Hepatic Insulin Clearance Is Closely Related to Metabolic Syndrome Components

OBJECTIVE Insulin clearance is decreased in type 2 diabetes mellitus (T2DM) for unknown reasons. Subjects with metabolic syndrome are hyperinsulinemic and have an increased risk of T2DM. We aimed to investigate the relationship between hepatic insulin clearance (HIC) and different components of metabolic syndrome and tested the hypothesis that HIC may predict the risk of metabolic syndrome. RESEARCH DESIGN AND METHODS Individuals without diabetes from the Metabolic Syndrome Berlin Brandenburg (MeSyBePo) study (800 subjects with the baseline examination and 189 subjects from the MeSyBePo recall study) underwent an oral glucose tolerance test (OGTT) with assessment of insulin secretion (insulin secretion rate [ISR]) and insulin sensitivity. Two indices of HIC were calculated. RESULTS Both HIC indices showed lower values in subjects with metabolic syndrome (P < 0.001) at baseline. HIC indices correlate inversely with waist circumference, diastolic blood pressure, fasting glucose, triglycerides, and OGTT-derived insulin secretion index. During a mean follow-up of 5.1 ± 0.9 years, 47 individuals developed metabolic syndrome and 33 subjects progressed to impaired glucose metabolism. Both indices of HIC showed a trend of an association with increased risk of metabolic syndrome (HICC-peptide odds ratio 1.13 [95% CI 0.97–1.31], P = 0.12, and HICISR 1.38 [0.88–2.17], P = 0.16) and impaired glucose metabolism (HICC-peptide 1.12 [0.92–1.36], P = 0.26, and HICISR 1.31 [0.74–2.33] P = 0.36), although point estimates reached no statistical significance. CONCLUSIONS HIC was associated with different components of metabolic syndrome and markers of insulin secretion and insulin sensitivity. Decreased HIC may represent a novel pathophysiological mechanism of the metabolic syndrome, which may be used additionally for early identification of high-risk subjects.

[1]  A. Pfeiffer,et al.  Fibroblast Growth Factor 21 Predicts the Metabolic Syndrome and Type 2 Diabetes in Caucasians , 2012, Diabetes Care.

[2]  J. Rotter,et al.  Fasting insulin reflects heterogeneous physiological processes: role of insulin clearance. , 2011, American journal of physiology. Endocrinology and metabolism.

[3]  B. Balkau,et al.  Liver Enzymes Are Associated With Hepatic Insulin Resistance, Insulin Secretion, and Glucagon Concentration in Healthy Men and Women , 2011, Diabetes.

[4]  U. Wisløff,et al.  Caloric restriction reverses hepatic insulin resistance and steatosis in rats with low aerobic capacity. , 2010, Endocrinology.

[5]  S. Grundy,et al.  Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International As , 2009, Circulation.

[6]  M. Schulze,et al.  Polymorphisms within insulin-degrading enzyme (IDE) gene determine insulin metabolism and risk of type 2 diabetes , 2009, Journal of Molecular Medicine.

[7]  A. Pfeiffer,et al.  Glucose inhibits the insulin-induced activation of the insulin-degrading enzyme in HepG2 cells , 2009, Diabetologia.

[8]  A. Kotronen,et al.  Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. , 2008, Gastroenterology.

[9]  G. Reaven,et al.  Insulin Resistance and Hyperinsulinemia , 2008, Diabetes Care.

[10]  S. Wagenpfeil,et al.  Development of hyperinsulinemia and insulin resistance during the early stage of weight gain. , 2008, American journal of physiology. Endocrinology and metabolism.

[11]  A. Kotronen,et al.  Effect of liver fat on insulin clearance. , 2007, American journal of physiology. Endocrinology and metabolism.

[12]  J. Holst,et al.  Reduction of hepatic insulin clearance after oral glucose ingestion is not mediated by glucagon-like peptide 1 or gastric inhibitory polypeptide in humans. , 2007, American journal of physiology. Endocrinology and metabolism.

[13]  Johannes D Veldhuis,et al.  Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. , 2005, Diabetes.

