The Effect of Chronic Hyperinsulinemia on Plasma Adiponectin Levels in Sprague-Dawley Rats

Abstract

Adiponectin is an important vascular protective substance whose levels are reduced in states of insulin resistance. The relationships between plasma insulin levels and adiponectin are not fully understood, and it is not known whether it is the elevated circulating levels of insulin or insulin resistance that directly affects adiponectin levels. The present study evaluates the direct effect of chronic hyperinsulinemia on plasma adiponectin levels. Male Sprague–Dawley rats were treated with insulin (n=15) administered by a sustained-release implant or were given a sham implantation (n=10) as a control group. Body weight, systolic blood pressure, plasma glucose, triglycerides, insulin, and adiponectin were measured at baseline and after 20 and 40 d of treatment. Insulin-treated rats and controls showed a similar increase in body weight. The insulin-treated group had a significant increase in plasma insulin levels and a decrease in plasma glucose levels compared with the sham group, with no change in blood pressure or triglyceride levels. Adiponectin levels remained unchanged despite the significant increase in insulin levels. High circulating insulin levels do not affect plasma adiponectin levels. These results support the concept that the primary defect that results in insulin resistance and hyperinsulinemia is responsible for the altered plasma adiponectin levels in the metabolic syndrome and type 2 diabetes.

