Animal care and use has been regulated in Israel since 1994 when the Animal Welfare Law—Animal Experiments (Law) was legislated. At the heart of the Law is the National Council (Council), which operates in the Ministry of Health. The chairman is appointed by the Minister of Health from the National Academy of Sciences. The Council has all legal authority regarding animal testing, and is entrusted with regulation and supervision duties. Every institution that wishes to carry out research with animals has to establish an Animal Care and Use Program (Program) and appoint an attending veterinarian (AV). All the experiments with animals require an Animal Experiment Permit (Permit), which can be obtained from an Institutional Animal Care and Use Committee. Applications can be submitted by an appropriately trained principal investigator. The Council places a particular importance to the issue of training, and each of the training courses is approved by the Council. All courses are built on a unified national framework of two levels: a basic training part and specific supplementary practical part for each animal species not covered by the basic course. The legal basis for animal experimentation in Israel is comprised of the Law, Council regulations, and the instructions of the American NRC Guide for the Care and Use of Laboratory Animals (Guide) which has an official status in Israel. The Law places special importance to the role of the AV, whose post is a legal requirement, and who is entrusted among other things with supervisory duties at the institution. Institutions are required to report to the Council on all approved permits, on the actual progress of the research projects, and on the veterinary conditions. Institutions are also supervised by the professionals of the Council who have all the authority to carry out their duty and can even instruct the revoking of permits.

Hepatocellular carcinoma is the second leading cause of cancer death worldwide. DNA microarray analysis identified the ornithine aminotransferase (OAT) gene as a prominent gene overexpressed in hepatocellular carcinoma (HCC) from Psammomys obesus. In vitro studies demonstrated inactivation of OAT by gabaculine (1), a neurotoxic natural product, which suppressed in vitro proliferation of two HCC cell lines. Alpha-fetoprotein (AFP) secretion, a biomarker for HCC, was suppressed by gabaculine in both cell lines, but not significantly. Because of the active site similarity between GABA aminotransferase (GABA-AT) and OAT, a library of 24 GABA-AT inhibitors was screened to identify a more selective inhibitor of OAT. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidene)cyclopentane-1-carboxylic acid (2) was found to be an inactivator of OAT that only weakly inhibits GABA-AT, l-aspartate aminotransferase, and l-alanine aminotransferase. In vitro administration of 2 significantly suppressed AFP secretion in both Hep3B and HepG2 HCC cells; in vivo, 2 significantly suppressed AFP serum levels and tumor growth in HCC-harboring mice, even at 0.1 mg/kg. Overexpression of the OAT gene in HCC and the ability to block the growth of HCC by OAT inhibitors support the role of OAT as a potential therapeutic target to inhibit HCC growth. This is the first demonstration of suppression of HCC by an OAT inactivator.

Liver steatosis is a common characteristic of obesity and type 2 diabetes, and fatty liver disease is increasingly recognized as a major health burden. Accumulating evidence suggests that β-glycosphingolipids play an important role in insulin sensitivity and thus could affect hepatic steatosis. To determine the effect associated with β-glycosphingolipid-mediated amelioration of liver injury, seven groups of Psammomys obesus on a high-energy diet were studied. Animals were treated with daily injections of β-glucosylceramide, β-lactosylceramide, or a combination of both. β-glycosphingolipids ameliorated the hepatic injury manifested by decreased liver enzymes, liver weight, and hepatic fat, and improved liver histology. Administration of both β-glucosylceramide and β-lactosylceramide also decreased interferon (IFN)-γ serum levels. These effects were associated with improved serum cholesterol and triglyceride levels. These data suggest that β-glycosphingolipids ameliorate liver injury in an animal model of nonalcoholic steatohepatitis.

