Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects.

UNLABELLED The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU x kg(-1) x min(-1)) clamp and a two-step euglycemic IGF-I (26 and 52 pmol x kg(-1) x min(-1)) clamp with [3-(3)H]glucose, [1-(14)C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal (R(d)) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of R(d) (second clamp step) in response to both insulin and IGF-I was reduced by approximately 40-50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin (P < 0.01-0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects (P < 0.05-0.01). CONCLUSIONS 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I.

[1]  F. Horber,et al.  Low dose recombinant human insulin-like growth factor-I fails to affect protein anabolism but inhibits islet cell secretion in humans. , 1992, The Journal of clinical endocrinology and metabolism.

[2]  J. Massagué,et al.  The subunit structures of two distinct receptors for insulin-like growth factors I and II and their relationship to the insulin receptor. , 1982, The Journal of biological chemistry.

[3]  H. Vestergaard,et al.  Short- and long-term metabolic effects of recombinant human IGF-I treatment in patients with severe insulin resistance and diabetes mellitus. , 1997, European journal of endocrinology.

[4]  D. Moller,et al.  Recombinant human insulin-like growth factor-I therapy improves glycemic control and insulin action in the type A syndrome of severe insulin resistance. , 1994, The Journal of clinical endocrinology and metabolism.

[5]  M. Davidson,et al.  Insulin-like growth factor I receptors in adult rat liver: characterization and in vivo regulation. , 1990, The American journal of physiology.

[6]  L. Groop,et al.  Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. , 1989, The Journal of clinical investigation.

[7]  G. Hetényi,et al.  Glucoregulatory responses in normal and diabetic dogs recorded by a new tracer method. , 1971, Metabolism: clinical and experimental.

[8]  K. Alberti,et al.  A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growth hormone secretion in humans. , 1993, The Journal of clinical investigation.

[9]  R F Kushner,et al.  Bioelectrical impedance analysis: a review of principles and applications. , 1992, Journal of the American College of Nutrition.

[10]  R. Ross,et al.  Administration of human recombinant insulin‐like growth factor‐I to patients following major gastrointestinal surgery , 1992, Clinical endocrinology.

[11]  G. Sesti,et al.  Increased abundance of insulin/IGF-I hybrid receptors in adipose tissue from NIDDM patients , 1997, Molecular and Cellular Endocrinology.

[12]  E. Froesch,et al.  Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. , 1987, The New England journal of medicine.

[13]  E. Van Obberghen,et al.  The insulin and insulin-like growth factor-I receptor substrate IRS-1 associates with and activates phosphatidylinositol 3-kinase in vitro. , 1993, The Journal of biological chemistry.

[14]  G. Shulman,et al.  Metabolic effects of IGF-I and insulin in spontaneously diabetic BB/w rats. , 1991, The American journal of physiology.

[15]  C T Roberts,et al.  Molecular and cellular aspects of the insulin-like growth factor I receptor. , 1995, Endocrine reviews.

[16]  P. Gluckman,et al.  Body growth, carcass composition, and endocrine changes in lambs chronically treated with recombinantly derived insulin-like growth factor-I. , 1992, Endocrinology.

[17]  R. DeFronzo,et al.  Recombinant human insulin-like growth factor I treatment for 1 week improves metabolic control in type 2 diabetes by ameliorating hepatic and muscle insulin resistance. , 2000, The Journal of clinical endocrinology and metabolism.

[18]  T. R. Hennessy,et al.  A comparison of the effects of IGF‐I and insulin on glucose metabolism, fat metabolism and the cardiovascular system in normal human volunteers , 1995, European journal of clinical investigation.

[19]  M. Bayne,et al.  Impaired insulin-like growth factor I-mediated stimulation of glucose incorporation into glycogen in vivo in the ob/ob mouse , 1989, Diabetologia.

[20]  R G Shulman,et al.  Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. , 1990, The New England journal of medicine.

[21]  C. Chu,et al.  The Role of Fatty Acids in Mediating the Effects of Peripheral Insulin on Hepatic Glucose Production in the Conscious Dog , 1997, Diabetes.

[22]  R. Sherwin,et al.  Acute effects of insulin-like growth factor I on glucose and amino acid metabolism in the awake fasted rat. Comparison with insulin. , 1989, The Journal of clinical investigation.

[23]  U. Keller,et al.  Comparison of the effects of recombinant human insulin-like growth factor-I and insulin on glucose and leucine kinetics in humans. , 1993, The Journal of clinical investigation.

[24]  W. Tamborlane,et al.  Comparison of the metabolic effects of recombinant human insulin-like growth factor-I and insulin. Dose-response relationships in healthy young and middle-aged adults. , 1994, The Journal of clinical investigation.