[14]  A. Pfeiffer,et al.  Reduced hepatic insulin extraction in response to gastric inhibitory polypeptide compensates for reduced insulin secretion in normal-weight and normal glucose tolerant first-degree relatives of type 2 diabetic patients. , 2004, Diabetes.

[15]  M. Stumvoll,et al.  Association of the -514C→T polymorphism in the Hepatic Lipase Gene (LIPC) Promoter with Elevated Fasting Insulin Concentrations, but not Insulin Resistance, in Non-diabetic Germans , 2004, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[16]  Geltrude Mingrone,et al.  Insulin Clearance in Obesity , 2003, Journal of the American College of Nutrition.

[17]  Ralph B D'Agostino,et al.  Prediction of type 2 diabetes using simple measures of insulin resistance: combined results from the San Antonio Heart Study, the Mexico City Diabetes Study, and the Insulin Resistance Atherosclerosis Study. , 2003, Diabetes.

[18]  J. Yanovski,et al.  Indices of insulin action, disposal, and secretion derived from fasting samples and clamps in normal glucose-tolerant black and white children. , 2002, Diabetes care.

[19]  J. Janosky,et al.  Hyperinsulinemia in african-american children: decreased insulin clearance and increased insulin secretion and its relationship to insulin sensitivity. , 2002, Diabetes.

[20]  B. Balkau,et al.  Insulin: in search of a syndrome , 2002, Diabetic medicine : a journal of the British Diabetic Association.

[21]  R. Bergman,et al.  Longitudinal Compensation for Fat-induced Insulin Resistance Includes Reduced Insulin Clearance and Enhanced ␤-cell Response Research Design and Methods , 2022 .

[22]  J. Meigs,et al.  Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. , 2000, American journal of epidemiology.

[23]  R. N. Bergman,et al.  Non-esterified fatty acids and the liver: why is insulin secreted into the portal vein? , 2000, Diabetologia.

[24]  N. Schneiderman,et al.  Validation of the insulin sensitivity index (ISI(0,120)): comparison with other measures. , 2000, Diabetes research and clinical practice.

[25]  M. Stumvoll,et al.  Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. , 2000, Diabetes care.

[26]  W. Duckworth,et al.  Insulin degradation: progress and potential. , 1998, Endocrine reviews.

[27]  A. Lanzone,et al.  Heterogeneity in beta cell activity, hepatic insulin clearance and peripheral insulin sensitivity in women with polycystic ovary syndrome. , 1997, Human reproduction.

[28]  S. Haffner,et al.  Prospective analysis of the insulin-resistance syndrome (syndrome X). , 1992, Diabetes.

[29]  S. Haffner,et al.  Prospective Analysis of The Insulin-Resistance Syndrome (Syndrome X) , 1992, Diabetes.

[30]  R. Simon,et al.  Flexible regression models with cubic splines. , 1989, Statistics in medicine.

[31]  G. Reaven.  Role of Insulin Resistance in Human Disease , 1988, Diabetes.

[32]  G. Reaven.  Banting lecture 1988. Role of insulin resistance in human disease. , 1988, Diabetes.

[33]  B H Frank,et al.  Dose-dependent effects of oral and intravenous glucose on insulin secretion and clearance in normal humans. , 1988, The American journal of physiology.

[34]  R. Rizza,et al.  Incretin Effect Due to Increased Secretion and Decreased Clearance of Insulin in Normal Humans , 1988, Diabetes.

[35]  B H Frank,et al.  Quantitative study of insulin secretion and clearance in normal and obese subjects. , 1988, The Journal of clinical investigation.

[36]  K. Polonsky,et al.  The Limitations to and Valid Use of C-Peptide as a Marker of the Secretion of Insulin , 1986, Diabetes.

[37]  H. Kehlet,et al.  Discrepancy Between Plasma C-Peptide and Insulin Response to Oral and Intravenous Glucose , 1983, Diabetes.

[38]  K. Polonsky,et al.  Differences in the hepatic and renal extraction of insulin and glucagon in the dog: evidence for saturability of insulin metabolism. , 1983, Acta endocrinologica.

[39]  T. Lehtimäki,et al.  Effect of weight loss on liver free fatty acid uptake and hepatic insulin resistance. , 2009, The Journal of clinical endocrinology and metabolism.