Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes

SummaryIntegrated incremental immunoreactive insulin and connecting peptide responses to an oral glucose load of 50 g and an “isoglycaemic” intravenous glucose infusion, respectively, were measured in 14 Type 2 (non-insulin-dependent) diabetic patients and 8 age- and weight-matched metabolically healthy control subjects. Differences between responses to oral and intravenous glucose administration are attributed to factors other than glucose itself (incretin effect). Despite higher glucose increases, immunoreactive insulin and connecting peptide responses after oral glucose were delayed in diabetic patients. Integrated responses were not significantly different between both groups. However, during “isoglycaemic” intravenous infusion, insulin and connecting peptide responses were greater in diabetic patients than in control subjects as a consequence of the higher glycaemic stimulus. The contribution of incretin factors to total insulin responses was 72.8 ± 6.9% (100% = response to oral load) in control subjects and 36.0 ± 8.8% in diabetic patients (p ≦ 0.05). The contribution to connecting peptide responses was 58.4 ± 7.6% in control subjects and 7.6 ± 14.5% (p ≦ 5 0.05) in diabetic patients. Ratios of integrated insulin to connecting peptide responses suggest a reduced (hepatic) insulin extraction in control subjects after oral as compared to intravenous glucose. This was not the case in diabetic patients. Immunoreactive gastric inhibitory polypeptide responses were not different between control subjects and diabetic patients. A reduced or lost incretin effect in the face of normal gastric inhibitory polypeptide response in Type 2 diabetic patients may be explained by decreased sensitivity of the B cells towards the insulinotropic effect of gastric inhibitory polypeptide or to hyposecretion or reduced effectiveness of as yet unidentified humoral or nervous gut factors with incretin activity.

[1]  K. Tranberg.  Hepatic uptake of insulin in man. , 1979, The American journal of physiology.

[2]  K. Polonsky,et al.  Glucose ingestion in dogs alters the hepatic extraction of insulin. In vivo evidence for a relationship between biologic action and extraction of insulin. , 1982, The Journal of clinical investigation.

[3]  W. Creutzfeldt,et al.  Influence of gastric inhibitory polypeptide antiserum on glucose-induced insulin secretion in rats. , 1982, Endocrinology.

[4]  J. Halter,et al.  Potentiation of insulin secretory responses by plasma glucose levels in man: evidence that hyperglycemia in diabetes compensates for imparied glucose potentiation. , 1979, The Journal of clinical endocrinology and metabolism.

[5]  Classification and Diagnosis of Diabetes Mellitus and Other Categories of Glucose Intolerance , 1979, Diabetes.

[6]  K. Polonsky,et al.  C-Peptide as a Measure of the Secretion and Hepatic Extraction of Insulin: Pitfalls and Limitations , 1984, Diabetes.

[7]  H. Imura,et al.  [Radioimmunoassay of gastric inhibitory polypeptide]. , 1983, Horumon to rinsho. Clinical endocrinology.

[8]  Reaven Gm,et al.  Steady State Plasma Insulin Response to Continuous Glucose Infusion in Normal and Diabetic Subjects , 1969 .

[9]  E. Pfeiffer,et al.  Über die radioimmunologische Bestimmung von Insulin im Blut , 1965, Klinische Wochenschrift.

[10]  M. Nauck,et al.  Disturbances of the entero-insular axis. , 1983, Scandinavian journal of gastroenterology. Supplement.

[11]  R. Hamman,et al.  The Effect of Insulin Treatment on Insulin Secretion and Insulin Action in Type II Diabetes Mellitus , 1985, Diabetes.

[12]  C. Ito,et al.  Review of Criteria for Diagnosis of Diabetes Mellitus Based on Results of Follow-up Study , 1983, Diabetes.

[13]  P. Giacomoni,et al.  Gastric inhibitory polypeptide release after oral glucose: relationship to glucose intolerance, diabetes mellitus, and obesity. , 1982, The Journal of clinical endocrinology and metabolism.

[14]  K. Polonsky,et al.  Metabolism of C-peptide in the dog. In vivo demonstration of the absence of hepatic extraction. , 1983, The Journal of clinical investigation.

