Impaired Mitochondrial Function and Insulin Resistance of Skeletal Muscle in Mitochondrial Diabetes

Abstract

OBJECTIVE -Impaired muscular mitochondrial function is related to common insulin resistance in type 2 diabetes. Mitochondrial diseases frequently lead to diabetes, which is mostly attributed to defective ␤-cell mitochondria and secretion.RESEARCH DESIGN AND METHODS -We assessed muscular mitochondrial function and lipid deposition in liver (hepatocellular lipids [HCLs]) and muscle (intramyocellular lipids [IMCLs]) using 31 P/ 1 H magnetic resonance spectroscopy and insulin sensitivity and endogenous glucose production (EGP) using hyperinsulinemic-euglycemic clamps combined with isotopic tracer dilution in one female patient suffering from MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome and in six control subjects.RESULTS -The MELAS patient showed impaired insulin sensitivity (4.3 vs. 8.6 Ϯ 0.5 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and suppression of EGP (69 vs. 94 Ϯ 1%), and her baseline and insulin-stimulated ATP synthesis were reduced (7.3 and 8.9 vs. 10.6 Ϯ 1.0 and 12.8 Ϯ 1.3 mol ⅐ l Ϫ1 ⅐ min Ϫ1 ) compared with those of the control subjects. HCLs and IMCLs were comparable between the MELAS patient and control subjects.CONCLUSIONS -Impairment of muscle mitochondrial fitness promotes insulin resistance and could thereby contribute to the development of diabetes in some patients with the MELAS syndrome. Diabetes Care 32:677-679, 2009T he MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome is caused by a maternally inherited mtDNA mutation, resulting in defective cellular respiration. MELAS-associated diabetes has been primarily attributed to insufficient insulin secretion due to mitochondrial dysfunction of pancreatic ␤-cells. Insulinresistant populations show reduced mitochondrial function and increased soleus muscle lipids (intramyocellular lipids [IMCLs]) and liver lipids (hepatocellular lipids [HCLs]) (1). The sequence of events, particularly the possibility of muscle mitochondria leading to insulin resistance, is unclear.RESEARCH DESIGN AND METHODS -One female patient (age 37 years, BMI 24 kg/m 2 , A1C 7.4%) suffering from MELAS (mtDNA mutation A3243G, ϳ60% heteroplasmy in leukocytes, confirmed by PCR amplification) was compared with six nondiabetic female control subjects (age 45 Ϯ 4 years, BMI 24 Ϯ 1 kg/m 2 , A1C 5.2 Ϯ 0.1%). The protocol was approved by an institutional ethics board, and written informed consent was obtained. The patient developed bilateral labyrinthine hypacusis and insulin-dependent diabetes at 26 years of age, underwent surgery for ptosis, and showed vascular lesions in her periventricular white matter.Whole-body insulin sensitivity (insulin-mediated glucose disposal, M) and endogenous glucose production (EGP) were assessed during a normoglycemichyperinsulinemic clamp with infusion of insulin (40 mU ⅐ m body surface area Ϫ1 ⅐ min Ϫ1

The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes

“…Inflammation and cytokine signalling appear to be important, and recent studies have linked insulin resistance with mitochondrial dysfunction. This includes reduced mitochondrial content and in some [2][3][4][5], but not all, studies, reduced mitochondrial functional capacity [2,4,[6][7][8][9][10][11][12].…”

Antidiabetic potential of mangrove plants: a review

“…The oxidative stress has been shown to downregulate the expression of GLUT4, which in turn decreases Mitochondria also play an important role in the release of insulin from β-cells in response to blood glucose levels (Rains & Jain 2011). The mitochondrial dysfunction by oxidative stress is reported to be involved in insulin resistance and may be an underlying cause in the development of diabetes (Szendroedi et al 2009). …”

Mitochondrial dysfunction in patients with primary congenital insulin resistance

“…Studying patients with mitochondrial genetic defects producing primary mitochondrial dysfunction seems at first sight to offer the potential to conduct a similar Mendelian randomization experiment to test whether mitochondrial dysfunction in humans can produce insulin resistance, but this is likely to be confounded by deleterious effects of generalized mitochondrial dysfunction on β cell and muscle function (17,18). However, patients with congenital, severe insulin resistance due to mutations in the insulin receptor (INSR) gene are well described and, though uncommon, afford instead the reciprocal opportunity to test whether primary insulin resistance can produce mitochondrial dysfunction, potentially accounting for some but not necessarily all of their observed association in commoner forms of insulin resistance.…”