REVIEW ARTICLE
doi: 10.1111/j.1463-1326.2004.00392.x
Development and application of rodent models for type 2 diabetes Desu Chen and Ming-Wei Wang The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China
The increasing worldwide incidence of diabetes in adults constitutes a global public health burden. It is predicted that by 2025, India, China and the United States will have the largest number of people with diabetes [1]. According to the 2003 estimates of the International Diabetes Federation, the diabetes mellitus prevalence in the USA is 8.0% and approximately 90–95% of diabetic Americans have type 2 diabetes – about 16 million people. Type 2 diabetes is a complex, heterogeneous, polygenic disease characterized mainly by insulin resistance and pancreatic b-cell dysfunction. Appropriate experimental models are essential tools for understanding the molecular basis, pathogenesis of the vascular and neural lesions, actions of therapeutic agents and genetic or environmental influences that increase the risks of type 2 diabetes. Among the animal models available, those developed in rodents have been studied most thoroughly for reasons such as short generation time, inherited hyperglycaemia and/or obesity in certain strains and economic considerations. In this article, we review the current status of most commonly used rodent diabetic models developed spontaneously, through means of genetic engineering or artificial manipulation. In addition to these models, the Psammomys obesus, rhesus monkeys and many other species are studied intensively and reviewed by Shafrir [2], Bailey and Flatt [3,4] and Hansen [5]. Keywords: pharmacology, rodents, type 2 diabetes Received 23 December 2003; returned for revision 5 April 2004; revised version accepted 20 April 2004
Spontaneously Diabetic Rodents The information described in this review was obtained through a search of MEDLINE/PubMed for literatures published between 1993 and 2003. Search terms used include ‘type 2 diabetes’, ‘OLETF rats’, ‘GK rats’, ‘db/db mice’, ‘ZDF rats’ and ‘ob/ob mice’. The analysis of our search results is summarized in table 1, and the details of each model are given in the order of its citation frequency and synopsized in table 2.
Otsuka Long-Evans Tokushima Fatty Rats A spontaneously diabetic rat with polyuria, polydipsia and mild obesity was discovered in 1984 in an outbred colony
of Long-Evans rats, which was purchased from Charles River, Canada in 1982. A strain of rats developed from this rat by selective breeding has since been maintained at the Otsuka Pharmaceutical and named OLETF [6]. The characteristics of Otsuka Long-Evans Tokushima Fatty (OLETF) rats include: (a) late onset of hyperglycaemia (after 18 weeks of age); (b) a chronic course of disease; (c) mild obesity; (d) clinical onset of diabetes mostly in males; (e) multiple recessive genes are involved in the induction of diabetes, and the transmittal of one of the diabetogenic genes, designated as odb-1, is linked to the X-chromosome of OLETF rats; (f) the changes of pancreatic islets can be classified into three stages – an early stage (less than 9 weeks of age) with mild lymphocyte infiltration, a hyperplastic stage
Correspondence: Dr Ming-Wei Wang, The National Center for Drug Screening, 189, Guo Shou Jing Road, Shanghai 201203, PR China. E-mail:
[email protected]
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Table 1 Citation frequency of spontaneously diabetic rodents Rodent Model
Articles Frequency (%)
Otsuka Long-Evans Tokushima Fatty rats 290 Goto-Kakizaki rats 170 db/db (C57BL/KsJ-db/db) mice 148 Zucker Diabetic Fatty rats 135 ob/ob (C57BL/6J-ob/ob) mice 114
33.8 19.8 17.3 15.8 13.3
(10–40 weeks of age) with hyperplastic alterations and fibrosis in or around islets and a final stage (more than 40 weeks of age) showing atrophy of islets; and (g) diabetic nephropathy manifested by diffused glomerulosclerosis and nodular lesions (e.g. thickening of basement membranes, mesangial proliferation and fibrin cap). These clinical and pathological features in OLETF rats resemble those of human type 2 diabetes [7]. Expression of cholecystokinin A (CCK-A) receptor mRNA in the pancreas, small intestine and brain was not detected in OLETF rats by the reverse transcriptase polymerase chain reaction (RT-PCR). The lack of CCK-A receptors results in a reduced ability to process nutrientelicited gastrointestinal satiety signals, which leads to
increases in meal size, overall hyperphagia and obesity [8–10]. Analyses of patterns of hypothalamic gene expression in OLETF rats indicate the presence of a primary deficit in dorsomedial hypothalamus neuropeptide Y signalling. Thus, the obesity in OLETF rats may be the outcome of two regulatory disruptions, one depending upon a peripheral pathway such as meal satiety and the other relating to a central pathway critical to overall energy balance [11]. In OLETF rats, hypertriglyceridaemia led to elevated triglyceride (TG) storage in islets, which subsequently inhibited glucose-induced insulin secretion, via reduced glucokinase activity in the islet. Fat droplets in islets may play an important role in accelerating the development of diabetes [12]. The total content of glucose transporter 4 (GLUT4) protein significantly decreased while the plasma membrane content of the GLUT4 protein in muscles of the diabetic OLETF rats was increased in the basal state. Hyperinsulinaemic clamps increased GLUT4 levels in the plasma membrane in muscles of normal rats but failed to do so in diabetic OLETF rats. The distribution of GLUT4 in OLETF rats is reminiscent of the characteristics of human type 2 diabetes [13].
