Horm Metab Res 2002; 34(1): 21-26
DOI: 10.1055/s-2002-19962
Original Clinical

© Georg Thieme Verlag Stuttgart · New York

Plasma Glucose Regulation and Insulin Secretion in Hypertriglyceridemic Mice

M.  E. C.  Amaral 1 , H.  C. F.  Oliveira 1 , E.  M.  Carneiro 1 , V.  Delghingaro-Augusto 1 , E.  C.  Vieira 1 , J.  A.  Berti 1 , A.  C.  Boschero 1
  • 1Departamento de Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), CP Campinas, SP, Brasil
Further Information

Publication History

Received 3 April 2001

Accepted after Revision 20 August 2001

Publication Date:
14 August 2002 (online)

Abstract

In this study, we examined glucose homeostasis and insulin secretion in transgenic mice overexpressing the human apolipoprotein CIII gene (apo CIII tg). These mice have elevated plasma levels of triglycerides, FFA and cholesterol compared to control mice. The body weight, plasma glucose, and insulin levels, glucose disappearance rates, areas under the ipGTT curve for adult (4 - 8 mo. old) and aged (20 - 24 mo. old) apo CIII tg mice and the determination of insulin during the ipGTT were not different from those of control mice. However, an additional elevation of plasma FFA by treatment with heparin for 2 - 4 h impaired the ipGTT responses in apo CIII tg mice compared to saline-treated mice. The glucose disappearance rate in heparin-treated transgenic mice was slightly lower than in heparin-treated controls. Glucose (22.2 mmol/l) stimulated insulin secretion in isolated islets to the same extent in saline-treated control and apo CIII tg mice. In islets from heparin-treated apo CIII tg mice, the insulin secretion at 2.8 and 22.2 mmol glucose/l was lower than in heparin-treated control mice. In conclusion, hypertriglyceridemia per se or a mild elevation in FFA did not affect insulin secretion or insulin resistance in adult or aged apo CIII tg mice. Nonetheless, an additional elevation of FFA induced by heparin in hypertriglyceridemic mice impaired the ipGTT by reducing insulin secretion.