The role of AMPK in regulating energy storage and depletion remains unexplored in the intestine. This study will to define its status, composition, regulation and lipid function, as well as to examine the impact of insulin resistance and type 2 diabetes on intestinal AMPK activation, insulin sensitivity, and lipid metabolism. Caco-2/15 cells and Psammomys obesus (P. obesus) animal models were experimented. We showed the predominance of AMPKα1 and the prevalence of α1/β2/γ1 heterotrimer in Caco-2/15 cells. The activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside and metformin resulted in increased phospho(p)-ACC. However, the down-regulation of p-AMPK by compound C and high glucose lowered p-ACC without affecting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Administration of metformin to P. obesus with insulin resistance and type 2 diabetes led to 1) an up-regulation of intestinal AMPK signaling pathway typified by ascending p-AMPKα(-Thr172); 2) a reduction in ACC activity; 3) an elevation of carnitine palmitoyltransferase 1; 4) a trend of increase in insulin sensitivity portrayed by augmentation of p-Akt and phospho-glycogen synthetase kinase 3β; 5) a reduced phosphorylation of p38-MAPK and ERK1/2; and 6) a decrease in diabetic dyslipidemia following lowering of intracellular events that govern lipoprotein assembly. These data suggest that AMPK fulfills key functions in metabolic processes in the small intestine.

Objectives The proprotein convertase subtillisin/kexin type 9 (PCSK9) regulates cholesterol metabolism via degradation of low-density lipoprotein receptor (LDLr). Although PCSK9 is abundantly expressed in the intestine, limited data are available on its functions. The present study aims at determining whether PCSK9 plays important roles in cholesterol homeostasis and lipid transport in the gut. Methods and results Caco-2/15 cells were used allowing the exploration of the PCSK9 secretory route through the apical and basolateral compartments corresponding to intestinal lumen and serosal circulation, respectively. The output of PCSK9 occurred through the basolateral membrane, a site characterized by the location of LDLr. Co-immunoprecipitation studies indicated an association between PCSK9 and LDLr. Addition of purified recombinant wild type and D374Y gain-of function PCSK9 proteins to the basolateral medium was followed by a decrease in LDLr concomitantly with the accumulation of both forms of PCSK9. Furthermore, the latter caused a significant enhancement in cholesterol uptake also evidenced by a raised protein expression of cholesterol transporters NPC1L1 and CD36 without changes in SR-BI, ABCA1, and ABCG5/G8. Moreover, exogenous PCSK9 altered the activity of HMG-CoA reductase and acylcoenzyme A: cholesterol acyltransferase, and was able to enhance chylomicron secretion by positively modulating lipids and apolipoprotein B-48 biogenesis. Importantly, PCSK9 silencing led to opposite findings, which validate our data on the role of PCSK9 in lipid transport and metabolism. Moreover, PCSK9-mediated changes persisted despite LDLr knockdown. Conclusions These findings indicate that, in addition to its effect on LDLr, PCSK9 modulates cholesterol transport and metabolism, as well as production of apo B-containing lipoproteins in intestinal cells.

Background and purpose: Cannabidiol (CBD), a non-psychoactive component of Cannabis sativa, has been shown by us, to have an anti-inflammatory effect in collagen-induced arthritis in DBA mice and in type 1 diabetes in NOD mice. As inflammation is a process involved in diabetes type 2, we administered CBD to Psammomys obesus (sand rats), a species which develops diabetes type 2 when fed high-energy (HE) diet, to investigate whether we can hinder the development of the disease. Experimental Approach: Male Psammomys obesus were kept on a high energy diet during the experiments. They were treated with CBD (i.p injection, 5 mg/kg, 5 times/week) for 4 weeks and kept (without CBD) for another 29 - 39 days. The weights of the animals as well as blood glucose and plasma insulin levels were determined and the morphology of the pancreatic islets was examined. Key results: CBD significantly reduced blood glucose levels in Psammomys obesus, without effecting body weight. Plasma insulin levels were significantly higher in the CBD-treated group. The most striking effect noted was the marked decrease of the destruction of pancreatic islets and beta cells. Conclusions and implications: CBD partially protects pancreatic islets and beta cells from destruction. CBD lowers significantly the blood glucose level and increases insulin level in Psammomys obesus with diabetes type 2, but does not lead to obesity. As CBD already has been administered to patients for other medical indications we propose its use as a therapeutic agent in diabetes type 2.

