Human Type 2 Diabetes Mellitus Research Articles

Low glycemic load diets protect against metabolic syndrome and Type 2 diabetes mellitus in the male Nile rat

BackgroundDietary modification helps prevent and manage Metabolic Syndrome (MetS) and Type 2 Diabetes Mellitus (T2DM) in humans and Nile rats. Specifically fibrous legumes, like lentils, benefit humans, but whether this reflects a specific change in the Glycemic Load (GLoad) remains controversial. Accordingly, low-GLoad foods were tested in the glucose-sensitive Nile rat. Methods131 male Nile rats aged 3 weeks to 15 months were challenged during four experiments with 15 dietary exposures that varied Glycemic Index (GI, 36–88), GLoad (102–305/2000 kcal), and cumulative GLoad (Cum GLoad=days×GLoad, 181–537g total glucose). ResultsLentil diets with low GLoads (102, 202) prevented, delayed, reduced, even reversed the progress of MetS and T2DM as measured by blood glucose (fasting, random, and oral glucose tolerance test) and plasma lipid parameters (plasma cholesterol and triglycerides) plus necropsy findings (liver and kidney pathology plus adipose reserves). The benefit from lentils exceeded dietary factors such as macronutrient composition (%Energy from carbohydrate:fat:protein, between 70:10:20 to 40:40:20), total fiber (0–24%), or dietary caloric density (2.9–4.7 kcal/g). The benefit of a low GLoad applied equally to rats inherently susceptible or resistant to T2DM, based on random glucose above or below 75 mg/dl, respectively, during interventions of 7-17 weeks. ConclusionsMeasuring total food intake and the novel concept of Cum GLoad during growth generated strong correlations (up to r=0.93) between Cum GLoad and parameters of MetS and T2DM, especially during sexual maturation. The present experiments confirm the applicability of male Nile rats to diet-induced human T2DM, and suggest dietary compositions to deter MetS and T2DM in humans.

Evaluation of EGFR as a prognostic and diagnostic marker for head and neck squamous cell carcinoma patients.

Approximately 90% of all head and neck tumors are squamous cell carcinomas. The overall survival of patients with head and neck squamous cell carcinoma (HNSCC) is low (≤50%). A non-invasive marker of disease progression is sorely required. The present study focused on the plasmatic levels of epidermal growth factor receptor (EGFR) in HNSCC patients (N=92) compared with healthy (N=29) and diabetic [type 2 diabetes mellitus (T2DM); N=26] controls. Enzyme-linked immunosorbent assay using antibodies against the extracellular region of EGFR (L25-S645) was performed. No significant changes were observed between diabetic and healthy controls. However, there were significantly higher EGFR plasma levels in HNSCC patients compared with both control groups (P=0.001 and 0.005, respectively). Receiver operating characteristic curve analysis identified a sensitivity of 76.09%, a specificity of 67.27% and an area under curve of 0.727 for this comparison. No significant association was observed between EGFR plasma levels and tumor stage, tumor grade, lymph node or distant metastasis occurrence, smoking habit or hypertension. However, the presence of human papillomavirus infection and T2DM in HNSCC patients had borderline effect on the plasma EGFR levels. Survival analysis revealed no significant influence of plasmatic EGFR levels on the overall and disease-specific survival of HNSCC patients. In conclusion, EGFR plasma levels appear to be a relatively promising diagnostic, but poor prognostic, HNSCC marker.

Validity of leptin receptor-deficiency (db/db) type 2 diabetes mellitus mice as a model of secondary osteoporosis.

