Body and Liver Fat Mass Rather Than Muscle Mitochondrial Function Determine Glucose Metabolism in Women With a History of Gestational Diabetes Mellitus

OBJECTIVE Ectopic lipid storage in muscle (intramyocellular lipids [IMCL]) and liver (hepatocellular lipids [HCL]) coexists with impaired myocellular flux through ATP synthase (fATPase) in certain cohorts with increased risk of type 2 diabetes. Because women with a history of gestational diabetes mellitus (pGDM) have elevated ectopic lipids and diabetes risk, we tested whether deteriorated energy metabolism contributes to these abnormalities. RESEARCH DESIGN AND METHODS A total of 23 glucose-tolerant nonobese pGDM and eight women with normal glucose metabolism during pregnancy with similar age, body mass, and physical activity underwent oral glucose tolerance tests (OGTT) and intravenous glucose tolerance tests at 4–5 years after delivery. OGTT values <463 mL ⋅ min−1 ⋅ m−2 were considered to indicate insulin resistance. pGDM were further stratified into insulin-resistant (pGDM-IR) and insulin-sensitive (pGDM-IS) groups. IMCL, HCL, and fATPase were measured with 1H/31P magnetic resonance spectroscopy. RESULTS pGDM had 36% higher fat mass and 12% lower insulin sensitivity. Log-transformed fATPase was lower in pGDM (10.6 ± 3.8 µmol ⋅ mL muscle−1 ⋅ min−1 vs. 12.1 ± 1.4 µmol ⋅ mL muscle−1 ⋅ min−1, P < 0.03) and related to plasma adiponectin after adjustment for body fat (r = 0.44, P < 0.04). IMCL were 61% and 69% higher in pGDM-IR (P < 0.05 vs. pGDM-IS) and insulin resistant women (P < 0.003 vs. insulin sensitive), respectively. HCL were doubled (P < 0.05) in pGDM and insulin resistant women, and correlated positively with body fat mass (r = 0.50, P < 0.01) and inversely with insulin sensitivity (r = −0.46, P < 0.05). CONCLUSIONS Glucose-tolerant pGDM show increased liver fat but only slightly lower muscular insulin sensitivity and ATP synthesis. This suggests that alteration of hepatic lipid storage represents an early and predominant abnormality in this cohort.

[1]  Ewald Moser,et al.  Abnormal hepatic energy homeostasis in type 2 diabetes , 2009, Hepatology.

[2]  M. Roden,et al.  Ectopic lipids and organ function , 2009, Current opinion in lipidology.

[3]  J. Schwimmer,et al.  Hepatic, Cardiovascular, and Endocrine Outcomes of the Histological Subphenotypes of Nonalcoholic Fatty Liver Disease , 2008, Seminars in liver disease.

[4]  S. Kahn,et al.  Within-subject variability of measures of beta cell function derived from a 2 h OGTT: implications for research studies , 2007, Diabetologia.

[5]  X. Papademetris,et al.  The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome , 2007, Proceedings of the National Academy of Sciences.

[6]  M. Wolzt,et al.  Muscle Mitochondrial ATP Synthesis and Glucose Transport/Phosphorylation in Type 2 Diabetes , 2007, PLoS medicine.

[7]  E. Ravussin,et al.  Role of adiponectin in human skeletal muscle bioenergetics. , 2006, Cell metabolism.

[8]  P. Scherer,et al.  Adipose tissue-derived factors: impact on health and disease. , 2006, Endocrine reviews.

[9]  R. DeFronzo,et al.  Insulin Secretion and Action in Subjects With Impaired Fasting Glucose and Impaired Glucose Tolerance , 2006, Diabetes.

[10]  T. Buchanan,et al.  Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. , 2006, Diabetes.

[11]  W. Backes,et al.  Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects , 2006, Diabetologia.

[12]  Peter Nowotny,et al.  Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle. , 2006, Diabetes.

[13]  A. Brazzale,et al.  Comparative evaluation of simple insulin sensitivity methods based on the oral glucose tolerance test , 2005, Diabetologia.

[14]  B. Goodpaster,et al.  Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. , 2005, Diabetes.

[15]  T. Funahashi,et al.  Plasma adiponectin, insulin sensitivity, and subclinical inflammation in women with prior gestational diabetes mellitus. , 2004, Diabetes care.

[16]  K. Petersen,et al.  Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. , 2004, The New England journal of medicine.

[17]  F. Schick,et al.  Intramyocellular lipids: anthropometric determinants and relationships with maximal aerobic capacity and insulin sensitivity. , 2003, The Journal of clinical endocrinology and metabolism.

[18]  Andrea Tura,et al.  Increased intramyocellular lipid concentration identifies impaired glucose metabolism in women with previous gestational diabetes. , 2003, Diabetes.

[19]  Catherine Kim,et al.  Gestational diabetes and the incidence of type 2 diabetes: a systematic review. , 2002, Diabetes care.

[20]  A. Häkkinen,et al.  Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. , 2002, Obesity research.

[21]  T. Buchanan,et al.  Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. , 2002, Diabetes.

[22]  Andrea Mari,et al.  A Model-Based Method for Assessing Insulin Sensitivity From the Oral Glucose Tolerance Test , 2001 .

[23]  T. Buchanan,et al.  Response of pancreatic beta-cells to improved insulin sensitivity in women at high risk for type 2 diabetes. , 2000, Diabetes.

[24]  L. DiPietro,et al.  Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study , 1999, Diabetologia.

[25]  Giovanni Pacini,et al.  Insulin sensitivity and glucose effectiveness: minimal model analysis of regular and insulin-modified FSIGT. , 1998, American journal of physiology. Endocrinology and metabolism.