Background The possibility of restoring sevoflurane postconditioning (sevo-postC) cardioprotection in diabetic animals is uncertain. We hypothesized that attenuation of myocardial injury by sevo-postC might be hindered by inhibition of signal transducer and activator of transcription (STAT) 3-regulated activity of phosphatidylinositol 3-kinase (PI3K) in diabetic animals. To determine whether postC cardioprotection can be restored by normoglycemia, we treated rats with insulin. Methods Diabetic or nondiabetic rats were randomly subjected to 30-min ischemia/reperfusion, with ischemic postC or sevo-postC, with and without mitochondrial adenosine triphosphate-dependent potassium channel blocker 5-hydroxy decanoate sodium and PI3K antagonist wortmannin. The infarct area, phosphorylated STAT3, and apoptosis were examined. Studies were repeated after insulin treatment. Results Ischemic postC and sevo-postC significantly reduced infarct size by 50% in the nondiabetic rats (P < 0.002), a phenomenon completely reversed by 5-hydroxy decanoate sodium and wortmannin. Diabetes mellitus blocked the protective effect of postC, and insulin treatment to achieve normoglycemia did not restore cardioprotection. Phosphorylated STAT3 nuclear retention was significantly increased after ischemia-reperfusion and was further enhanced in response to ischemic postC (P < 0.05) but was significantly reduced in diabetic rats (by 43%; P < 0.01). Conclusions The effective reduction in infarct size and apoptosis in the nondiabetic rat heart by postC was completely abrogated in diabetic rats. This inhibition is not relieved by insulin-induced normoglycemia. The PI3K pathway and mitochondrial adenosine triphosphate-dependent potassium channel activation are involved in the mechanism of postC. In diabetic rats, STAT3 activation was strongly reduced, as was postC cardioprotection, suggesting that the inability of insulin to restore postC may be attributed to diabetes-induced STAT3-mediated inhibition of PI3K signaling.

Trials assessing the effectiveness and safety of the Atkins diet for weight loss in obese diabetic patients are limited and adherence is problematic. The current trial compared an Atkins-like diet to a conventional ADA-recommended diet over a one year period. 52 type 2 diabetes patients, aged 35–75, BMI 30–39.9 kg/m2, HbA1c > 7%, treated by diet or oral medication, were initially placed on a DASH diet for one month, then randomly assigned to a modified Atkins diet (ATK) with unrestricted calorie intake or a standard American Diabetes Association (ADA) calorie-restricted diet. Weight, fasting blood glucose, lipid profile, blood pressure, and microalbuminuria were measured at baseline and after 1.5, 3, 6 and 12 months, and compliance with the diets was assessed. Similar weight loss and decrease in HbA1c were observed in both groups. Improvement in glycemic control and cardiovascular risk factor levels accompanied the modest weight reduction, with no significant between-group differences. ATK was not associated with untoward renal effects. Substantial drop-out in both groups was noted. There was no statistically significant advantage in terms of weight loss or glucose control for the Atkins-like diet. Adherence to a very low carbohydrate diet in a population accustomed to a Mediterranean-type diet rich in fruits and vegetables was modest, thus restricting its applicability to selected obese diabetes patients.

