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Figure 6 The hyperbolic insulin sensitivity/secretion curve. In normal individuals, insulin secretion and insulin sensitivity are related and follow a hyperbolic curve. As insulin sensitivity decreases (or insulin resistance increases) by moving up the curve from point A to point B, insulin secretion increases. In individuals with abnormal glucose homeostasis, insulin secretion cannot compensate appropriately for a change in insulin resistance, leading to the development of impaired glucose tolerance (IGT; point C) or type 2 diabetes (T2DM; point D). (Adapted with permission from Kahn, S. E. J. Clin. Endocrinol. Metab. 2001, 86, 4047. Copyright 2001, The Endocrine Society.)

of b-cells; 'exhaustion' of b-cell function secondary to long-standing insulin resistance; b-cell desensitization from glucose or lipid toxicity as a result of chronic hyperglycemia; and elevated FFA levels, and amyloid deposition, causing a reduced b-cell mass.

6.19.4 Animal Models of Diabetes

Animal models have been essential to diabetes research since before the discovery of insulin in 1922. For more than 50 years, the insulin used clinically for treatment was isolated from bovine and swine pancreases obtained at packing houses throughout the world. Animal models have been very informative for studies of regulation of nutrient metabolism and understanding the mechanisms of insulin resistance. Models of T1DM consist of insulinopenic animals whose b-cells have been destroyed chemically by autoimmunity or are genetically absent. Animal models of T2DM have been developed by the selective breeding of naturally diabetic animals and genetic alterations inducing diabetes, obesity, or insulin resistance. This section is not intended to be a comprehensive review of animal models of diabetes, but to provide a sample of current research models. Table 4 summarizes the animal models that are currently used in diabetes research.37

6.19.4.1 Animal Models of Type 1 Diabetes

6.19.4.1.1 Animals with p-cell destroyed by chemical cytotoxins

Alloxan, a pyrimidine structurally similar to glucose and uric acid, directly disrupts b-cell membrane permeability and produces irreversible b-cell damage within 12 h in most animals. Intracellularly, alloxan is reduced to dialuric acid, which then undergoes autoreoxidation to alloxan. As a byproduct of this cycle, superoxide radicals are produced and cause damage to various cellular constituents.38 Furthermore, inhibition of the tricarboxylic acid cycle and calcium (Ca2 + )-dependent dehydrogenases in the mitochondria causes ATP deficiency, cessation of insulin production, and eventual b-cell death.

Streptozotocin is an equally destructive agent for b-cells. The molecular structure of streptozotocin includes a glucose-like moiety that facilitates transportation across the cell membrane, and a nitrosourea moiety that causes b-cell toxicity. Streptozotocin induces DNA strand breaks and reduces the intracellular level of NAD, a substrate for poly (ADP-ribose) synthase that is involved in DNA repair.39 Streptozotocin-treated animals may retain some insulin-secreting capacity due to its dose-dependent effects, thereby avoiding a ketotic state and dependence on exogenous insulin for survival. Streptozotocin-treated animals, however, have a high frequency of pancreatic islet tumors.

Table 4 Animal models in diabetes research

Animals with ß-cells destroyed by chemical cytokines

Animals with autoimmune diabetes with spontaneous onset causing b-cell loss

Genetically altered animals with various forms of diabetes Insulin-resistant mutant rodents with diabetes and obesity

Rodents with spontaneous diabetes of varying etiology

Rodents with overnutrition-evoked diabetes and obesity

Diabetic rodents isolated by selective breeding from normal pools

Diabetic non-rodents

Alloxan Streptozocin

BB rats NOD mice LETL rats Torri rat

LEW1AR1/ZTM-iddm rat

Multiple transgenic and gene-disrupted animals (mainly mice)

C57BKs db mice (leprdb) C57BL6J ob mice (lepob) Yellow Av and Avy mice KK mice NZO mice

Zucker fa rats (lep/") and BBZ/Wor rats Zdf/Drtfa rats

Wistar-Kyoto diabetic/fatty rat group

Corpulent rat group including SHR/N-cp, LA/N-cp,

SHHF/Mcc-cp NON mice WBN/Kob rats eSS rats BHE/Cdb rats OLETF rats NSY mice

Koletzky (SHROB) rats (fa*) Hypertriglyceridemic (HTG) rats

Psammomys obesus (sand rats) Acomys cahirinus (spiny mice) C57BL/6J mice

GK (Goto-Kakizaki) rats Cohen sucrose-induced rats

Primates Dogs and cats

Reprinted from Shafrir, E. In Ellenberg & Rifkin's Diabetes Mellitus, McGraw-Hill: New York, 2003, Chapter 16, p 231, with permission

6th ed.; Porte, D., Jr., Sherwin, R. S., Baron, A., Eds.; from McGraw-Hill.

6.19.4.1.2 Animals with autoimmune diabetes

Animal models of T1DM (autoimmune diabetes in BB rats and NOD mice) have been highly instrumental in the rapid development of our current understanding of the basic mechanisms of autoimmune disorders in humans, especially T1DM.

BB rats abruptly develop classic features of decompensated diabetes (weight loss, polyuria, polydipsia, glucosuria, and ketoacidosis) between 60 and 120 days of age. They have marked hyperglycemia, hypoinsulinemia, insulitis, and loss of b-cells. Over the course of 1-5 days, endogenous insulin levels diminish and these diabetic animals become totally insulin dependent for survival. The autoimmune process40 in BB rats is not isolated to the islet cells, but frequently results in a polyendocrine syndrome associated with lymphocytic thyroiditis, and autoantibodies against smooth and skeletal muscle, gastric parietal cells, thyroglobulin, and thyroid cells.