Table 2 Synopsis of pharmacological applications of spontaneously diabetic rodents Species
Pharmacologically related characteristics
OLETF rats
Lack of CCK-A receptors; deficit in dorsomedial hypothalamus neuropeptide Y signalling; elevated triglyceride storage in islets; significantly decreased total content of GLUT4 in muscles Twofold higher activities of both basal and insulin-stimulated PTP1B; GK-VMH rats as a useful model for non-obese type 2 diabetes with microangiopathy and macroangiopathy Correlations between the glucagon/insulin ratio and the hepatic glucose-6-phosphatase/fructose1,6-diphosphatase activities; elevated renal cortical activities of PI3 kinase, protein kinase B, extracellular signal-regulated protein kinase 1/2-type mitogen-activated protein kinase 25–55% reduction of GLUT4 in the adipose tissue, heart and skeletal muscle; loss of pancreatic duodenal homeobox gene expression; FFA and nitric oxide induced suppression of insulin output
GK rats
db/db mice
ZDF rats
ob/ob mice
Overproduced neuropeptide Y in the hypothalamus; 45% higher hepatic microsomal TG transfer protein mRNA level; b-adrenergic receptor mRNA levels in white and brown adipose tissues reduced by 300-fold
Studies of anti-diabetic agents Beneficial effects of Ca2þ antagonist (Cilnidipine), metformin and truncated GLP-1 on insulin-resistance; PPARg (pioglitazone) agonist improves daily profiles of energy expenditure Long-term and favourable influences of GLP-1 or exendin-4 on b-cell mass and glycemic control
Long-lasting glycemic control by GLP-1 receptor agonist in a dose-dependent manner; combination therapy of PPARg and PPARa agonists improved body weight and glucose-stimulated insulin secretion; PTP1B inhibitors modulates insulin signalling in the liver and fat tissues Nicotinamide or aminoguanidine halted inducible nitric oxide synthase expression in islets; metformin significantly reduced FFA levels; rosiglitazone maintained cell proliferation and blocked b-cell death; b-3-adrenergic receptor agonist improved glucose tolerance and insulin responsiveness GLP-1 increased frequency of large, rapid spikes of [Ca2þ]i; exendin-4 treatment led to weight loss and improved insulin sensitivity; PTP1B antisense oligonucleotides decreased PTP1B protein and elevating other elements in insulin signalling pathway
CCK-A, cholecystokinin A; FFA, free fatty acid; GLUT4, glucose transporter protein 4; GLP-1, glucagons-like peptide 1; GK, Goto-Kakizaki; OLETF, Otsuka Long-Evans Tokushima Fatty; PTP1B, protein tyrosine phosphatase 1B; TG, triglyceride.