The Psammomys obesus lives in natural desert habitat on low energy (LE) diet, however when maintained in laboratory conditions with high energy (HE) diet it exhibits pathological metabolic changes resembling those of type 2 diabetes. We have evaluated and correlated the histopathology, metabolic and functional renal alterations occurring in the diabetic Psammomys. Renal function determined by measuring glomerular filtration rate (GFR), protein excretion, protein/creatinine ratio and morpho-immunocytochemical evaluations were performed on HE diet diabetic animals and compared to LE diet control animals. The diabetic animals present a 54% increase in GFR after one month of hyperglycemic condition and a decrease of 47% from baseline values after 4 months. Protein excretion in diabetic animals was 5 folds increased after 4 months. Light microscopy showed an increase in glomeruli size in the diabetic Psammomys, and electron microscopy and immunocytochemical quantitative evaluations revealed accumulation of basement membrane material as well as frequent splitting of the glomerular basement membrane. In addition, glycogen-filled Armanni-Ebstein clear cells were found in the distal tubules including the thick ascending limbs of the diabetic animals. These renal complications in the Psammomys, including changes in GFR with massive proteinuria sustained by physiological and histopathological changes, are very similar to the diabetic nephropathy in human. The Psamommys obesus represents therefore a reliable animal model of diabetic nephropathy.

OBJECTIVE:SAR1b plays a significant role in the assembly, organization, and function of the coat protein complex II, a critical complex for the transport of proteins from the endoplasmic reticulum to the Golgi. Recently, mutations in SARA2 have been associated with lipid absorption disorders. However, functional studies on Sar1b-mediated lipid synthesis pathways and lipoprotein packaging have not been performed. METHODS AND RESULTS:Sar1b was overexpressed in Caco-2/15 cells and resulted in significantly augmented triacylglycerol, cholesteryl ester, and phospholipid esterification and secretion and markedly enhanced chylomicron production. It also stimulated monoacylglycerol acyltransferase/diacylglycerol acyltransferase activity and enhanced apolipoprotein B-48 protein synthesis, as well as elevated microsomal triglyceride transfer protein activity. Along with the enhanced chylomicrons, microsomes were characterized by abundant Sec12, the guanine exchange factor that promotes the localization of Sar1b in the endoplasmic reticulum. Furthermore, coimmunoprecipitation experiments revealed high levels of the complex components Sec23/Sec24 and p125, the Sec23-interacting protein. Finally, a pronounced interaction of Sec23/Sec24 with sterol regulatory element binding protein (SREBP) cleavage-activating protein and SREBP-1c was noted, thereby permitting the transfer of the transcription factor SREBP-1c to the nucleus for the activation of genes involved in lipid metabolism. CONCLUSION:Our data suggest that Sar1b expression may promote intestinal lipid transport with the involvement of the coat protein complex II network and the processing of SREBP-1c.

BACKGROUND:The possibility of restoring sevoflurane postconditioning (sevo-postC) cardioprotection in diabetic animals is uncertain. We hypothesized that attenuation of myocardial injury by sevo-postC might be hindered by inhibition of signal transducer and activator of transcription (STAT) 3-regulated activity of phosphatidylinositol 3-kinase (PI3K) in diabetic animals. To determine whether postC cardioprotection can be restored by normoglycemia, we treated rats with insulin.METHODS:Diabetic or nondiabetic rats were randomly subjected to 30-min ischemia/reperfusion, with ischemic postC or sevo-postC, with and without mitochondrial adenosine triphosphate-dependent potassium channel blocker 5-hydroxy decanoate sodium and PI3K antagonist wortmannin. The infarct area, phosphorylated STAT3, and apoptosis were examined. Studies were repeated after insulin treatment.RESULTS:Ischemic postC and sevo-postC significantly reduced infarct size by 50% in the nondiabetic rats (P < 0.002), a phenomenon completely reversed by 5-hydroxy decanoate sodium and wortmannin. Diabetes mellitus blocked the protective effect of postC, and insulin treatment to achieve normoglycemia did not restore cardioprotection. Phosphorylated STAT3 nuclear retention was significantly increased after ischemia-reperfusion and was further enhanced in response to ischemic postC (P < 0.05) but was significantly reduced in diabetic rats (by 43%; P < 0.01).CONCLUSIONS:The effective reduction in infarct size and apoptosis in the nondiabetic rat heart by postC was completely abrogated in diabetic rats. This inhibition is not relieved by insulin-induced normoglycemia. The PI3K pathway and mitochondrial adenosine triphosphate-dependent potassium channel activation are involved in the mechanism of postC. In diabetic rats, STAT3 activation was strongly reduced, as was postC cardioprotection, suggesting that the inability of insulin to restore postC may be attributed to diabetes-induced STAT3-mediated inhibition of PI3K signaling.