The non-obese diabetic (NOD) mouse has provided insight into the complex interaction between a genetic predisposition for T1DM and the role of environmental, nutritional, and hormonal influences on disease penetrance. NOD mice have a polygenic mutation that causes the absence of a histocompatibility molecule and affects immune function. NOD mice develop insulitis around 4-5 weeks of age, characterized by lymphocytic islet infiltration and P-cell destruction.41 Progression to overt diabetes occurs between 13 and 30 weeks. Classically, the mice develop severe hyperglycemia, insulin deficiency, and p-cell loss.

6.19.4.2 Animal Models of Type 2 Diabetes

6.19.4.2.1 Genetically altered animals

Genetic manipulation has been widely used to delete specific genes in the insulin signal transduction pathway, providing significant insights into molecular mechanism and biochemical pathways of human metabolism. Homologous recombination targeted gene knockouts in mice have become a powerful strategy for the study of monogenic and polygenic disorders.

Monogenic defects in insulin action have been demonstrated through deletion of whole-body or tissue-specific components of the insulin-signaling pathway (Figure 4). Various degrees of insulin resistance can be created in mice, depending on the specific protein and on its localization or importance in the insulin-signaling cascade. Insulin receptor heterozygous knockout mice exhibit a 50% reduction in insulin receptor expression and develop overt diabetes. IRS-deficient mice manifest significant hepatic insulin resistance and lack compensatory p-cell hyperplasia.42 GLUT-4 heterozygotic knockout mice show a 50% decrease in GLUT-4 expression in adipose tissue and skeletal muscle and have a phenotype with hypertension, insulin resistance, and T2DM. However, GLUT-4 homozygotic knockout mice only develop moderate insulin resistance, suggesting a compensatory mechanism for glucose transport that has not been identified. Polygenic models support the hypothesis that multiple minor defects in insulin secretion and insulin action leads to T2DM and emphasize the importance of interactions of different genetic loci in the production of diabetes. Knockout animal models, however, provide insight only into the function of specific gene products and do not necessarily invoke meaning into interspecies physiology.

6.19.4.2.2 Insulin-resistant mutant rodents with diabetes and obesity

Homozygous mice for Lepob mutation fail to produce leptin, resulting in a markedly obese, hyperphagic mouse with insulin resistance and elevated insulin levels. Additional hypothalamic abnormalities of leptin deficiency contribute to obesity by causing a hypometabolic state. Mice with homozygosity for the leptin receptor mutation (Lepr3®) have a more severe diabetic phenotype, becoming mildly hyperglycemic at 6-8 weeks and overtly diabetic within 4-6 months due to P-cell dysfunction.43 The New Zealand obese (NZO) mouse44 has a defect in the glycolytic pathway in pancreatic p-cells resulting in defective glucose-dependent insulin secretion and increased adiposity. Subsequent hepatic and peripheral insulin resistance with glucose intolerance is seen in obese NZO males. Unfortunately, NZO mice are extremely susceptible to autoimmune disorders affecting both connective tissue and the insulin receptor, which make analysis of this model complicated. The Zucker Diabetic Fatty (ZDF) rat is a useful model for T2DM in that it develops impaired glucose tolerance in the presence of an inherited obesity gene mutation that results in a shortened leptin receptor protein and leptin insensitivity. The ZDF rat phenotype includes obesity, elevated leptin levels, hyperglycemia, insulin resistance, T2DM, hypertriglyceridemia, and hypercholesterolemia. Female ZDF rats do not have the same profile as their male counterparts, possibly due to a slower P-cell depletion rate than that of the male.

6.19.4.2.3 Rodents with spontaneous diabetes

Breeding stock for the Bureau of Home Economics (BHE/Cdb) rat45 was selected for the presence of hyperlipidemia and hyperglycemia in the absence of obesity and renal dysfunction. Maternally inherited mitochondrial DNA mutations are responsible for hepatic defects in the coupling of mitochondrial respiration to ATP synthesis and results in elevated rates of gluconeogenesis. Initially, the increase in hepatic glucose production is compensated by increased peripheral tissue glucose uptake, oxidation, and lipogenesis. Diminished glucose-stimulated insulin secretion follows and leads to diabetes.

Otsuka Long-Evans Tokushima Fatty (OLETF) rats46 have a selective deletion mutation in a cholecystokinin receptor and are associated with a sex-linked gene Odb-1 that leads to a phenotype comparable to T2DM. The characteristic features of OLETF rats are mild obesity, hyperlipidemia, a late onset of hyperglycemia (after 18 weeks of age) followed by development of overt DM.

6.19.4.2.4 Rodents with overnutrition-evoked diabetes and obesity

C57BL/6J mice develop severe obesity, hyperglycemia, hyperinsulinemia, and hyperlipidemia if exposed to a high-fat, high-sucrose diet after weaning. Insulin resistance and a blunted glucose-dependent insulin secretion have been observed in this animal model. The gerbil, Psammomys obesus (sand rat),47 is characterized by primary insulin resistance and is a well-defined model for dietary-induced T2DM. Feeding Psammomys a high caloric diet results in a reversible metabolic syndrome consisting of hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and a moderate elevation in body weight. Reducing caloric intake restores normoglycemia in 90% of the animals with recovery of insulin secretion and b-cell granulation. The metabolism of Psammomys is well adapted toward life in a low-energy environment as found in the desert. The capacity to constantly accumulate adipose tissue allows for sustenance and breeding in periods of scarcity.

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