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Exercise training is effective at preventing the development of diabetes mellitus in OLETF rats. The cumulative incidences of diabetes mellitus in sedentary (in conventional cages) and trained-control rats (in cages with a fixed rotary wheel) were 78 and 50%, respectively, while neither trained OLETF rats (in exercise wheel cages) nor non-diabetic Long-Evans rats became diabetic. The preventive effect of exercise training against the development of type 2 diabetes lasted for at least 3 months after the cessation of exercise [14,15]. Injection of insulin to OLETF rats was effective at preventing b-cell dysfunction and morphological changes in the pancreas [16]. Cilnidipine, a long-acting dihydropyridine Ca2þ antagonist, had beneficial effects on both insulin resistance and hypertension in OLETF rats [17]. Metformin-induced improvement of insulin resistance in OLETF rats could lower blood pressure, decrease sympathetic activity and reduce body weight [18]. Acarbose prevented and reversed the metabolic derangement and histopathological changes of pancreas in OLETF rats. Moreover, treatment with acarbose, even for a short period, produced a marked delay in the development of insulin insensitivity and obvious diabetes [19]. Administration of pioglitazone, a peroxisome proliferator-activated receptor g (PPARg) agonist, improved daily profiles of energy expenditure through affecting glucose and fat metabolism [20]. A long-term infusion of truncated glucagon-like peptide 1 (GLP-1) increased the glucose infusion rate significantly during a euglycaemic–hyperinsulinaemic clamp experiment. This suggests that truncated GLP-1 is capable of augmenting insulin action in peripheral tissues of diabetics, which can contribute, in part, to improve glucose intolerance in OLETF rats [21].
Goto-Kakizaki Rats The Goto-Kakizaki (GK) rat is a non-obese rodent model of mild type 2 diabetes with early hyperglycaemia, hyperinsulinaemia and insulin resistance. This model was obtained by selective breeding of individuals with mild glucose intolerance from a non-diabetic Wistar rat colony. In GK rats, the neonatal b-cell-mass deficit is considered to be the primary defect leading to basal hyperglycaemia, which is detectable around 3.5 weeks of age. After 8 weeks, hyperglycaemia deteriorates and glucose-stimulated insulin release by the islets is more severely impaired [22]. Heritability of defective b-cell mass and its function in the GK model is thought to reflect the complex interactions of the following
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pathogenic factors: (a) three independent loci containing genes responsible for impaired insulin secretion; (b) heritable gestational metabolic (hyperglycaemic) impairment inducing deficiency in endocrine pancreas; and (c) secondary (acquired) loss of b-cell differentiation due to long-term exposure to hyperglycaemia (glucotoxicity) [23]. Through metabolism, glucose generates adenosine triphosphate (ATP) needed for the closure of the ATP-sensitive Kþ channels and membrane depolarization. In the GK rat pancreatic islet, Kþ induces a delayed [Ca2þ]i response that probably results from a defective metabolism of glucose in this tissue [24,25]. Immunoprecipitation of protein tyrosine phosphatase 1B (PTP1B) from skeletal muscle lysates, and analysis of the enzyme activity indicate that both basal and insulin-stimulated PTP1B activities were twofold higher in skeletal muscle of diabetic GK rats than those of normal rats. This alteration was associated with an increased expression of the enzyme protein. Elevated PTP1B activity would enhance tyrosine dephosphorylation of insulin receptor and its substrates and thereby lead to impaired glucose tolerance and insulin resistance in GK rats [26]. The effects of GLP-1 and its long-acting analogue, exendin-4 (Ex-4), were investigated during the prediabetic period of GK rats. Treatment with GLP-1 or Ex-4 demonstrated long-term and favourable influences on b-cell mass, resulting from enhancement of differentiation (neogenesis), proliferation and glycaemic control in adulthood. Compared to untreated animals, basal plasma glucose levels in 2-month-old treated rats were significantly decreased [27]. In GK rats, a marked prolongation in mean circulation time and a significant reduction in segmental blood flow appeared at an early stage of diabetes. This tendency continued for a period of 5 months, and the endothelial/pericyte ratio was found to be higher in 8-month-old animals as well as in animals greater than 24–30 months of age. These findings suggest that the GK rat appears to be a suitable model for experimental studies on initial or latent-phase diabetic retinopathy [28–30]. Prolonged exposure to hyperglycaemia is one of Key factors in the induction of progressive diabetic nephropathy in humans. The same phenomenon was observed in GK rats. Noticeable morphological changes in kidneys, such as segmental glomerulosclerosis and tubulointerstitial fibrosis, were found only in 2-year-old animals. The renal alterations seen in GK rats at a later stage were similar to those of progressive human diabetic nephropathy [31]. Experimental ventromedial hypothalamic (VMH) lesions induced marked hyperglycaemia
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and a distinct reduction in pancreatic insulin content in male GK rats. Histological examinations of the kidneys from these rats revealed that the glomerular basement membrane was thicker than that of controls. The descending aorta in GK-VMH rats also showed morphologic changes in the intima, characteristic of an early stage of atherosclerosis. Thus, male GK-VMH rats may be a useful animal model for non-obese type 2 diabetes with typical complications such as microangiopathy and macroangiopathy [32,33].