Insulin resistance and type 2 diabetes (T2D) are characterized by hyperlipidemia. The aim of the present study was to elucidate whether T2D contributes to abnormal cholesterol (CHOL) homeostasis. Experiments were carried out in the small intestine and liver of Psammomys obesus, a model of nutritionally induced T2D. Our results show that diabetic animals exhibited a lower intestinal CHOL uptake, which was associated with a decrease in 1) the gene and protein expression of Niemann-Pick C1 like 1 that plays a pivotal role in CHOL incorporation in the enterocytes; and 2) mRNA of ATP-binding cassette transporters (ABC)A1 that mediates CHOL efflux from intestinal cells to apolipoprotein A-I and high-density lipoprotein. No changes were observed in the other intestinal transporters scavenger receptor-class B type I (SR-BI) and annexin 2. On the other hand, in diabetic animals, a significant mRNA decrease was noticed in intestinal ABCG5 and ABCG8 responsible for the secretion of absorbed CHOL back into the lumen. Furthermore, jejunal PCSK9 protein was diminished and low-density lipoprotein receptor was raised, along with a significant down-regulation in jejunal 3-hydroxy-3-methylglutaryl-coenzyme A reductase in P. obesus with T2D. Finally, among the transcription factors tested, only an increase in liver X receptors alpha and a decrease in peroxisome proliferator-activated receptors delta/beta mRNAs were detected in the intestine. In the liver, there was 1) an augmentation in the protein mass of Niemann-Pick C1 like 1, SR-BI, and annexin 2; 2) an up-regulation of SR-BI mRNA; 3) a fall in ABCG8 protein content as well as in ABCG5 and ABCA1 mRNA; and 4) an augmentation in liver X receptors alpha and peroxisome proliferator-activated receptors beta/delta mRNA, together with a drop in sterol regulatory element binding protein-2 protein. Our findings show that the development in P. obesus with T2D modifies the whole intraenterocyte and hepatocyte machinery responsible for CHOL homeostasis.

Background Metabolic syndrome is associated with subsequent development of cardiovascular diseases and type 2 diabetes. It is characterized by reduced response to insulin, central obesity, and dyslipidemia. Intake of plant sterols (PS) has been shown to confer a healthier lipid profile and ameliorate cardiovascular disease risk factors in experimental animals and humans. In this study we used an animal model of type 2 diabetes to assess the effects of a preparation of PS esterified to high oleic sunflower oil fatty acids mixed with dietary diacylglycerol (PS-HOSO) on diabetic related metabolic parameters. Psammomys obesus ( P. obesus ) were fed high energy (HE) diet supplemented by either PS-HOSO or control oil. Following 4.5 weeks of intervention, animals were divided into fasting and non-fasting modes prior to outcome measurements. Glucose and insulin levels as well as blood lipid profile, body weight, and fat accumulation were evaluated in fasting and non-fasting modes. Results P. obesus fed with a HE diet displayed a characteristic heterogeneity in their blood glucose and insulin levels with a subset group displaying type 2 diabetes symptoms. PS-HOSO treatment significantly reduced total cholesterol (24%, P < 0.001) and non-HDL cholesterol (34%, P < 0.01) compared to the control diet. Among fasting animals, body weight at end point and epididymal fat-to-liver weight ratio were significantly ( P < 0.05 each) reduced (7% and 16%, respectively) compared to controls. Interestingly, fasting blood glucose levels were similar between groups, whereas plasma insulin level at end point was 44% lower in the PS-HOSO group compared to control group ( P < 0.0001) Conclusion PS-HOSO supplementation to diabetes-prone gerbils counteracts the increase in body weight and epididymal fat accumulation, and also results in a drop in circulating insulin levels. These effects are pointing out that PS-HOSO may serve as a functional ingredient for metabolic syndrome or diabetic sufferers, which not only influences body weight, but also prevents or reverses insulin resistance and hyperlipidemia.

