
Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Telengana, Hyderabad, 500007, India.
Debabrata
D
Chowdhury
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telengana, 500046, India.
Bhaskar
B
Kandagatla
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telengana, 500046, India.
Srinivas
S
Oruganti
Center of Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, India.
Utpal
U
Bhadra
Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Telengana, Hyderabad, 500007, India.
Manika Pal
MP
Bhadra
Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Telengana, Hyderabad, 500007, India.
Shasi Vardhan
SV
Kalivendi
Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Telengana, Hyderabad, 500007, India.
Swetha Pavani
SP
Rao
University of Hyderabad Health Center, University of Hyderabad, Gachibowli, Hyderabad, Telengana, 500046, India.
Anupama
A
Row
Department of Biochemistry, National Institute of Nutrition, Hyderabad 500007, India.
A
A
Ibrahim
Microsoft India (R&D) Pvt. Ltd, Gachibowli, Hyderabad, Telengana, 500032, India.
Partha Pratim
PP
Ghosh
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telengana, 500046, India.
Prasenjit
P
Mitra
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries / Q000494:pharmacology*
D001786:Blood Glucose; D007328:Insulin; D054852:Small Molecule Libraries; D002784:Cholesterol; D005947:Glucose