Poster Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Statin-mediated alteration of cellular cholesterol blunts maximal insulin secretion in β-cells (#212)

Gaewyn Ellison 1 2 , Rodrigo Carlessi 1 2 , Ricky R Lareu 1 2 , Heloisa H De Oliveira Alves 1 2 , Philip Newsholme 1 2 , Ross M Graham 1 2 , Cyril Mamotte 1 2
  1. Curtin Health Innovation Research Institute, Perth, WA, Australia
  2. Curtin University, Bentley, WA, Australia

Introduction

Obesity and hypercholesterolaemia are risk factors for Type 2 Diabetes (T2D). However, treatment with the statin class of cholesterol-lowering drugs is also associated with an increased incidence of T2D. Statins reduce cholesterol by competitively inhibiting the rate-limiting enzyme in cholesterol synthesis. Changes in intracellular cholesterol may thus influence insulin­­-mediated metabolic homeostasis.

Objectives

To determine how changes in the cholesterol content of pancreatic β‑cells, including those induced by statins, influence insulin secretion.

Methods

Using the pancreatic β‑cell line, BRIN-BD11, we increased or decreased intracellular cholesterol with cholesterol-loaded methyl-β‑cyclodextrin or statins (1 or 10 µM fluvastatin, atorvastatin, pravastatin), respectively, and measured insulin secreted in response to nutritional and therapeutic secretagogues.  We also fed mice a normal (ND) or high fat diet (HFD) with or without statin medication (10 mg/kg/day pravastatin or atorvastatin) and measured glucose tolerance, plasma insulin and glucagon.

Results

Maximal insulin secretion was blunted in vitro by both cholesterol enriching and depleting treatments, while basal secretion was unchanged.  Lipophilic atorvastatin and fluvastatin blunted insulin secretion to a greater extent than hydrophilic pravastatin during maximal stimulation with amino acids, sulphonylureas or Exendin-4.  In our mouse studies, HFD increased insulin resistance (IR), fasting plasma insulin and glucagon compared to ND. IR was also increased in atorvastatin-treated ND mice, though not significantly. A delayed return to normoglycaemia after glucose loading was observed in statin plus HFD mice.

Conclusions

These results suggest that maintenance of intracellular cholesterol homeostasis is required for optimal β‑cell function. Different statins also vary in their effects on reducing in vitro insulin secretion.  Increased dietary cholesterol impacted in vivo metabolic parameters more than therapeutically reduced cholesterol synthesis.