LETTER TO THE EDITORA useful list of spontaneously arising animal models of obesity and diabetesEleazar Shafrir and Ehud ZivEleazar Shafrir and Ehud ZivPublished Online:01 Jun 2009https://doi.org/10.1152/ajpendo.00113.2009MoreSectionsPDF (69 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat to the editor: over the years, we have had the opportunity to edit books and compendia that characterize diverse animal models of obesity and diabetes. Most of those animal models have been either selected through inbreeding or characterized following spontaneously arising mutations. It is now timely to provide, in a summary manner, a concise list of such models as an update and reference for future research. The major defects are described in the references cited. In some cases, insulin resistance has been linked to impaired insulin signaling at various levels, including negative feedback at the level of the insulin receptor substrate (IRS)-1 (5, 15, 24). However, in most cases the mechanism of the diabetogenic changes has not been exhaustively investigated. We hope that this list will guide studies geared at elucidating specific defects in the signal flow and how these studies may explain the metabolic failures leading to the diabetic proneness of the models as well as the mechanism of the ensuing complications. These animal models should also enable the discovery of therapeutic modalities with relevance to human diabetes and should continue to be a useful tool along with specific target-generated transgenic and knockout animals so amply used to understand metabolism and energy balance.Obesity and diabetes in mice with mutations in leptin or leptin receptor genes.Since the discovery that ob is a mutation in the leptin structural gene and db is a mutation in the leptin receptor gene, the nomenclature for these mutations has been changed to reflect their molecular basis. The Lepob mutation on chromosome 6 was discovered in the Jackson Laboratory, Bar Harbor, ME, and recognized by marked obesity and hyperphagia. This mutation was subsequently transferred to the B6 inbred strain background. On this genetic background, the mutation produces juvenile-onset obesity, hyperinsulinemia, and insulin resistance with mild hyperglycemia and a sustained hyperplasia of the pancreatic β-cells.The Leprdb mutation is a recessive mutation on chromosome 4 that occurred spontaneously in the C57BLKS/J inbred strain. The obesity/diabetes syndrome is associated with progressively severe hyperglycemia and correlated with pancreatic cell necrosis and islet atrophy at the end stage. The ob mutation is predominantly obese and exhibits only mild hyperglycemia.The current genetic nomenclature for these mice is as follows: LepobJ, common name "obese" gene product; leptin or leptin mRNA and Leprdb-IJ, common name "diabetic" gene product leptin receptor or leptin receptor mRNA. Detailed information on these strains can be found in Chua et al. (2).Zucker diabetic fatty rat with a leptin receptor defect.The Zucker diabetic fatty (ZDF) rat exhibits leptin receptor defects. This type of obesity, although associated with insulin resistance, is unlike common forms of human obesity. The ZDF rat was developed into a reproducible type 2 diabetic model at Indiana University (16) from a Zucker rat colony (leprfa) in which certain individuals exhibited a propensity to diabetes. The male rat is characterized by hyperinsulinemia and hyperglycemia at 6–7 wk of age, with glucose reaching levels of 500 mg/dl and insulin levels dropping successively. The female rat requires a high-fat diet for the expression of diabetes. The ZDF rat carries a genetic defect in β-cell transcription that is independent of the leptin receptor mutation, causing obesity and insulin resistance likely to be inherited in the β-cell gene.Goto-Kakizaki rat with impaired β-cell mass and function due to polygenic inheritance.The Goto-Kakizaki rat is a nonobese substrain of Wistar rat origin with inherited chronic hyperglycemia. It was selected through a group of eight generation-inbreeding Wistar rats displaying high glucose levels during a glucose tolerance test. They present "starfish-shaped" islet