adiponectin - insulin - Sprague-Dawley rats

References

• 1 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.  Science. 1993;  259 87-91
• 2 Shimomura I, Funahashi T, Takahashi M. et al . Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity.  Nat Med. 1996;  2 800-803
• 3 Zhang Y, Proenca R, Maffei M. et al . Positional cloning of the mouse obese gene and its human homologue.  Nature. 1994;  372 425-432
• 4 Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity.  J Biol Chem. 1996;  271 10697-10703
• 5 Maeda K, Okubo K, Shimomura I. et al . cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1).  Biochem Biophys Res Commun. 1996;  221 286-289
• 6 Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes.  J Biol Chem. 1995;  270 26746-26749
• 7 Funahashi T, Matsuzawa Y. Hypoadiponectinemia: a common basis for diseases associated with overnutrition.  Curr Atheroscler Rep. 2006;  8 433-438
• 8 Okamoto Y, Kihara S, Funahashi T, Matsuzawa Y, Libby P. Adiponectin: a key adipocytokine in metabolic syndrome.  Clin Sci (Lond). 2006;  110 267-278
• 9 Kumada M, Kihara S, Ouchi N. et al . Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages.  Circulation. 2004;  109 2046-2049
• 10 Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome.  Arterioscler Thromb Vasc Biol. 2004;  24 29-33
• 11 Yamauchi T, Kamon J, Waki H. et al . Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis.  J Biol Chem. 2003;  278 2461-2468
• 12 Arita Y, Kihara S, Ouchi N. et al . Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.  Biochem Biophys Res Commun. 1999;  257 79-83
• 13 Ouchi N, Ohishi M, Kihara S. et al . Association of hypoadiponectinemia with impaired vasoreactivity.  Hypertension. 2003;  42 231-234
• 14 Trujillo ME, Scherer PE. Adiponectin – journey from an adipocyte secretory protein to biomarker of the metabolic syndrome.  J Intern Med. 2005;  257 167-175
• 15 Despres JP, Lamarche B, Mauriege P. et al . Hyperinsulinemia as an independent risk factor for ischemic heart disease.  N Engl J Med. 1996;  334 952-957
• 16 Lempiainen P, Mykkanen L, Pyorala K, Laakso M, Kuusisto J. Insulin resistance syndrome predicts coronary heart disease events in elderly nondiabetic men.  Circulation. 1999;  100 123-128
• 17 Orchard TJ, Becker DJ, Bates M, Kuller LH, Drash AL. Plasma insulin and lipoprotein concentrations: an atherogenic association?.  Am J Epidemiol. 1983;  118 326-337
• 18 Ross R. Atherosclerosis – an inflammatory disease.  N Engl J Med. 1999;  340 115-126
• 19 Wingard DL, Barrett-Connor EL, Ferrara A. Is insulin really a heart disease risk factor.  Diabetes Care. 1995;  18 1299-1304
• 20 Bogan JS, Lodish HF. Two compartments for insulin-stimulated exocytosis in 3T3-L1 adipocytes defined by endogenous ACRP30 and GLUT4.  J Cell Biol. 1999;  146 609-620
• 21 Motoshima H, Wu X, Sinha MK. et al . Differential regulation of adiponectin secretion from cultured human omental and subcutaneous adipocytes: effects of insulin and rosiglitazone.  J Clin Endocrinol Metab. 2002;  87 5662-5667
• 22 Pereira RI, Draznin B. Inhibition of the phosphatidylinositol 3'-kinase signaling pathway leads to decreased insulin-stimulated adiponectin secretion from 3T3-L1 adipocytes.  Metabolism. 2005;  54 1636-1643
• 23 Fain JN, Buehrer B, Tichansky DS, Madan AK. Regulation of adiponectin release and demonstration of adiponectin mRNA as well as release by the non-fat cells of human omental adipose tissue.  Int J Obes (Lond). 2007; 
• 24 Wolfing B, Neumeier M, Buechler C. et al . Interfering effects of insulin, growth hormone and glucose on adipokine secretion.  Exp Clin Endocrinol Diabetes. 2007; 
• 25 Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes.  Biochem Biophys Res Commun. 2002;  290 1084-1089
• 26 Halleux CM, Takahashi M, Delporte ML. et al . Secretion of adiponectin and regulation of apM1 gene expression in human visceral adipose tissue.  Biochem Biophys Res Commun. 2001;  288 1102-1107
• 27 Dullaart RP, Riemens SC, Meinardi JR, Wolffenbuttel BH, Sluiter WJ. Plasma adiponectin is modestly decreased during 24-hour insulin infusion but not after inhibition of lipolysis by Acipimox.  Scand J Clin Lab Invest. 2005;  65 523-531
• 28 Kamari Y, Grossman E, Oron-Herman M. et al . Metabolic stress with a high carbohydrate diet increases adiponectin levels.  Horm Metab Res. 2007;  39 384-388
• 29 Bursztyn M, Ben-Ishay D, Mekler J, Raz I. Chronic exogenous hyperinsulinaemia without sugar supplementation: acute salt-sensitive hypertension without changes in resting blood pressure.  J Hypertens. 1993;  11 703-707
• 30 Bursztyn M, Ben-Ishay D, Mekler J, Raz I. Chronic exogenous hyperinsulinaemia accelerates the development of hypertension in spontaneously hypertensive rats.  Clin Exp Pharmacol Physiol Suppl. 1995;  22 S28-S29
• 31 Bursztyn M, Mekler J, Peleg E, Bernheim J. Subpressor dose of L-NAME unmasks hypertensive effect of chronic hyperinsulinemia.  Hypertension. 2000;  36 872-877
• 32 Pfeiffer AF. Adipose tissue and diabetes therapy: do we hit the target?.  Horm Metab Res. 2007;  39 734-738
• 33 Bedi D, Clarke KJ, Dennis JC. et al . Endothelin-1 inhibits adiponectin secretion through a phosphatidylinositol 4,5-bisphosphate/actin-dependent mechanism.  Biochem Biophys Res Commun. 2006;  345 332-339
• 34 Fasshauer M, Kralisch S, Klier M. et al . Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes.  Biochem Biophys Res Commun. 2003;  301 1045-1050
• 35 Cong L, Chen K, Li J. et al . Regulation of adiponectin and leptin secretion and expression by insulin through a PI3K-PDE3B dependent mechanism in rat primary adipocytes.  Biochem J. 2007;  403 519-525
• 36 Liu BH, Wang YC, Wu SC. et al . Insulin regulates the expression of adiponectin and adiponectin receptors in porcine adipocytes.  Domest Anim Endocrinol. 2007; 
• 37 Krusinova E, Klementova M, Kopecky J. et al . Effect of acute hyperinsulinaemia with and without angiotensin II type 1 receptor blockade on resistin and adiponectin concentrations and expressions in healthy subjects.  Eur J Endocrinol. 2007;  157 443-449

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