References

  • 1 DeFronzo R A. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes.  Diabetes Rev. 1997;  5 177-268
  • 2 Randle P J. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years.  Diabetes Metab Rev. 1998;  14 263-283
  • 3 Boden G, Chen X, Ruiz J, White J V, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake.  J Clin Invest. 1994;  93 2438-2446
  • 4 Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.  J Clin Invest. 1995;  96 1261-1268
  • 5 Randle P J, Garland P B, Hales C N. The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.  Lancet. 1963;  I 785-789
  • 6 Zhou Y-P, Priestman D A, Randle P J, Grill V E. Fasting and decreased B cell sensitivity: important role for fatty acid-induced inhibition of PDH activity.  Am J Physiol. 1996;  270 E988-E994
  • 7 Roden M, Price T B, Perseghin G, Petersen K F, Rothman D L, Cline G W, Shulman G I. Mechanism of free fatty acid-induced insulin resistance in humans.  J Clin Invest. 1996;  97 2859-2865
  • 8 Roden M, Krssak M, Stingl H, Gruber S, Hofer A, Fürnsinn C, Moser E, Waldhäusl W. Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans.  Diabetes. 1999;  48 358-364
  • 9 Choi C S, Kim C-H, Lee W-J, Park J-Y, Hong S-K, Lee K-U. Elevated plasma proinsulin/insulin ratio is a marker of reduced insulin secretory capacity in healthy young men.  Horm Metab Res. 1999;  31 267-270
  • 10 Matschinsky F M. Banting lecture 1995: a lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm.  Diabetes. 1996;  45 223-241
  • 11 Prentki M, Corkey B E. Are the B-cell signaling molecules malonyl-CoA and cytosolic long-chain acyl-CoA implicated in multiple tissue defects of obesity in NIDDM?.  Diabetes. 1996;  45 273-283
  • 12 Zhou Y-P, Grill V E. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.  J Clin Invest. 1994;  93 870-876
  • 13 Zhou Y-P, Berggren P-O, Grill V. A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of B-cell dysfunction in the obese diabetic db/db mouse.  Diabetes. 1996;  46 580-586
  • 14 Capito K, Hansen S E, Hedeskov C J, Islin H, Thams P. Fat-induced changes in mouse pancreatic islet insulin secretion, insulin biosynthesis and glucose metabolism.  Acta Diabetol. 1992;  28 193-198
  • 15 Aalto-Setala K, Fisher E A, Chen X, Chajek-Shaul T, Hayek T, Zechner R, Walsh A, Ramakrishnan R, Ginsberg H N, Breslow J L. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice.  J Clin Invest. 1992;  90 1889-1900
  • 16 Aalto-Setala K, Weinstock P H, Bisgaier C L, Wu L, Smith J D, Breslow J L. Further characterization of the metabolic properties of triglyceride-rich lipoproteins from human and mouse apoC-III transgenic mice.  J Lipid Res. 1996;  37 1802-1811
  • 17 Ito Y, Azrolan N, O'Connel A, Walsh A, Breslow L J. Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice.  Science. 1990;  249 790-793
  • 18 Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM.  Diabetes. 1997;  46 3-10
  • 19 Laws A. Free fatty acid, insulin resistance and lipoprotein metabolism.  Curr Opin Lipidol. 1996;  7 172-177
  • 20 Reaven G M, Mondon C E, Chen Y-D I, Breslow J L. Hypertriglyceridemic mice transgenic for the human apolipoprotein CIII gene are neither insulin resistant nor hyperinsulinemic.  J Lipid Res. 1994;  35 820-824
  • 21 Trinder P. Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen.  J Clin Pathol. 1969;  22 158-161
  • 22 Wahlefeld A W. Determination after enzymatic hydrolysis. In: Bergmeyer HU (ed) Methods of enzymatic analysis. N.Y.; Academic Press 1974: 1831-1835
  • 23 Allain C A, Poon L S, Chun C SG, Richmond W, FU P C. Enzymatic determination of total serum cholesterol.  Clin Chem. 1974;  20 470-475
  • 24 Scott A M, Atwater I, Rojas E. A method for the simultaneous measurement of insulin release and B-cell membrane potential in single mouse islets of Langerhans.  Diabetologia. 1981;  21 470-475
  • 25 Withers D J, Gutierrez J S, Towery H, Burks D J, Ren J, Previs S, Zhang Y, Bernal D, Pons S, Schulman G I, Bonner-Weir S, White M F. Disruption of IRS-2 causes type 2 diabetes in mice.  Nature. 1998;  391 900-904
  • 26 Matthews J NS, Altman D G, Campbell M J, Royston P. Analysis of serial measurements in medical research.  Brit Med J. 1990;  27 230-235
  • 27 Bonora E, Moghetti P, Zancanaro C, Cigolini M, Querena M, Cacciatori V, Corgnati A, Muggeo M. Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies.  J Clin Endocrinol Metab. 1989;  68 374-378
  • 28 Boschero A C, Szpak-Glasman M, Carneiro E M, Bordin S, Paul I, Rojas E, Atwater I. Oxotremorine-m potentiation of glucose-induced insulin release from rat islets involves M3 muscarinic receptors.  Am J Physiol. 1995;  268 E336-E342
  • 29 Higashi K, Sighe H, Ito T, Nakajima K, Ishikawa T, Nakamura H, Ohsuku F. Impaired glucose tolerance without hypertriglyceridemia does not enhance postprandial lipemia.  Horm Metab Res. 2001;  33 101-105
  • 30 Chen M, Breslow J L, Li W, Leff T. Transcriptional regulation of the apo C-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels.  J Lipid Res. 1994;  35 1918-1924
  • 31 Piatti P M, Monti L D, Baruffaldi L, Magni F, Paroni R, Fermo I, Costa S, Santambrogio G, Nasser R, Marchi M, Galli-Kienle M, Pontiroli A E, Pozza G. Effects of an acute increase in plasma triglycerides levels on glucose metabolism in man.  Metabolism. 1995;  44 883-889
  • 32 Deeney J T, Gromada J, Høy M, Olsen L, Rhodes C J, Prentki M, Bergreen P-O, Corkey C E. Acute stimulation with long chain acyl-CoA enhances exocytosis in insulin-secreting cells (HIT-T15 and NMRI β-cells).  J Biol Chem. 2000;  275 9363-9368
  • 33 Vettor R, Lombardi A M, Fabris R, Serra R, Pagano C, Macor C, Federspil G. Substrate competition and insulin action in animal models.  Int J Obes Relat Metab Disord. 2000;  24 (Suppl. 2) S22-S24
  • 34 Purrello F, Rabuazzo A M. Metabolic factors that affect beta-cell function and survival.  Diabetes Nutr Metab. 2000;  13 84-91
  • 35 Cruz W S, Kwon G, Marshall C A, McDaniel M L, Semenkovich F. Glucose and insulin stimulate heparin-releasable lipoprotein lipase activity in mouse islets and INS-1 cells: a potential link between insulin resistance and β-cell dysfunction.  J Biol Chem. 2001;  276 12 162-12 168
  • 36 Marshall B A, Tordjman K, Host H H, Ensor N J, Kwon G, Marshall C A, Coleman T, McDaniel M L, Semenkovich C F. Relative hypoglycemia and hyperinsulinemia in mice with heterozygous lipoprotein lipase (LPL) deficiency.  J Biol Chem. 1999;  274 27 426-27 432

A. C. Boschero

Departamento de Fisiologia e Biofísica · Instituto de Biologia · Universidade Estadual de Campinas (UNICAMP) · CP 6109 Campinas, SP

13083-970 Brasil

Fax: + 55 (19) 289 3124

Email: boschero@unicamp.br

    >