This study aimed to evaluate the validation of the leptin receptor-deficient mice model for secondary osteoporosis associated with type 2 diabetes mellitus (T2DM) at bone micro-architectural level. Thirty three 36-week old male mice were divided into four groups: normal control (db/m) (n = 7), leptin receptor-deficient T2DM (db/db) (n = 8), human C-reactive protein (CRP) transgenic normal control (crp/db/m) (n = 7), and human CRP transgenic T2DM (crp/db/db) (n = 11). Lumber vertebrae (L5) and bilateral lower limbs were scanned by micro-CT to analyze trabecular and cortical bone quality. Right femora were used for three-point bending to analyze the mechanical properties. Trabecular bone quality at L5 was better in db/db or crp/db/db group in terms of bone mineral density (BMD), bone volume fraction, connectivity density, trabecular number and separation (all p < 0.05). However the indices measured at proximal tibia showed comparable trabecular BMD and microarchitecture among the four groups. Femur length in crp/db/db group was significantly shorter than db/m group (p < 0.05) and cortices were thinner in db/db and crp/db/db groups (p > 0.05). Maximum loading and energy yield in mechanical test were similar among groups while the elastic modulus in db/db and crp/db/db significantly lower than db/m. The leptin-receptor mice is not a proper model for secondary osteoporosis associated with T2DM.

An Overview of Murine High Fat Diet as a Model for Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is a worldwide epidemic, which by all predictions will only increase. To help in combating the devastating array of phenotypes associated with T2DM a highly reproducible and human disease-similar mouse model is required for researchers. The current options are genetic manipulations to cause T2DM symptoms or diet induced obesity and T2DM symptoms. These methods to model human T2DM have their benefits and their detractions. As far as modeling the majority of T2DM cases, HFD establishes the proper etiological, pathological, and treatment options. A limitation of HFD is that it requires months of feeding to achieve the full spectrum of T2DM symptoms and no standard protocol has been established. This paper will attempt to rectify the last limitation and argue for a standard group of HFD protocols and standard analysis procedures.

High insulin levels in KK-Ay diabetic mice cause increased cortical bone mass and impaired trabecular micro-structure.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by hyperglycemia, hyperinsulinemia and complications, including obesity and osteoporosis. Rodents have been widely used to model human T2DM and investigate its effect on the skeleton. We aimed to investigate skeletal alterations in Yellow Kuo Kondo (KK-Ay) diabetic mice displaying high insulin and glucose levels. Bone mineral density (BMD), micro-architecture and bone metabolism-related genes were analyzed. The total femoral areal BMD (aBMD), cortical volumetric BMD (vBMD) and thickness were significantly increased in KK-Ay mice, while the trabecular vBMD and mineralized bone volume/tissue volume (BV/TV), trabecular thickness and number were decreased compared to C57BL mice. The expression of both osteoblast-related genes, such as osteocalcin (OC), bone sialoprotein, Type I Collagen, osteonectin, RUNX2 and OSX, and osteoclast-related genes, such as TRAP and TCIRG, were up-regulated in KK-Ay mice. Correlation analyses showed that serum insulin levels were positively associated with aBMD, cortical vBMD and thickness and negatively associated with trabecular vBMD and micro-architecture. In addition, serum insulin levels were positively related to osteoblast-related and osteoclast-related gene expression. Our data suggest that high insulin levels in KK-Ay diabetic mice may increase cortical bone mass and impair trabecular micro-structure by up-regulating osteoblast-and osteoclast-related gene expression.

Diabetes Mellitus in Cats Relevant to Human Type 2 Diabetes – Current Knowledge and New Treatment Strategies – A Review

Abstract Diabetes mellitus is one of the most commonly encountered endocrinopathies in domestic cats. Numerous studies have shown that feline diabetes mellitus (FDM) closely resembles human type 2 diabetes mellitus (T2DM), a common pathogenesis including insulin resistance and impaired insulin secretion as well as the same risk factors. This similarity provides ground for better understanding of their pathogenesis as well as more efficient management, novel treatment and prevention options for the disease in both species. Recently, modulation of the incretin system has become a new area of active investigations by several pharmaceutical companies. Concerning the role of incretins in glucose homeostasis, therapies based on activating the incretin axis have proved highly effective in treating T2DM. Glucagon-like peptide 1 (GLP-1) receptors agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors have been recently developed agents for diabetes therapy. Furthermore, studies in healthy cats demonstrated that those drugs stimulate insulin secretion and lower glucagon levels. There is a need of additional clinical evaluation of action of the drugs in cats suffering from FDM. Moreover, studies in cats may contribute to the development of knowledge on the use of new drugs in treatment of human T2DM because cats are an excellent model for the study of diabetes.

Type 2 diabetes mellitus non-genetic Rhesus monkey model induced by high fat and high sucrose diet.

