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.
Key words
Glucose Homeostasis
- Insulin Secretion - Apolipoprotein CIII - Transgenic Mice
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