Db/db (C57BL/KsJ-db/db) Mice The diabetes db gene mutation occurred spontaneously in the leptin-receptor-deficient C57BL/KsJ strain of mice from Bar Harbor, ME, USA [34]. It is an autosomal recessive mutation on chromosome 4 with complete penetrance. In diabetic mutant db/db mice, progressive impairment of insulin response to glucose is observable with increasing age. Blood glucose levels do not differ significantly between 5-week-old db/db and þ/þ mice but increase with age in the former until they are 16 weeks old. Consistent with the idea of a protective effect of oestrogen on the pancreatic b-cell, female diabetic db/ db mice survive longer than males. While plasma levels of insulin and glucagon in db/db mice, which peaked at 7 weeks of age, do not reflect the state of hyperglycaemia, the G/I (glucagon/insulin) ratio is roughly in parallel with the development of hyperglycaemia. Analysis of individual values revealed statistically significant correlations between plasma glucose levels and hepatic glucose-6-phosphatase or fructose1,6-diphosphatase activities. There were also marked correlations between the G/I ratio and activities of these two hepatic gluconeogenic enzymes [35]. NN2211, a long-acting, metabolically stable GLP-1 derivative, with enhanced stability due to attachment of the fatty acid moiety, dose dependently reduced glycaemia levels in db/db mice, with an antihyperglycaemic activity still evident 24 h after treatment. b-Cell proliferation rate and mass size were also significantly increased [36]. Another novel GLP-1 receptor agonist, ZP10A, decreased db/db mouse glycosylated haemoglobin A1c (HbA1c) from 8.4% to 6.2% in a dosedependent manner. Fasting blood glucose and glucose tolerance after an oral glucose tolerance test were notably improved. These effects lasted for 40 days after cessation of treatment [37]. Studies have shown that combination therapy of PPARg and PPARa agonists may have beneficial effects on body weight and glucose-stimulated insulin secretion
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(GSIS) in db/db mice. Body-weight gain in db/db mice was less with dual PPAR agonists treatment than with a single agonist such as pioglitazone or pioglitazone plus bezafibrate. Plasma glucose, insulin, TG and free fatty acid (FFA) levels were significantly ameliorated and GSIS was increased [38]. Adipocyte complement-related protein (30 kDa) (Acrp30, adiponectin or AdipoQ) is a fat-derived secreted protein that circulates in blood. Adipose tissue expression of Acrp30 is lower in insulinresistant state, and it is implicated in the regulation of in vivo insulin sensitivity. In obese diabetic db/db mice, mean plasma Acrp30 protein levels increased after long-term treatment using PPARg agonists. Induction of adipose tissue Acrp30 expression and consequent rises in circulating Acrp30 levels represent a novel potential mechanism for PPARg-mediated enhancement of whole-body insulin sensitivity. Acrp30 is likely to be a biomarker of in vivo PPARg activation [39]. In db/db mice, PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion and HbA1c. Hyperinsulinemia was also reduced, with improved insulin sensitivity. PTP1B protein and mRNA were reduced in liver and fat tissues with no effect on skeletal muscle. Insulin signalling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3) kinase regulatory subunit p50a were increased, and PI3-kinase p85a expression was decreased in the liver and fat tissues. These changes in protein expression correlated with increased insulin-stimulated protein kinase B phosphorylation. The expression of liver gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and fructose-1, 6bisphosphatase, was also downregulated. The findings suggest that PTP1B modulates insulin signalling in the liver and fat tissues and that therapeutic modalities targeting PTP1B inhibition may have clinical benefits in type 2 diabetes [40]. Indeed, a series of azolidinediones, prepared as PTP1B inhibitors, with IC50 values in the range of 0.12–0.30 mM, normalized plasma glucose and insulin levels in db/db mice [41]. Experimental data demonstrate that a variety of receptor signalling pathways are activated in the renal cortex of db/db mice, pointing to a role of augmented insulin receptor activity in nephropathy of type 2 diabetes. In db/db mice, renal cortical activities of PI3 kinase, protein kinase B (PKB) and extracellular signal-regulated protein kinase (ERK)1/2type mitogen-activated protein (MAP) kinase were all elevated considerably. The increased renal cortical PI3 kinase activity was partially due to insulin receptor activation, as PI3 kinase activity associated with
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insulin receptor b-chain was increased nearly fourfold. Additionally, the kinase activity of immunoprecipitated b-chain in the diabetic renal cortex and tyrosine phosphorylation of insulin receptor were both augmented [42].
