Indomethacin Does Not Affect Endogenous Glucose Production in Type 2 Diabetes Mellitus

In healthy subjects, basal endogenous glucose production is partly regulated by paracrine intrahepatic factors. It is currently unknown whether paracrine intrahepatic factors also influence the increased basal endogenous glucose production in patients with type 2 diabetes mellitus. Administration of indomethacin to patients with type 2 diabetes mellitus stimulates endogenous glucose production and inhibits insulin secretion. Our aim was to evaluate whether this stimulatory effect on glucose production is solely attributable to inhibition of insulin secretion. In order to do this, we administered indomethacin to 5 patients with type 2 diabetes during continuous infusion of somatostatin to block endogenous insulin and glucagon secretion and infusion of basal concentrations of insulin and glucagon in a placebo-controlled study. Endogenous glucose production was measured 3 hours after the start of the somatostatin, insulin and glucagon infusion, for 4 hours after administration of placebo/indomethacin, by primed, continuous infusion of [6,6-²H₂] glucose. At the time of administration of placebo or indomethacin, there were no significant differences in plasma glucose concentrations and endogenous glucose production rates between the two experiments (16.4 ± 2.09 mmol/l vs. 16.6 ± 1.34 mmol/l and 17.7 ± 1.05 µmol/kg/min and 17.0 ± 1.06 µmol/kg/min), control vs. indomethacin). Plasma glucose concentration did not change significantly in the four hours after indomethacin or placebo administration. Endogenous glucose production in both experiments was similar after both placebo and indomethacin. Mean plasma C-peptide concentrations were all below the detection limit of the assay, reflecting adequate suppression of endogenous insulin secretion by somatostatin. There were no differences in plasma concentrations of insulin (76 ± 5 vs. 74 ± 4 pmol/l) and glucagon (69 ± 8 vs. 71 ± 6 ng/l) between the studies with levels remaining unchanged in both experiments. Plasma concentrations of cortisol, epinephrine, and norepinephrine were similar in the two studies and did not change significantly. We conclude that indomethacin stimulates endogenous glucose production in patients with type 2 diabetes mellitus by inhibition of insulin secretion.

Key words:

Somatostatin - Insulin - Indomethacin - Endogenous Glucose Production - Type 2 Diabetes

References

• 1 Corssmit E P, Romijn J A, Endert E, Sauerwein H P. Indomethacin stimulates basal glucose production in humans without changes in concentrations of glucoregulatory hormones.  Clin Science. 1993;  85 679-685
• 2 Bowen H F, Moorhouse J A. Glucose turnover and disposal in maturity-onset diabetes.  J Clin Invest. 1973;  52 3033-3045
• 3 Dresner A, Laurent D, Marcucci M, Griffin M E, Dufour S, Cline G W, Slezak L A, Andersen D K, Hundal R S, Rothman D L, Petersen K F, Shulman G I. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.  J Clin Invest. 1999;  103 253-259
• 4 Figlewicz D P, Patterson T A, Zavosh A, Brot M D, Roitman M, Szot P. Neurotransmitter transporters: target for endocrine regulation.  Horm Metab Res. 1999;  31 335-339
• 5 Mevorach M, Giacca A, Aharon Y, Hawkins M, Shamoon H, Rossetti L. regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus.  J Clin Invest. 1998;  102 744-753
• 6 Pereira Arias A M, Romijn J A, Corssmit E P, Ackermans M T, Nijpels G, Endert E, Sauerwein H P. Indomethacin decreases insulin secretion in patients with type 2 diabetes mellitus.  Metabolism. 2000;  49 839-844
• 7 Sindelar D K, Chu C A, Venson P, Donahue E P, Neal D W, Cherrington A D. Basal hepatic glucose production is regulated by the portal vein insulin concentration.  Diabetes. 1998;  47 523-529
• 8 Hother-Nielsen O, Beck-Nielsen H. On the determination of basal glucose production rate in patients with type 2 (non-insulin-dependent) diabetes mellitus using primed-continuous 3-³H-glucose infusion.  Diabetologia. 1990;  33 603-610
• 9 Reinauer H F, Gries A, Hubinger A, Knode O, Severing K, Susanto F. Determination of glucose turnover and glucose oxidation rates in man with stable isotope tracers.  J Clin Chem Clin Biochem. 1990;  28 505-511
• 10 Steele R. Influences of glucose loading and of injected insulin on hepatic glucose output.  Ann NY Acad Sci. 1959;  82 420-430
• 11 Turk J J, Colca R, Kotagal N, McDaniel M L. Arachidonic acid metabolism in isolated pancreatic islets. I. Identification and quantitation of lipoxygenase and cyclooxygenase products.  Biochim Biophys Acta. 1984;  794 110-124
• 12 Robertson R P, Gavareski D J, Porte D J, Bierman E L. Inhibition of in vivo insulin secretion by prostaglandin E1.  J Clin Invest. 1974;  54 310-315
• 13 Endres S, Cannon J G, Ghorbani R, Dempsey R A, Sisson S D, Lonnemann G, Van der Meer J W, Wolff S M, Dinarello C A. In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition, and evidence of independent gene regulation.  Eur J Immunol. 1989;  19 2327-2333
• 14 Robertson R P. Dominance of cyclooxygenase-2 in the regulation of pancreatic islet prostaglandin synthesis. [Review, 30 refs].  Diabetes. 1998;  47 1379-1383
• 15 McDaniel M L, Kwon G, Hill J R, Marshall C A, Corbett J A. Cytokines and nitric oxide in islet inflammation and diabetes. [Review, 41 refs].  Proc Soc Exp Biol. 1996;  211 24-32
• 16 Kulkarni R N, Bruning J C, Winnay J N, Postic C, Magnuson M A, Kahn C R. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes.  Cell. 1999;  96 329-339
• 17 Christensen J R, Hammond B J, Smith G D. Indomethacin inhibits endocytosis and degradation of insulin.  Biochem Biophys Res Commun. 1990;  173 127-133