To build an ideal animal model for studying the mechanism of occurrence, developing and treating of diabetes become a more important issue, facing with the fact that the big threat of diabetes to human health has been worsen. First, we used the normal control diets or the high-fat/high-sucrose diets to feed the adult rhesus monkeys and the macaques induced by the high-fat/high-sucrose diets in the high-fat/high-sucrose group and the type 2 diabetes mellitus (T2DM) group developed the hyperglycemia, hyperinsulinemia at 6 months in accordance with the precious researches that reported that minipigs, rats and mice could develop hyperglycemia, hyperinsulinemia, hyperlipidemia and obesity after being induced with high-fat/high-carbohydrate diets. Second, the rhesus monkeys in T2DM group were injected STZ at a low dosage of 35 mg/kg BW to induce glucose persistent elevation which maintained pretty well after 12 months. Third, we took the assay of glucose tolerance test and insulin resistance index, assessed the changing tendency of serum resistin and analysed the pathological characteristics of the tissues like pancreas and liver by staining in different ways. The results indicate the rhesus monkeys in T2DM group have lots of clinical features of T2DM. The experimental non-genetic T2DM rhesus monkeys model not only contribute to simulating of clinical manifestations and pathological features of human T2DM, but also may be a good kind of model for research on the treatment of T2DM and for new drugs evaluation.

You are what you eat, or are you? The challenges of translating high-fat-fed rodents to human obesity and diabetes.

Obesity and type 2 diabetes mellitus (T2DM) are rapidly growing worldwide epidemics with major health consequences. Various human-based studies have confirmed that both genetic and environmental factors (particularly high-caloric diets and sedentary lifestyle) greatly contribute to human T2DM. Interactions between obesity, insulin resistance and β-cell dysfunction result in human T2DM, but the mechanisms regulating the interplay among these impairments remain unclear. Rodent models of high-fat diet (HFD)-induced obesity have been used widely to study human obesity and T2DM. With >9000 publications on PubMed over the past decade alone, many aspects of rodent T2DM have been elucidated; however, correlation to human obesity/diabetes remains poor. This review investigates the reasons for this translational discrepancy by critically evaluating rodent HFD models. Dietary modification in rodents appears to have limited translatable benefit for understanding and treating human obesity and diabetes due—at least in part—to divergent dietary compositions, species/strain and gender variability, inconsistent disease penetrance, severity and duration and lack of resemblance to human obesogenic pathophysiology. Therefore future research efforts dedicated to acquiring translationally relevant data—specifically human data, rather than findings based on rodent studies—would accelerate our understanding of disease mechanisms and development of therapeutics for human obesity/T2DM.

A genetic strategy to measure circulating Drosophila insulin reveals genes regulating insulin production and secretion.

Insulin is a major regulator of metabolism in metazoans, including the fruit fly Drosophila melanogaster. Genome-wide association studies (GWAS) suggest a genetic basis for reductions of both insulin sensitivity and insulin secretion, phenotypes commonly observed in humans with type 2 diabetes mellitus (T2DM). To identify molecular functions of genes linked to T2DM risk, we developed a genetic tool to measure insulin-like peptide 2 (Ilp2) levels in Drosophila, a model organism with superb experimental genetics. Our system permitted sensitive quantification of circulating Ilp2, including measures of Ilp2 dynamics during fasting and re-feeding, and demonstration of adaptive Ilp2 secretion in response to insulin receptor haploinsufficiency. Tissue specific dissection of this reduced insulin signaling phenotype revealed a critical role for insulin signaling in specific peripheral tissues. Knockdown of the Drosophila orthologues of human T2DM risk genes, including GLIS3 and BCL11A, revealed roles of these Drosophila genes in Ilp2 production or secretion. Discovery of Drosophila mechanisms and regulators controlling in vivo insulin dynamics should accelerate functional dissection of diabetes genetics.

Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes.

