Hostname: page-component-76fb5796d-r6qrq Total loading time: 0 Render date: 2024-04-27T00:52:04.436Z Has data issue: false hasContentIssue false
  • English
  • Français

Improvement of insulin response in the streptozotocin model of insulin-dependent diabetes mellitus. Insulin response with and without a long-acting insulin treatment

Published online by Cambridge University Press:  01 May 2009

L. Nordquist  and
M. Sjöquist
L. Nordquist*
Affiliation:
Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University, Uppsala, Sweden
M. Sjöquist
Affiliation:
Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University, Uppsala, Sweden
*
E-mail: Lina.Nordquist@medcellbiol.uu.se
Get access

Abstract

Streptozotocin-induced diabetes mellitus (STZ-DM) in rats is a model of type 1 diabetes, which is commonly used to study diabetes, but differs from human diabetic pathophysiology in its insulin resistance. An STZ-DM rat can be administered five times the dose of insulin compared to that of a diabetic patient. Thus, attaining normoglycaemia in STZ-DM rats with insulin injections is complicated, and it involves an obvious risk of overdosing before getting a response. This study was designed to investigate whether suboptimal treatment with long-acting insulin restores insulin sensitivity in the STZ-DM rat, and thus an approach to more closely mimic the human condition. Male Sprague-Dawley rats were made diabetic by means of a single intravenous injection of STZ (55 mg/kg body weight (BW)), resulting in an increase in blood glucose (BG) from 6.5 ± 0.2 to 22.5 ± 1.0 mmol/l (P ⩽ 0.05) within 24 h. After treating the STZ-DM rats with vehicle for 14 days, BG was 26.1 ± 1.1 mmol/l, and the response to a single injection of fast-acting insulin (Humalog, 5 IE/kg BW) was a 23% reduction in BG. Thereafter, the rats were treated daily with a suboptimal dose of long-acting insulin for a total of 7 days (Insulatard, 5 IE/kg per day), which resulted in a BG level of 19.4 ± 2.7. The response to fast-acting insulin after the suboptimal treatment was a 61% reduction in BG. Thereafter, the animals were vehicle-treated for another 7 days, which resulted in a response to fast-acting insulin similar to the initial values (−34%). Furthermore, the group treated with suboptimal doses of long-acting insulin had a longer duration of the reduction in BG (150 min, as opposed to 90 min in the vehicle-treated groups). We conclude that the development of a decreased insulin response occurs rapidly within the first 2 weeks after the onset of diabetes in STZ-DM rats. This leads to a brief and significantly reduced decrease in BG when fast-acting insulin is administered. The insulin response is increased by treatment with suboptimal doses of long-acting insulin, but rapidly decreases again when treatment is withdrawn. Regular administration of suboptimal insulin doses may provide an approach to eliminate the effects of a lowered insulin response.