Zucker Diabetic Fatty Rats The diabetic trait in this model originated from a colony of outbred Zucker rats in the laboratory of Dr Walter Shaw at Eli Lilly Research Laboratories in Indianapolis, IN, USA, during 1974–1975. Several groups of animals with diabetic lineage were identified and redefined at the beginning of 1981. The inbred line of Zucker diabetic fatty (ZDF) rats was established in 1985 and developed to a genetic model in 1991. Male Zucker rats homozygous for non-functional leptin receptors (fa/fa) develop obesity, hyperlipidemia and hyperglycaemia, but rats with homozygous dominant (þ/þ) and heterozygous (fa/þ) genotypes remain lean and normoglycaemic. Insulin resistance occurs in young fa/fa rats followed by evolution of an insulinsecretory defect that triggers hyperglycaemia [43]. Thus, the ZDF male rat has become an experimental model for type 2 diabetes, with a predictable progression from prediabetic to diabetic state. Hyperglycaemia is initially manifested at about 7 weeks of age, and all obese male rats are fully diabetic by 12 weeks. Between 7 and 10 weeks, serum insulin levels are high but subsequently drop as pancreatic b-cells cease to respond to glucose stimulus [44]. In this diabetic model, GLUT4 in the adipose tissue, heart and skeletal muscle is reduced by 25–55% [45]. The ZDF rat has both insulin resistance (as a result of a mutant leptin receptor that causes obesity) and inadequate b-cell compensation. Studies demonstrate that the ZDF rat carries a genetic defect in b-cell transcription that is inherited independently of the leptin receptor mutation and insulin resistance. The genetic reduction in b-cell gene transcription in homozygous animals probably contributes to the development of diabetes in the background of insulin resistance [46]. In prediabetic ZDF rats, there is no change in insulin mRNA levels. However, significant reductions (30–70%) of many other islet mRNA levels, such as glucokinase, mitochondrial glycerol-3-phosphate dehydrogenase, voltage-dependent Ca2þ and Kþ channels, CA2þ-ATPase and transcription factor islet-1, could be detected. In contrast, glucose-6phosphatase and 12-lipoxygenase mRNA levels are increased by 40–50%. Gene-expression patterns in the islets of diabetic ZDF rats show marked alterations, including a decrease in insulin mRNA levels associated
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with reduced islet insulin secretion [47]. Chronic and progressive hyperglycaemia in diabetic ZDF rats is related to the loss of insulin and pancreatic duodenal homeobox (PDX-1) mRNAs and lack of glucosestimulated insulin secretion. Prevention of hyperglycaemia could block the associated defects in insulin and PDX-1 gene expression and improve insulin secretion [48]. The lipoapoptosis of b-cells observed in fat-laden islets of ZDF rats results from the overproduction of ceramide, an initiator of the apoptotic cascade which is induced by long-chain fatty acids (FA). The onset of type 2 diabetes is preceded by a striking increase in the plasma levels of FFA and by a sixfold rise in TG content in the pancreatic islets. FFA could be the signal from adipocytes that elicits b-cell compensation sufficient to prevent diabetes [49,50]. Studies show that FFAinduced suppression of insulin output in prediabetic ZDF rats is mediated by nitric oxide (NO). In cultured prediabetic ZDF islets, FFA induced a fourfold rise in NO, upregulated mRNA of inducible nitric oxide synthase (iNOS) and reduced insulin output. Both nicotinamide and aminoguanidine, which lower NO, prevented the FFA-mediated increase in iNOS mRNA, reduced NO and minimized the loss of insulin secretion. In vivo nicotinamide or aminoguanidine treatment of prediabetic ZDF rats stopped iNOS expression in islets and mitigated b-cell dysfunction through blocking b-cell destruction and hyperglycaemia [51]. In ZDF rats, hyperphagia leads to hyperinsulinemia, which upregulates transcription factors that stimulate lipogenesis. This causes ectopic deposition of triacylglycerol in non-adipocytes, thereby providing FA substrate for pathological non-oxidative metabolism, such as ceramide synthesis. In b-cells and myocardium, the resulting functional impairment and apoptosis lead to diabetes and