abnormalities and pancreatic hormone deficiencies, resembling the polygenic basis of human type 2 diabetes (14).New Zealand obese mouse.This is a model of obesity, glucose intolerance, and metabolic syndrome of polygenic nature. This animal exhibits hepatic and peripheral leptin insensitivity, insulin resistance, impaired insulin secretion, hypercholesteremia, and hypertension (6). It displays classic features of obesity, including excessive body weight hyperphagia and reduced energy expenditure. Such obesity is responsible for its impaired glucose metabolism.JCR:LA-cp rat: exhibiting metabolic syndrome with micro- and macrovascular disease.The prediabetic state in the JCR:LA-cp rat is characterized by abdominal obesity, hypertriglyceridemia and insulin resistance, and a marked damage to the vascular system, which is associated with atherosclerosis, vasculopathy, and ischemic end-stage disease (19). It is a unique model of the obesity/insulin resistance syndrome with cardiovascular implications of polygenic derivation.SHROB rat: a model of metabolic syndrome.The spontaneously obese SHROB (Koletzky) rat is an overtly nondiabetic rat with the primary and secondary characteristics associated with the human metabolic syndrome, including insulin resistance. It exhibits a single recessive trait, a nonsense mutation causing loss of hypothalamic leptin receptors designated as fak (12), and its insulin-signaling defects were initially reported by Friedman et al. (7).Otsuka Long-Evans Tokushima fatty rat with metabolic syndrome and diabetic nephropathy.The Otsuka Long-Evans Tokushima fatty (OLETF) rat was developed by selective breeding of a line of Long-Evans rats with diabetic characteristics along with a control line designated as Long-Evans Tokushima. OLETF rats show hyperphagia with obesity, hyperlipidemia, insulin resistance, and glucosuria, and these rats are prone to glomerular lesions (11).Neonatally streptozotocin-induced diabetic rats.Rats with diabetes induced by injection of streptozotocin on the day of birth, or soon thereafter, are used to study the long-term consequences of reduced β-cell mass that resemble those seen in human type 2 diabetes. The neonatally streptozotocin-treated rats become transiently diabetic for 3 to 5 days after birth but recover thereafter with altered β-cell function and mass and impaired response of insulin secretion to glucose administration. They are suitable to evaluate the effect of various diabetes modulators and complications (18).Rhesus monkey macaca mulatta with features of type 2 diabetes.The nonhuman primate Macaca mulatta provides the most human-like model of metabolic disorders in diabetes representative of other monkey species prone to diabetes. On an ad libitum diet they gradually become overweight or obese and progress to classical biochemical and pathophysiological symptoms of type 2 diabetes (8). Specific defects in this animal model have been reported by Angeloni and Hansen (1).Psammomys obesus gerbil with nutritionally induced type 2 diabetes and β-cell loss.The Psammomys obesus is a desert gerbil in which transition from native diet to laboratory rodent chow induces hyperinsulinemia followed by hyperglycemia. However, the hyperinsulinemia, which is a compensatory response for the insulin resistance, is not sustained. As a result, pancreatic insulin is depleted, and the secretion pressure leads to β-cell apoptosis. The reason for insulin resistance is overexpression of protein kinase C (PKC)ε isoform, which inhibits the activity of tyrosine kinase and promotes serine phosphorylation on IRS, thereby inhibiting to tyrosine phosphorylation and downstream insulin signaling. Peptides from the catalytic domain of PKC abrogated the serine phosphorylation and restored insulin signaling and normoglycemia (13). Psammomys is a good model for research of insulin resistance and testing of antidiabetic drugs (24).Torii rat with type 2 diabetes and human-like retinopathy lesions.Type 2 diabetes was discovered among males in an outbred colony of Sprague-Dawley rats. When sister-brother repeatedly mated with females of the same strain, the diabetes was established in males with numerous ocular