Keywords

insulin responsereversalSTZ-DMdiabetesanimal model
Type
Full Paper
Information
animal , Volume 3 , Issue 5 , May 2009 , pp. 685 - 689
Copyright
Copyright © The Animal Consortium 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ader, M, Richey, JM, Bergman, RN 1998. Evidence for direct action of alloxan to induce insulin resistance at the cellular level. Diabetologia 41, 1327–1336.CrossRefGoogle ScholarPubMed
Ahmed, AB, Mallias, J, Home, PD 1998. Optimization of evening insulin dose in patients using the short-acting insulin analog lispro. Diabetes Care 21, 1162–1166.CrossRefGoogle ScholarPubMed
Bikhazi, AB, Azar, ST, Birbari, AE, El-Zein, GN, Haddad, GE, Haddad, RE, Bitar, KM 2000. Characterization of insulin-resistance: role of receptor alteration in insulin-dependent diabetes mellitus, essential hypertension and cardiac hypertrophy. European Journal of Pharmaceutical Science 11, 299–306.CrossRefGoogle ScholarPubMed
Bonini, JA, Colca, J, Hofmann, C 1995. Altered expression of insulin signaling components in streptozotocin-treated rats. Biochemical and Biophysical Research Communications 212, 933–938.CrossRefGoogle ScholarPubMed
Burvin, R, Armoni, M, Karnieli, E 1994. In vivo insulin action in normal and streptozotocin-induced diabetic rats. Physiology and Behavior 56, 1–6.CrossRefGoogle ScholarPubMed
Cameron-Smith, D, Collier, GR, O’Dea, K 1994. Reduction in hyperglycemia by mild food restriction in streptozotocin induced diabetic rats improves insulin sensitivity. Hormone and Metabolic Research 26, 316–321.CrossRefGoogle ScholarPubMed
Cheta, D 1998. Animal models of type I (insulin-dependent) diabetes mellitus. Journal of Pediatric Endocrinology and Metabolism 11, 11–19.CrossRefGoogle ScholarPubMed
Churchill, P, Churchill, M, Bidani, A, Dunbar, J Jr 1993. Streptozotocin-induced renal hemodynamic changes in isogenic Lewis rats: a kidney transplant study. American Journal of Physiology 264, F100–F105.Google ScholarPubMed
Cournarie, F, Auchere, D, Chevenne, D, Lacour, B, Seiller, M, Vauthier, C 2002. Absorption and efficiency of insulin after oral administration of insulin-loaded nanocapsules in diabetic rats. International Journal of Pharmaceutics 242, 325–328.CrossRefGoogle ScholarPubMed
Feldman, EC, Nelson, RW 2004. Canine and feline endocrinology and reproduction, 3rd edition. W.B. Saunders, Philadelphia.Google Scholar
Gai, W, Schott-Ohly, P, Schulte im Walde, S, Gleichmann, H 2004. Differential target molecules for toxicity induced by streptozotocin and alloxan in pancreatic islets of mice in vitro. Experimental and Clinical Endocrinology and Diabetes 112, 29–37.CrossRefGoogle ScholarPubMed
Goto, Y, Kida, K, Kaino, Y, Inoue, T, Ikeuchi, M, Miyagawa, T, Matsuda, H 1988. Insulin action on glucose uptake by soleus muscles of nonobese diabetic mice and streptozotocin diabetic mice. Metabolism 37, 74–78.CrossRefGoogle ScholarPubMed
Gross, ML, Ritz, E, Schoof, A, Adamczak, M, Koch, A, Tulp, O, Parkman, A, El-Shakmak, A, Szabo, A, Amann, K 2004. Comparison of renal morphology in the streptozotocin and the SHR/N-cp models of diabetes. Laboratory Investigation 84, 452–464.CrossRefGoogle ScholarPubMed
Hussin, AH, Skett, P 1988. Lack of effect of insulin in hepatocytes isolated from streptozotocin-diabetic male rats. Biochemical Pharmacology 37, 1683–1686.CrossRefGoogle ScholarPubMed
Junod, A, Lambert, AE, Stauffacher, W, Renold, AE 1969. Diabetogenic action of streptozotocin: relationship of dose to metabolic response. Journal of Clinical Investigation 48, 2129–2139.CrossRefGoogle ScholarPubMed
Karnieli, E, Armoni, M 1990. Regulation of glucose transporters in diabetes. Hormone Research 33, 99–104.CrossRefGoogle ScholarPubMed
Karnieli, E, Hissin, PJ, Simpson, IA, Salans, LB, Cushman, SW 1981. A possible mechanism of insulin resistance in the rat adipose cell in streptozotocin-induced diabetes mellitus. Depletion of intracellular glucose transport systems. Journal of Clinical Investigation 68, 811–814.CrossRefGoogle ScholarPubMed