cardiomyopathy. Interventions that lower ectopic lipid accumulation or block FA non-oxidative metabolism and ceramide formation could completely prevent these complications [52]. Metformin prevented hyperglycaemia in diabetic ZDF rats aged between 6 and 12 weeks and significantly reduced TG and FFA levels. It delays the onset of diabetes in the ZDF rat, which is correlated with improvement in b-cell function, consistent with the lipotoxicity hypothesis for adipogenic diabetes [53]. Treatment with rosiglitazone protected obese ZDF rats against loss of b-cell mass through maintaining cell proliferation and blocking increased b-cell death [54]. Insulin release was defective in ZDF obese rats and could be partially restored by GLP-1 therapy. In ZDF islets, the action of GLP-1 is mediated via Ca2þ-independent
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signalling pathway. Infusion of GLP-1 (7–37) in hyperinsulinemic and hyperglycaemic ZDF rats produced a transitory increase in plasma insulin concentration and normalized blood glucose level [55–57]. Studies on dipeptidyl peptidase-IV (DPP-IV) inhibitors in ZDF rats indicated their therapeutic value of delaying progression from impaired glucose tolerance to type 2 diabetes [58]. Long-term b-3-adrenergic receptor agonist treatment in obese ZDF rats improved glucose tolerance and insulin responsiveness through a mechanism similar to that induced by chronic cold exposure, i.e. by stimulating facultative thermogenesis, mitochondriogenesis and glucose utilization in brown and white adipose tissues. The reduction in plasma FFA levels may enhance glucose uptake in skeletal muscles (a tissue that does not express typical b-3-adrenergic receptors) via the glucose–fatty acid cycle [59].
Ob/ob (C57BL/6J-ob/ob) Mice The C57BL/6J-ob/ob mouse originated from the Jackson Laboratory in Bar Harbor, ME, USA [60]. The ob gene was transferred from the stock of origin onto the B/6 genomic background and is located on chromosome 6. The obesity syndrome, which is prominent in ob/ob mice, results from the lack of leptin, a hormone released by fat cells and which acts on brain to suppress feeding and stimulate metabolism. The ob/ob mice are less hyperglycaemic than the db/db mice. Neuropeptide Y (NPY) is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. The same strain of mice deficient in NPY is less obese because of reduced food intake and increased energy expenditure. As a result, these animals are less affected by diabetes, sterility and somatotropic defects. This suggests that NPY is a central effector of leptin deficiency [61]. Chronically elevated NPY levels in the hypothalamus, as seen in genetically obese ob/ob mice, are associated with obesity, a typical symptom of type 2 diabetes, and infertility. Crossing the Y2-receptor knockout mouse [Y2(–/–)] onto the ob/ob background attenuates increased adiposity, hyperinsulinaemia, hyperglycaemia and increased hypothalamic–pituitary–adrenal axis activity of ob/ob mice [62]. Recent studies demonstrate that microsomal TG transfer protein (MTP) is a rate-limiting factor for the assembly and secretion of apoB-containing lipoproteins. Obese diabetic ob/ob mice have 45% higher hepatic MTP mRNA level, 54% higher microsomal TG transfer activity and 70% higher TG concentration compared to
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ob/þ mice. These observations indicate that obesityinduced type 2 diabetes in mice causes increases in hepatic MTP expression and increases the secretion of TG-rich lipoproteins [63]. All b-adrenergic receptor (b-AR) mRNA levels in white and brown adipose tissues were dramatically reduced (by approximately 300-fold) in 12-week-old obese mice. The reduction in the expression of b-1AR and b-3AR impaired b-AR agonist-stimulated, adenylylcyclase response, over a broad concentration range, by greatly lowering the maximum stimulation and shifting the adrenergic sensitivity at low concentrations from a mixed b-1AR/b-2AR response to predominantly b-2AR [64]. The effects of GLP-1 (7–36 amide, GLP-1a) on [Ca2þ]i were determined using Fura-2 fluorescence ratio imaging on cultured ob/ob mouse pancreatic bcells. GLP-1a increases the frequency of sustained, stable plateau responses to elevated glucose