[15]  C. Hales,et al.  Oral glucose decreases hepatic extraction of insulin. , 1983, British medical journal.

[16]  R. Eaton,et al.  Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. , 1986, The Journal of clinical endocrinology and metabolism.

[17]  J. Brown,et al.  Response of gastric inhibitory polypeptide (GIF) to test meal in chronic pancreatitis — Relationship to endocrine and exocrine insufficiency , 1976, Diabetologia.

[18]  J. M. May,et al.  The Effect of Endogenous Gastric Inhibitory Polypeptide on Glucose-induced Insulin Secretion in Mild Diabetes , 1978, Diabetes.

[19]  G. Wolters,et al.  EFFECTS OF FASTING ON INSULIN RELEASE, CYCLIC-AMP AND GLUCOSE OXIDATION IN ISOLATED ISLETS OF LANGERHANS , 1975 .

[20]  D. Andersen,et al.  Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. , 1983, Diabetes.

[21]  W. Creutzfeldt,et al.  Reversal of impaired GIP and insulin secretion in patients with pancreatogenic steatorrhea following enzyme substitution , 1980, Diabetologia.

[22]  D. Steiner,et al.  Secretion of Proinsulin C-Peptide by Pancreatic β Cells and its Circulation in Blood , 1969, Nature.

[23]  S. Price,et al.  The Determinants of Insulin Extraction in the Isolated Perfused Rat Liver* , 1979, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[24]  H. Kehlet,et al.  Pancreatic beta cell secretion during oral and intravenous glucose administration. , 2009, Acta medica Scandinavica. Supplementum.

[25]  D L Horwitz,et al.  Kinetics of human connecting peptide in normal and diabetic subjects. , 1978, The Journal of clinical investigation.

[26]  S. Madsbad,et al.  Effect of porcine gastric inhibitory polypeptide on beta-cell function in type I and type II diabetes mellitus. , 1987, Metabolism: clinical and experimental.

[27]  L. Heding.  Radioimmunological determination of human C-peptide in serum , 1975, Diabetologia.

[28]  W. Creutzfeldt,et al.  Preservation of incretin activity after removal of gastric inhibitory polypeptide (GIP) from rat gut extracts by immunoadsorption , 1983, Diabetologia.

[29]  R Luft,et al.  The plasma insulin response to glucose infusion in healthy subjects and in diabetes mellitus. , 1967, Acta endocrinologica.

[30]  W. Creutzfeldt,et al.  The incretin concept today , 1979, Diabetologia.

[31]  E. Mazzaferri,et al.  Gastric Inhibitory Polypeptide (GIP) in Maturity-onset Diabetes Mellitus , 1976, Diabetes.

[32]  R. Unger,et al.  Entero-insular axis. , 1969, Archives of internal medicine.

[33]  J. Brown,et al.  Hypersecretion of Gastric Inhibitory Polypeptide Following Oral Glucose in Diabetes Mellitus , 1977, Diabetes.

[34]  D. Kipnis,et al.  Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects. , 1967, The Journal of clinical investigation.

[35]  T. Kuzuya,et al.  Disappearance rate of endogenous human C-peptide from blood , 1976, Diabetologia.

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

[37]  M. T. Brennan,et al.  Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. , 1967, The Journal of clinical investigation.

[38]  W. Creutzfeldt,et al.  Release of gastric inhibitory polypeptide (GIP) by intraduodenal acidification in rats and humans and abolishment of the incretin effect of acid by GIP-antiserum in rats. , 1979, Gastroenterology.

[39]  G. Reaven,et al.  Steady State Plasma Insulin Response to Continuous Glucose Infusion in Normal and Diabetic Subjects , 1969, Diabetes.

[40]  P. Alto,et al.  Locating the Site(s) of Insulin Resistance in Patients with Nonketotic Diabetes Mellitus , 1976, Diabetes.

[41]  W. Waldhäusl,et al.  Insulin production rate following glucose ingestion estimated by splanchnic C-peptide output in normal man , 1979, Diabetologia.