Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis

Abstract

Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 mM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 mM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by B40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by B50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These effects of SGAs on adipocytes could explain, in part, the association of SGAs with weight gain and diabetes. Neuropsychopharmacology (2007) 32, 765-772.

Effects of Olanzapine and Ziprasidone on Glucose Tolerance in Healthy Volunteers

“…On a peripheral level, it has been shown that olanzapine impairs insulin-stimulated glucose transport, increases lipogenesis and inhibits lipolysis in adipocytes (Vestri et al, 2006). Interestingly, a number of studies show evidence for acute, non-adiposity linked mechanisms (Houseknecht et al, 2005) and lack of correlation between weight gain and changes in glucose metabolism (Meyer, 2002;Lindenmayer et al, 2003;Simpson et al, 2004).…”

Zonisamide Prevents Olanzapine-Associated Hyperphagia, Weight Gain, and Elevated Blood Glucose in Rats

“…OLZ may influence hormones associated with the regulation of insulin and/or glucose (Vestri et al, 2007). The typical clinical path toward diabetes is associated with increased adiposity and subsequent changes in insulin sensitivity; however, the rapid onset of diabetes associated with SGA administration, and the disappearance of hyperglycemia after discontinuation in patients suggests that the development of diabetes in patients on SGAs may be an acute drug-related effect (Rettenbacher et al, 2007).…”

“…There is evidence that OLZ has direct effects on glucose regulation, possibly leading to hyperinsulinemia, hyperglycemia, and insulin resistance (Baptista et al, 2002;Graham et al, 2005;Melkersson and Hulting, 2001;Seemuller et al, 2005). Of note, recent experiments show that SGAs may impair both the insulinresponsive glucose transport system, as well as lipolysis in adipocytes (Vestri et al, 2007), demonstrating that antipsychotic drugs may differentially affect insulin action and metabolism through direct cellular effects in adipocytes. OLZ has also been associated with acute insulin resistance following a single dose in healthy animals (Houseknecht et al, 2007), emphasizing the need for therapies aimed at managing unwanted metabolic side effects.…”

Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat

“…However, a major side effect of SGAs is the development of symptoms similar to type 2 diabetes [1][2][3][4][5]. It is widely assumed that this is caused by peripheral insulin resistance following excessive weight gain observed with people prescribed these drugs [6][7][8].…”