and the frequency of large, rapid spikes of increased [Ca2þ]i associated with either plateaus or oscillations [65]. A series of novel GLP-1 analogues displays resistance to plasma DPP-IV degradation and enhances insulin-releasing and antihyperglycaemic activities in 20- to 25-week-old obese diabetic ob/ob mice [66]. Administration of Ex-4 leads to an anti-diabetic effect associated with weight loss and improved insulin sensitivity (up to 32% and 49% respectively) in ob/ob mice [67]. Studies on the effects of the GIP receptor antagonist and exendin (9–39) amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in ob/ob mice provide evidence that GIP is the major physiological incretin of the enteroinsular axis. Administration of (Pro3)GIP, exendin (9–39) amide or a combination of both peptides to fasted ob/ob mice decreased the plasma insulin responses by 42%, 54% or 49% respectively. The hyperinsulinaemia of non-fasted ob/ob mice was decreased by 19%, 27% or 18%, respectively, following injection of (Pro3)GIP, exendin (9–39) amide or combined peptides [68]. Semiquantitative RT-PCR experiments show that PPARg2 mRNA was significantly upregulated in ob/ob mouse liver in comparison with that of wild-type mice. In addition, insulin resistance index was positively associated with liver PPARg2 mRNA expression. The findings suggest a possible compensatory response through which type 2 diabetic and obese animals strive to maintain insulin sensitivity in liver [69]. Experimental obesity in rodents is related to severely defective resistin expression. In response to several different classes of PPARg agonists, resistin expression in ob/ob mouse adipose tissue was increased [70].
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Recent studies indicate that a reduction in PTP1B activity is sufficient to increase insulin-dependent metabolic signalling and to improve insulin sensitivity in ob/ob mice. In PTP1B-antisense-oligonucleotidetreated mice, in which PTP1B protein was decreased by 60% in the liver, there was elevated tyrosine phosphorylation of insulin receptor and its substrates (IRS-1 and IRS-2). A threefold increase in IRS-2associated PI3 kinase activity was accompanied by augmentations of PKB serine phosphorylation in the liver upon insulin stimulation, phosphorylation of PKB substrates and glycogen synthase kinases (3a and 3b) [71].
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Artificially Induced Diabetic Rodents Neonatal Streptozotocin-induced Diabetes Intraperitoneal administration of streptozotocin (STZ) to neonatal rats (2 days postpartum) produces a type 2 diabetes mellitus model in adulthood. At the fourth week, fed serum glucose concentration is normal or mildly elevated due to b-cell regeneration. However, hyperglycaemia develops progressively with age, and by the twelfth week, marked impairment of glucosestimulated insulin release could be observed [73–75].
STZ-Spontaneously Hypertensive Rat (SHR)
Genetically Engineered Diabetic Mice In recent years, genetically engineered mouse models, including transgenic and knockout mice, have been developed for the study of the pathophysiological consequences of defined alterations in a single gene or in a set of candidate diabetogenes, especially the expression of key actors in insulin signalling, action or secretion (table 3 reproduced with permission of EMBO Reports) [72]. In this review, besides the phenotypic alterations of the knockout models, the specific roles of individual genes in the control of glucose homeostasis are also comprehensively addressed. Genetically engineered mice open the door for investigating the role of gene–gene or gene–environment interactions in the development of type 2 diabetes.
Two-day-old SHRs intraperitoneally injected with STZ develop a hyperglycaemic syndrome, associated with other biochemical, morphological and haemodynamic properties that, to some extent, confer insulin resistance combined with hypertension. Plasma glucose levels in STZ-SHRs increase in a dose-dependent manner at the twelfth week. During long-term observations, hyperglycaemia persisted until the twenty-eighth week but later gradually ameliorated, accompanied by continued hypertension as measured at the fifty-second week [76,77].