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor-based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

Influence of diet on gut microbiota, inflammation and type 2 diabetes mellitus. First experience with macrobiotic Ma‐Pi 2 diet

Type 2 diabetes mellitus (T2DM) is a complex disorder influenced by both genetic and environmental factors. Recent studies have suggested that an imbalance of the intestinal microbiota may be involved in the development of several human diseases, including obesity and T2DM. The main regulators of the intestinal microbiota are age, ethnicity, the immune system and diet. A high-fat diet may induce dysbiosis, which can result in a low-grade inflammatory state, obesity and other metabolic disorders. Adding prebiotics to the diet may reduce inflammation, endotoxaemia and cytokine levels as well as improving insulin resistance and glucose tolerance. The administration of prebiotics such as fermentable dietary fibres, promotes glucagon-like peptide 1 and peptide YY (anorexigenic) and decreases ghrelin (orexigenic). In a recent 21-day, intervention study in patients with T2DM, the effect of using the macrobiotic Ma-Pi 2 diet was investigated. Results suggested that it could induce a significant improvement in fasting blood glucose, plasma lipid fractions, plasma insulin and homeostasis. It is therefore possible that a diet rich in prebiotics and probiotics can play a role in T2DM management, probably due to positive intestinal microbiota modulation. However, this must be demonstrated by larger studies including randomized controlled trials that measure indicators of inflammation.

Of rodents and men: Species-specific glucose regulation and type 2 diabetes research

Type 2 diabetes mellitus (T2DM) has reached epidemic proportions worldwide and animal models mimicking human T2DM are widely used to study mechanisms of disease and to develop pharmacotherapeutics. Over the last three decades, rodent models of T2DM have yielded more than 50 publications per month; however, many details of human T2DM pathogenesis remain unclear, and means of preventing disease progression remain elusive. This review investigates the reasons for this translational discrepancy by analyzing the experimental evidence from rodent models of T2DM. The analysis revealed significant species-specific differences at every level of glucose regulation, from gene/protein expression, cellular signaling, tissue and organ to whole organism level, when compared with data acquired using human cells, tissues, organs, and populations. Given the extensive species-specific barrier that creates an immutable translational gap, there is an urgent need to further employ and develop human-based research strategies to make significant strides against the current T2DM epidemic.

Epigenetic Regulation of the DLK1-MEG3 MicroRNA Cluster in Human Type 2 Diabetic Islets

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and nondiabetic organ donors. We identified a cluster of microRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β cells and dramatically downregulated in islets from T2DM organ donors. The downregulation of this locus strongly correlates with hypermethylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1, that cause increased β cell apoptosis upon overexpression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.

Ischemic conditioning protects the rat retina in an experimental model of early type 2 diabetes

Diabetic retinopathy is a leading cause of acquired blindness in adults, mostly affected by type 2 diabetes mellitus (T2DM). We have developed an experimental model of early T2DM in adult rats which mimics some features of human T2DM at its initial stages, and provokes significant retinal alterations. We investigated the effect of ischemic conditioning on retinal changes induced by the moderate metabolic derangement. For this purpose, adult male Wistar rats received a control diet or 30% sucrose in the drinking water, and 3weeks after this treatment, animals were injected with vehicle or streptozotocin (STZ, 25mg/kg). Retinal ischemia was induced by increasing intraocular pressure to 120mmHg for 5min; this maneuver started 3weeks after vehicle or STZ injection and was weekly repeated in one eye, while control eyes were submitted to a sham procedure. Fasting and postprandial glycemia, and glucose, and insulin tolerance tests were analyzed. At 12weeks of treatment, animals which received a sucrose-enriched diet and STZ showed significant differences in metabolic tests, as compared with control groups. Brief ischemia pulses in one eye and a sham procedure in the contralateral eye did not affect glucose metabolism in control or diabetic rats. Ischemic pulses reduced the decrease in the electroretinogram a-wave, b-wave, and oscillatory potential amplitude, and the increase in retinal lipid peroxidation, NOS activity, TNFα, Müller cells glial fibrillary acidic protein, and vascular endothelial growth factor levels observed in diabetic animals. In addition, ischemic conditioning prevented the decrease in retinal catalase activity induced by T2DM. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies to treat diabetic retinopathy associated with T2DM.