[25]  R. DeFronzo,et al.  Indirect calorimetry: methodological and interpretative problems. , 1990, The American journal of physiology.

[26]  E. Obberghen,et al.  Effect of IGF-I on Phosphatidylinositol 3-Kinase in Soleus Muscle of Lean and Insulin-Resistant Obese Mice , 1996, Diabetes.

[27]  R. DeFronzo,et al.  Sensitivity of insulin secretion to feedback inhibition by hyperinsulinaemia. , 1981, Acta endocrinologica.

[28]  U. Keller,et al.  Effect of increasing doses of recombinant human insulin-like growth factor-I on glucose, lipid, and leucine metabolism in man. , 1992, The Journal of clinical endocrinology and metabolism.

[29]  J. Poulos,et al.  Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver. , 1988, The Journal of clinical investigation.

[30]  G. Sesti,et al.  Increased expression of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of noninsulin-dependent diabetes mellitus subjects. , 1996, The Journal of clinical investigation.

[31]  R. DeFronzo,et al.  Comparison of the effects of human recombinant insulin-like growth factor I and insulin on plasma amino acid concentrations and leucine kinetics in humans , 1995, Diabetologia.

[32]  E. Schoenle,et al.  Effect of trypsin treatment of rat adipocytes on biological effects and binding of insulin and insulin-like growth factors: further evidence for the action of insulin-like growth factors through the insulin receptor. , 1981, European journal of biochemistry.

[33]  R. Steele,et al.  INFLUENCES OF GLUCOSE LOADING AND OF INJECTED INSULIN ON HEPATIC GLUCOSE OUTPUT * , 1959, Annals of the New York Academy of Sciences.

[34]  R. Moxley,et al.  Acute effects of insulin-like growth factor I and insulin on glucose metabolism in vivo. , 1990, The American journal of physiology.

[35]  G. Shulman,et al.  Simultaneous Insulinlike Growth Factor I and Insulin Resistance in Obese Zucker Rats , 1992, Diabetes.

[36]  K. Minaker,et al.  Effects of recombinant human IGF-I on glucose and leucine kinetics in men. , 1993, The American journal of physiology.

[37]  K. Siddle,et al.  Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity. , 1993, The Biochemical journal.

[38]  R. DeFronzo,et al.  Glucose clamp technique: a method for quantifying insulin secretion and resistance. , 1979, The American journal of physiology.

[39]  P. Arner,et al.  Characterisation of insulin-like growth factor I receptor in skeletal muscles of normal and insulin resistant subjects , 1988, Diabetologia.

[40]  M. White,et al.  IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase. , 1993, Endocrinology.

[41]  B. Ursø,et al.  Differences in Signaling Properties of the Cytoplasmic Domains of the Insulin Receptor and Insulin-like Growth Factor Receptor in 3T3-L1 Adipocytes* , 1999, The Journal of Biological Chemistry.

[42]  P. Arner,et al.  Studies of acute effects of insulin-like growth factors I and II in human fat cells. , 1987, The Journal of clinical endocrinology and metabolism.

[43]  M. T. Clandinin,et al.  Parallel insulin-like growth factor I and insulin resistance in muscles of rats fed a high fat diet. , 1995, Endocrinology.

[44]  R. DiMarchi,et al.  IGF-I–Stimulated Glucose Transport in Human Skeletal Muscle and IGF-I Resistance in Obesity and NIDDM , 1990, Diabetes.

[45]  E. Froesch,et al.  Acute metabolic effects and half-lives of intravenously administered insulinlike growth factors I and II in normal and hypophysectomized rats. , 1986, The Journal of clinical investigation.

[46]  R. DiMarchi,et al.  Mechanism of IGF-I-Stimulated Glucose Transport in Human Adipocytes: Demonstration of Specific IGF-I Receptors Not Involved in Stimulation of Glucose Transport , 1989, Diabetes.

[47]  C Cobelli,et al.  Effect of insulin on the distribution and disposition of glucose in man. , 1985, The Journal of clinical investigation.

[48]  R. DeFronzo.  PATHOGENESIS OF TYPE 2 DIABETES: METABOLIC AND MOLECULAR IMPLICATIONS FOR IDENTIFYING DIABETES GENES , 1997 .

[49]  L. Sidossis,et al.  A new correction factor for use in tracer estimations of plasma fatty acid oxidation. , 1995, The American journal of physiology.

[50]  R. DeFronzo,et al.  Metabolic Effects of IGF-I in Diabetic Rats , 1991, Diabetes.