Chemical Inhibition of Citrate Metabolism Alters Glucose Metabolism in Mice

Introduction

Diabetes mellitus is one of the most frequent health problems in westernized countries [1]. Type 2 diabetes mellitus is caused by a combination of impaired insulin secretion and decreased insulin sensitivity [2]. Recently, it was suggested that impaired mitochondrial metabolism precedes the development of diabetes mellitus, and may be found in insulin-resistant but otherwise healthy offspring of parents with type 2 diabetes [3]. Furthermore, impaired expression of mitochondrial and mitochondria-related genes has been observed in muscle biopsies from patients with type 2 diabetes [4] [5]. Impaired activity of mitochondrial aconitase (Aco-2) has been hypothetically linked with obesity [6], and hence might as well contribute to a diabetic phenotype.

We aimed to test this hypothesis by employing fluoroacetate, a competitive non-metabolizable inhibitor of aconitase and therefore citrate metabolism. We have chronically exposed C57bl6 mice to this particular substance, which leads to significant alterations in citrate metabolism and glucose metabolism, indicating specifically an improvement in insulin sensitivity.

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