Therapeutic efficacy of melatonin in reducing retinal damage in an experimental model of early type 2 diabetes in rats

Diabetic retinopathy (DR) is a leading cause of acquired blindness in adults, mostly affected by type 2 diabetes mellitus (T2DM). We have developed an experimental model of early T2DM in adult rats which mimics some features of human T2DM at its initial stages and provokes significant retinal alterations. The aim of this work was to analyze the effect of melatonin on retinal changes induced by the moderate metabolic derangement. For this purpose, adult male Wistar rats received a control diet or 30% sucrose in the drinking water. Three weeks after this treatment, animals were injected with vehicle or streptozotocin (STZ, 25mg/kg). One day or 3wk after vehicle or STZ injection, animals were subcutaneously implanted with a pellet of melatonin. Fasting and postprandial glycemia, and glucose, and insulin tolerance tests were analyzed. At 12wk of treatment, animals which received a sucrose-enriched diet and STZ showed significant differences in metabolic tests, as compared with control groups. Melatonin, which did not affect glucose metabolism in control or diabetic rats, prevented the decrease in the electroretinogram a-wave, b-wave, and oscillatory potential amplitude, and the increase in retinal lipid peroxidation, NOS activity, TNFα, Müller cells glial fibrillary acidic protein, and vascular endothelial growth factor levels. In addition, melatonin prevented the decrease in retinal catalase activity. These results indicate that melatonin protected the retina from the alterations observed in an experimental model of DR associated with type 2 diabetes.

Optogenetic Therapeutic Cell Implants

Optogenetic Therapeutic Cell Implants

Retinal changes in an experimental model of early type 2 diabetes in rats characterized by non-fasting hyperglycemia

Diabetic retinopathy is a leading cause of acquired blindness in young, but also in elder adults, mostly affected by type 2 diabetes mellitus (T2DM). The aim of this work was to develop an experimental model of early human T2DM in adult rats, and to analyze retinal functional, morphological, and biochemical changes arising during the early stages of the moderate metabolic derangement. For this purpose, animals were divided in four groups: adult male Wistar rats receiving: tap water and citrate buffer i.p. (group 1), tap water with 30% sucrose and citrate buffer i.p. (group 2), tap water and 25mg/kg i.p streptozotocin (STZ, group 3), or 30% sucrose and STZ (group 4). Fasting and postprandial glycemia, fructosamine and serum insulin levels were assessed. In addition, i.p. glucose and insulin tolerance tests were performed. Retinal function (electroretinogram, ERG) and morphology (optical microscopy), retinal nitric oxide synthase (NOS) activity (using 3H-arginine), lipid peroxidation (thiobarbituric acid reactive substances, TBARS), and TNFα levels (ELISA) were evaluated. At 6 and 12weeks of treatment, animals which received a sucrose-enriched diet and STZ showed significant differences in most metabolic tests, as compared with the other groups. At 12weeks of treatment, a significant decrease in the ERG a- and b- wave and oscillatory potential amplitudes, and a significant increase in retinal NOS activity, TBARS, TNFα, glial fibrillary acidic protein in Müller cells, and vascular endothelial growth factor levels were observed. These results indicate that the combination of diet-induced insulin resistance and a slight secretory impairment resulting from a low-dose STZ treatment mimics some features of human T2DM at its initial stages, and provokes significant retinal alterations.

Generation of fibroblasts overexpressing liver-specific PEPCK in a miniature pig model of human type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is one of the most common complex metabolic disorders in humans, and is characterized by hyperglycemia and metabolic alterations. In T2DM, fasting hyperglycemia is attributed to excessive hepatic glucose production, and increased gluconeogenesis has been ascribed to increased transcriptional expression of phosphoenolpyruvate carboxykinase (PEPCK). In this study, we analyzed porcine PEPCK promoter activities to generate liver-specific expression vectors. We generated miniature pig fibroblasts overexpressing PEPCK via transgenes to provide an animal model of human T2DM. Various regions of the promoter showed high levels of activity in the presence of glucocorticoids, a PEPCK gene inducer, in liver cells compared to a positive control promoter. The selected promoter region for a liver-specific expression system was adopted based on the current targeting vector containing two selection markers, green fluorescence protein and a neomycin-resistance gene. The linearized vector was introduced into pig fibroblasts which facilitated liver-specific PEPCK overexpression and screening according to the two selection markers. In the present study, we used a liposome-mediated transfection protocol rather than a virus-mediated gene delivery system, since the virus may cause side effects. Following transfection, 46 colonies out of 33 transfection trials had positively integrated the overexpression vector, indicating that a relatively high transfection efficiency rate was obtained by the liposomal-mediated system. Thus, we recommend the optimal liver-specific expression system for safe and effective transfection of pig cells. We plan to use these cells for somatic cell nuclear transfer to produce piglets that overexpress liver-specific PEPCK as an animal model for human T2DM.