Karnieli, E, Armoni, M, Cohen, P, Kanter, Y, Rafaeloff, R 1987. Reversal of insulin resistance in diabetic rat adipocytes by insulin therapy. Restoration of pool of glucose transporters and enhancement of glucose-transport activity. Diabetes 36, 925–931.CrossRefGoogle ScholarPubMed
Lager, I, Lonnroth, P, von Schenck, H, Smith, U 1983. Reversal of insulin resistance in type I diabetes after treatment with continuous subcutaneous insulin infusion. British Medical Journal (Clinical Research Edition) 287, 1661–1664.CrossRefGoogle ScholarPubMed
Lisato, G, Cusin, I, Tiengo, A, Del Prato, S, Jeanrenaud, B 1992. The contribution of hyperglycaemia and hypoinsulinaemia to the insulin resistance of streptozotocin-diabetic rats. Diabetologia 35, 310–315.CrossRefGoogle Scholar
Myers, MA, Laks, MR, Feeney, SJ, Mandel, TE, Koulmanda, M, Bone, A, Barley, J, Rowley, MJ, Mackay, IR 1998. Antibodies to ICA512/IA-2 in rodent models of IDDM. Journal of Autoimmunity 11, 265–272.CrossRefGoogle ScholarPubMed
Palm, F, Ortsäter, H, Hansell, P, Liss, P, Carlsson, PO 2004. Differentiating between effects of streptozotocin per se and subsequent hyperglycemia on renal function and metabolism in the streptozotocin-diabetic rat model. Diabetes/Metabolism Research and Reviews 20, 452–459.CrossRefGoogle ScholarPubMed
Peschke, E, Ebelt, H, Bromme, HJ, Peschke, D 2000. ‘Classical’ and ‘new’ diabetogens – comparison of their effects on isolated rat pancreatic islets in vitro. Cellular and Molecular Life Sciences 57, 158–164.CrossRefGoogle ScholarPubMed
Qi, D, Pulinilkunnil, T, An, D, Ghosh, S, Abrahani, A, Pospisilik, JA, Brownsey, R, Wambolt, R, Allard, M, Rodrigues, B 2004. Single-dose dexamethasone induces whole-body insulin resistance and alters both cardiac fatty acid and carbohydrate metabolism. Diabetes 53, 1790–1797.CrossRefGoogle ScholarPubMed
Rakieten, N, Rakieten, ML, Nadkarni, MV 1963. Studies on the diabetogenic action of streptozotocin (NSC-37917). Cancer Chemotherapy Reports 29, 91–98.Google ScholarPubMed
Rand, JS, Marshall, RD 2005. Diabetes mellitus in cats. Veterinary Clinics of North America: Small Animal Practice 35, 211–224.CrossRefGoogle ScholarPubMed
Rolla, A 2004. The pathophysiological basis for intensive insulin replacement. International Journal of Obesity and Related Metabolic Disorders: Journal of the International Association for the Study of Obesity 28 (suppl. 2), S3–S7.CrossRefGoogle ScholarPubMed
Scarlett, JA, Gray, RS, Griffin, J, Olefsky, JM, Kolterman, OG 1982. Insulin treatment reverses the insulin resistance of type II diabetes mellitus. Diabetes Care 5, 353–363.CrossRefGoogle ScholarPubMed
Solomon, SS, Deaton, J, Harris, G, Smoake, JA 1989. Studies of insulin resistance in the streptozotocin diabetic and BB rat: activation of low Km cAMP phosphodiesterase by insulin. American Journal of Medical Science 297, 372–376.CrossRefGoogle Scholar
Taniyama, H, Hirayama, K, Kagawa, Y, Kurosawa, T, Tajima, M, Yoshino, T, Furuoka, H 1999. Histopathological and immunohistochemical analysis of the endocrine and exocrine pancreas in twelve cattle with insulin-dependent diabetes mellitus (IDDM). The Journal of Veterinary Medical Science/the Japanese Society of Veterinary Science 61, 803–810.CrossRefGoogle ScholarPubMed
Veleminsky, J, Burr, IM, Stauffacher, W 1970. Comparative study of early metabolic events resulting from the administration of the two diabetogenic agents alloxan and streptozotocin. European Journal of Clinical Investigation 1, 104–108.CrossRefGoogle ScholarPubMed
Weintrob, N, Benzaquen, H, Galatzer, A, Shalitin, S, Lazar, L, Fayman, G, Lilos, P, Dickerman, Z, Phillip, M 2003. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens in children with type 1 diabetes: a randomized open crossover trial. Pediatrics 112, 559–564.CrossRefGoogle ScholarPubMed
Weiss, RB 1982. Streptozocin: a review of its pharmacology, efficacy, and toxicity. Cancer Treatment Reports 66, 427–438.Google ScholarPubMed
Wilson, GL, Leiter, EH 1990. Streptozotocin interactions with pancreatic beta cells and the induction of insulin-dependent diabetes. Current Topics in Microbiology and Immunology 156, 27–54.Google ScholarPubMed