complications such as cataract, retinopathy, neovascular glaucoma, and optic neuropathy (20).Cohen diabetic rat.Two contrasting rat strains were derived by selective inbreeding. One strain develops type 2 diabetes when fed a sucrose-rich, copper-poor diet, and the other does not. The diabetes is due to β-cell dysfunction and reduced insulin secretion. Cohen rats exhibit retinopathy and nephropathy, reduced fertility, and testicular degeneration. These rats have been crossed with spontaneously hypertensive rats to develop a hypertensive strain that presents diffuse glomerulosclerosis and hypertensive myocardial and vascular changes (22).KK and KKAy mice with type 2 diabetes and obesity.A strain of native mice originating from the Japanese natural environment habitat was found to lapse into spontaneous diabetes with moderate obesity and hyperglycemia, hyperlipidemia, insulin resistance, and renal glomerular changes. To strengthen the characteristics of diabetes in this KK mouse, the (Ay) dominant obese gene (from the agouti locus of yellow obese mice) was transferred by repeated crossing. The color of the hair changed from black to yellow (KKY). The mice genetic nature is polygenic and differs from the leprdb and leprob groups, whose diabetic state is induced by gene mutations (21).C57BL/6J mouse as a model of diet-induced type 2 diabetes and obesity.BL6 mice are susceptible to obesity-linked diabetes when maintained on a high-fat diet. They also present abnormalities in the autonomic nervous function, β-cells, and expression of uncoupling protein-2 in adipocytes. It is of interest that this mouse was used to receive the ob and db genes in the Jackson Laboratory, but it is itself prone to nutritionally induced diabetes and obesity as well as hypertension (17).Rats, mice, and dogs subjected to diet-induced obesity.Homeostatic and nonhomeostatic mechanisms exist in animals and humans regulating energy balance, the function of which can basically be regarded to protect against starvation. However, excess food intake leads to tissue deposition, primarily in adipocytes, resulting in untoward changes in metabolism. 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Shafrir, Hadassah University Hospital, Jerusalem 91120, Israel ([email protected]) Download PDF Previous Back to Top FiguresReferencesRelatedInformationCited ByCOMPARISON OF EFFECTS OF SITAGLIPTIN AND A COMBINATION OF NALTREXONE AND BUPROPION IN HIGH FAT DIET-INDUCED OBESITY MODEL IN RATS7 August 2022 | Asian Journal of Pharmaceutical and Clinical ResearchDiurnal rodents as pertinent animal models of human retinal physiology and pathologyProgress in Retinal and Eye Research, Vol. 74A high-density genetic map and molecular sex-typing assay for gerbils10 April 2019 | Mammalian Genome, Vol. 30, No. 3-4Suppression of Hepatic FLOT1 (Flotillin-1) by Type 2 Diabetes Mellitus Impairs the Disposal of Remnant Lipoproteins via Syndecan-1Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 38, No. 1Obesity and stroke: Can we translate from rodents to patients?1 October 2016 | Journal of Cerebral Blood Flow & Metabolism, Vol. 36, No. 12Establishment and Characterization of a Newly Established Diabetic Gerbil Line18 July 2016 | PLOS ONE, Vol. 11, No. 7Characterization of Micro-RNA Changes during the Progression of Type 2 Diabetes in Zucker Diabetic Fatty Rats3 May 2016 | International Journal of Molecular Sciences, Vol. 17, No. 5Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forwardAtherosclerosis, Vol. 247Animal Models of Menopausal Metabolism23 April 2013Involvement of visfatin in palmitate-induced upregulation of inflammatory cytokines in hepatocytesMetabolism, Vol. 60, No. 12Optimization of Adeno-Associated Viral Vector-Mediated Gene Delivery to the HypothalamusHuman Gene Therapy, Vol. 21, No. 6Contribution of animal models to the research of the causes of diabetesWorld Journal of Diabetes, Vol. 1, No. 5 More from this issue > Volume 296Issue 6June 2009Pages E1450-E1452 Copyright & PermissionsCopyright © 2009 the American Physiological Societyhttps://doi.org/10.1152/ajpendo.00113.2009PubMed19468077History Published online 1 June 2009 Published in print 1 June 2009 Metrics