The Battered β-Cell: Usual Suspects and Guilt by Association

Does it not astonish us that diabetes was recognized thousands of years ago and in a single century we rapidly developed life-saving therapies, yet we are still trying to identify initial causes of this disease (1–3)? It is true that we have made much more progress in understanding pathophysiological mechanisms for type 1 diabetes mellitus (T1DM) than we have for type 2 diabetes mellitus (T2DM). Perhaps there is a message in this. T2DM is roughly 20 times more common than T1DM, it has at least several different phenotypes in humans, and its prevalence varies significantly among ethnic and racial groups. This suggests that T2DM is not a disease at all, but rather a syndrome—more like an association of signs and symptoms, such as fever, anemia, or pneumonia. In clinics and scientific literature, we tend to refer to T1DM as a single autoimmune disease, but we are vague about T2DM and refer to it as a multifactorial and polygenic disease. This is a reasonable enough concept, but one that opens the door to the possibility that there is no single gene that will explain T2DM. It is true that there are known important mutations in a few transcription factors in a small number of families of humans. Otherwise, however, it may take the loss of more than one gene's expression to develop T2DM in a single human … or it may take overexpression of more than one gene … or it may take a combination of loss and overexpression of different genes to establish the disease. This picture becomes ever more complicated when one adds epigenetic events as a possibility, especially considering how acutely epigenetic changes can come and then go after DNA repair is completed. Small wonder we have not yet identified the genetic cause of human T2DM. Actually, the term T2DM implies that we know more than we do, i.e. that there are only two forms of diabetes. This term arose by default because we decided to change the name of juvenile-onset or insulin-dependent diabetes to “type 1.” The term “type 2” was invented to cover the other 95% of cases of diabetes. That's a pretty large wastebasket and one that invites even worse tongue-in-cheek imprecision, i.e. terms such as type 1 and 1/2 diabetes, which implies an entity midway between type 1 and type 2. Other diabetes phenotypes, such as late onset of T1DM in adults and T2DM in children, clearly provide important pathophysiological clues.

Effect oftrans-fat, fructose and monosodium glutamate feeding on feline weight gain, adiposity, insulin sensitivity, adipokine and lipid profile

The incidence of obesity and type 2 diabetes mellitus (T2DM) is increasing, and new experimental models are required to investigate the diverse aspects of these polygenic diseases, which are intimately linked in terms of aetiology. Feline T2DM has been shown to closely resemble human T2DM in terms of its clinical, pathological and physiological features. Our aim was to develop a feline model of diet-induced weight gain, adiposity and metabolic deregulation, and to examine correlates of weight and body fat change, insulin homeostasis, lipid profile, adipokines and clinical chemistry, in order to study associations which may shed light on the mechanism of diet-induced metabolic dysregulation. We used a combination of partially hydrogenated vegetable shortening and high-fructose corn syrup to generate a high-fat-high-fructose diet. The effects of this diet were compared with an isoenergetic standard chow, either in the presence or absence of 1.125 % dietary monosodium glutamate (MSG). Dual-energy X-ray absorptiometry body imaging and a glucose tolerance test were performed. The present results indicate that dietary MSG increased weight gain and adiposity, and reduced insulin sensitivity (P < 0.05), whereas high-fat-high-fructose feeding resulted in elevated cortisol and markers of liver dysfunction (P < 0.01). The combination of all three dietary constituents resulted in lower insulin levels and elevated serum β-hydroxybutyrate and cortisol (P < 0.05). This combination also resulted in a lower first-phase insulin release during glucose tolerance testing (P < 0.001). In conclusion, markers of insulin deregulation and metabolic dysfunction associated with adiposity and T2DM can be induced by dietary factors in a feline model.