Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control

Abstract

Aims/hypothesis: Hyperlipidaemia often occurs in patients with type 2 diabetes mellitus. Though HMGCoA reductase inhibitors (statins) are widely used for controlling hypercholesterolemia, atorvastatin has also been reported to have an adverse effect on glucose metabolism. Based on these findings, the aim of this study was to investigate the effects of statins on adipocytes, which play pivotal roles in glucose metabolism. Methods: In 3T3-L1 cells, effects of statins on adipocyte maturation were determined morphologically. Protein and mRNA levels of SLC2A4 and adipocyte marker proteins were determined by immunoblotting and RT-PCR, respectively. Type 2 diabetic NSY mice were treated with atorvastatin for 15 weeks, followed by glucose and insulin tolerance tests and examination of SLC2A4 expression in white adipose tissue (WAT). Seventy-eight Japanese subjects with type 2 diabetes and hypercholesterolaemia were treated with atorvastatin (10 mg/day), and its effects on lipid and glycaemic profiles were measured 12 weeks after treatment initiation.Results: Treatment with atorvastatin inhibited adipocyte maturation, SLC2A4 and C/EBPα expressions and insulin action in 3T3-L1 cells.Atorvastatin also attenuated SLC2A4 and C/EBPα expressions in differentiated 3T3-L1 adipocytes. These effects were reversed by L-mevalonate or geranylgeranyl pyrophosphate. In NSY mice, atorvastatin accelerated glucose intolerance as a result of insulin resistance and decreased SLC2A4 expression in WAT. In addition to improving hyperlipidaemia, atorvastatin treatment significantly increased HbA 1c but not fasting glucose levels in diabetic patients, and this effect was greater in the nonobese subgroup. Conclusions/interpretation: These results demonstrate that atorvastatin attenuates adipocyte maturation and SLC2A4 expression by inhibiting isoprenoid biosynthesis, and impairs glucose tolerance. These actions of atorvastatin could potentially affect the control of type 2 diabetes.

Statins and New-Onset Diabetes Mellitus and Diabetic Complications: A Retrospective Cohort Study of US Healthy Adults

“…68 On the other hand, several observational and experimental studies have noted that statin use was associated with high blood glucose levels. [4][5][6][7][8] The overall proportion of overweight/obesity in our cohort was high (exceeding 40 %), but is commensurate with recent estimates of overweight/obesity. 69 Evidence from in vitro studies indicates that statins can increase body and liver fat accumulation.…”

“…3 Several randomized trials and observational studies have noted that statin users have higher hemoglobin [Hb]A 1C and fasting plasma glucose measurements than nonusers. [4][5][6][7][8] Hence, it can be surmised that statins may increase the risk of diabetic complications.…”

Preferable Effect of Pravastatin Compared to Atorvastatin on Beta Cell Function in Japanese Early-state Type 2 Diabetes with Hypercholesterolemia

“…For instance, as lovastatin inhibited insulin secretion from isolated islets [31], simvastatin inhibited insulin secretion via the blockage of L-type calcium channels in rat pancreatic beta cell, while pravastatin did not [32]. While pravastatin prevented the deterioration of glucose tolerance in OLETF rats, a recent study reported that atorvastatin impaired glucose tolerance in NSY mice [33]. On the other hand, there have been several data disputing these results [34,35].…”

Medications affecting glycemic control

“…An observational study evaluating the effect of statins on FBG over a 2 year follow up period reported a statin-associated increase of 0.5 mmol/L in patients with DM and 0.2 mmol/L without DM [63]. The precise mechanism(s) for statin-induced DM remains unclear, although hypotheses include statin induced insulin resistance, inhibited β cell insulin secretion and synthesis, and decreased insulin-mediated cellular glucose uptake [64][65][66]. Based on current literature, the long-term CVD benefit of statins outweigh the risk of DM.…”

“…However, they have been linked to IGT, hyperglycemia more than NODM [61][62][63][64][65][66][67][68][69]. Hydrochlorothiazide or chlorthalidone have been reported to cause hyperglycemia more often than other diuretics, and a higher incidence of NODM was reported with chlorthalidone in the ALLHAT trial after 2 and 4 years follow-up [68].…”