Fat-fed/STZ-induced Diabetic Rodents Fat-fed/STZ diabetic rodents, developed by combination of diet-induced insulin resistance and relatively-low-dose STZ, provide a novel animal model for type 2 diabetes. It
Table 3 Monogenic and polygenic diabetic mice General or tissue-specific knockout mice GK–/– or b-cell GK–/– GLUT2–/– GLUT4–/– GLUT4–/– IR–/– IRS-1–/– IRS-2–/– IR–/–IRS-1–/– IR–/–IRS-1–/–IRS-2–/– IRS-1–/–GK–/– bIRKO LIRKO Liver GK–/– MIRKO MG4KO PG4KO
Phenotypic alterations Impaired insulin secretion, mild diabetes Moderate insulin resistance, glucose intolerance, decreased adipose mass Insulin resistance, diabetic hypertension Diabetic ketoacidosis, early postnatal death Growth retardation, mild insulin resistance, b-cell hyperplasia, hyperinsulinaemia Severe insulin resistance, b-cell hyperplasia, diabetes in 50% of adult mice Severe insulin resistance in liver, limited b-cell hyperplasia, diabetes in adult mice Sever insulin resistance, early onset of diabetes, marked b-cell hyperplasia Insulin resistance, b-cell hyperplasia, diabetes in adult mice Lack of glucose-induced first phase insulin release, glucose intolerance with ageing Sever insulin resistance, fasting hyperglycaemia, b-cell hyperplasia Mild hyperglycaemia Normal glucose homeostasis, dyslipidaemia, increased adiposity Insulin resistance, glucose intolerance Diabetic ketoacidosis, early postnatal death Insulin resistance in muscle and liver, glucose intolerance, hyperinsulinaemia
GK, Goto-Kakizaki; GLUT, glucose transporter protein; IR, insulin receptor; IRS, insulin receptor substrate.
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simulates the human syndrome and is suitable for expedient in vivo evaluation of anti-diabetic agents. In C57BL/6J mice, insulin resistance could be induced by diets enriched in either fructose or fat, and hyperglycaemia is introduced by injecting a dose of STZ that does not cause diabetes in chow-fed mice. Insulin concentrations initially increase in response to the fructose- or fatrich diets and then decrease to levels still higher than those in chow-fed mice following STZ injection. Accompanied by this decrease in insulin levels after STZ injection, fat- or fructose-fed C57BL/6J mice become significantly hyperglycaemic [78]. Another rodent model employs 7-week-old, nonobese, outbred male Sprague–Dawley rats. They are fed with a high-fat diet (40% of calories as fat) for 2 weeks and then injected with STZ (50 mg/kg intravenously). Before STZ injection, fat-fed rats have glucose concentrations similar to chow-fed counterparts. Plasma insulin levels in response to oral glucose are increased twofold by fat feeding, and adipocyte glucose clearance under maximal insulin stimulation is significantly reduced, suggesting that fat feeding induces insulin resistance. STZ injection elevates glucose, insulin, FFA and TG concentrations. Fat-fed/STZ rats are not insulin deficient compared to normal chow-fed rats but display hyperglycaemia associated with reduced insulinstimulated adipocyte glucose clearance [79].
Summary With worldwide rises of metabolic disease incidences, development of novel investigational methods and technologies becomes one of the top priorities in combating this health crisis. Newly emerged and available rodent models for the study of obesity, diabetes, hyperlipidaemia and other metabolic complications would accelerate the ongoing process of finding a cure. Spontaneously diabetic rodent models such as OLETF rats, GK rats, db/db mice, ZDF rats and ob/ob mice are most commonly used in drug discovery. OLETF rats closely simulate the metabolic abnormalities of the human syndrome, especially the diabetic nephropathy. While the GK rat appears to be a suitable model for nonobese diabetes, ZDF rats are generally applied to studies of diabetes with obesity and cardiovascular complications due to the dyslipidaemia background. Obesity is necessary but not sufficient alone for the development of type 2 diabetes. Inheritance is the more important factor. Genetically engineered diabetic mice represent new tools that provide us with invaluable insights into the pathogenesis, and further studies may identify potential targets for the development of novel therapeutic stra-
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tegies aimed at improving insulin action or b-cell function. The newly developed fat-fed/STZ-induced diabetic model offers significant advantages in replicating the natural history and metabolic characteristics of human conditions and is also cost-effective compared to the genetic models currently available. Because it is a complex, heterogeneous, multifactorial syndrome resulting from both genetic susceptibility and environmental risk factors, more promising animal models that closely simulate human type 2 diabetes regarding inheritance traits, environmental risks, pathogeneses and complications have yet to be developed in the future.
Acknowledgement We are indebted to Dr D. E. Mais for his valuable comments and suggestions.
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