T2DM In Humans Research Articles

Enhancing insulin sensitivity in type 2 diabetes mellitus using apelin-loaded small extracellular vesicles from Wharton’s jelly-derived mesenchymal stem cells: a novel therapeutic approach

BackgroundType 2 diabetes mellitus (T2DM), characterized by β-cell dysfunction and insulin resistance (IR), presents considerable treatment challenges. Apelin is an adipocyte-derived factor that shows promise in improving IR; however, it is limited by poor targeting and a short half-life. In the present study, engineered small extracellular vesicles (sEVs) derived from Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) loaded with apelin were used to address the limitations of the therapeutic application of apelin.MethodsWJ-MSCs were transduced to obtain engineered sEVs loaded with overexpressed apelin (apelin-MSC-sEVs) and the control sEVs (MSC-sEVs). T2DM mice were injected with apelin-MSC-sEVs and MSC-sEVs, and blood glucose monitoring, glucose and insulin tolerance tests, confocal microscopy, and immunocytochemical analysis were performed. IR models of 3T3-L1 adipocytes were employed to detect GLUT4 expression in each group using western blotting; the affected pathways were determined by measuring the changes in Akt and AMPK signaling and phosphorylation.ResultsUpon successful engineering, WJ-MSCs demonstrated significant overexpression of apelin. The genetic modification did not adversely impact the characteristics of sEVs, ranging from surface protein markers, morphology, to particle size, but generated apelin-overexpressed sEVs. Apelin-MSC-sEVs treatment resulted in notable enhancement of Akt and AMPK pathway activities within 3T3-L1 adipocytes and adipose tissues of T2DM mice. Furthermore, the apelin-loaded sEVs significantly reduced plasma glucose levels, increased pancreatic β-cell proliferation, improved insulin and glucose tolerance, and modulated pro-inflammatory cytokine profiles, compared to mice treated with the control sEVs.ConclusionOur study developed novel genetically engineered apelin-loaded sEVs derived from WJ-MSCs, and demonstrated their potent role in augmenting insulin sensitivity and regulating inflammatory responses, highlighting their therapeutic promise in T2DM management. The findings open new avenues for the development of clinically viable treatments for T2DM in humans using the apelin-loaded sEVs.

The relationship between gut microbiota and susceptibility to type 2 diabetes mellitus in rats

PurposeThe purpose of this study is to investigate the relationship between the susceptibility to type 2 diabetes and gut microbiota in rats and to explore the potential mechanism involved.MethodsThirty-two SPF-grade SD rats were raised as donor rats, and divided into control, type 2 diabetes mellitus (T2DM, fasting blood glucose ≥ 11.1 mmol/L), and Non-T2DM (fasting blood glucose < 11.1 mmol/L) groups. Feces were collected and prepared as fecal bacteria supernatants Diab (fecal bacteria supernatant of T2DM group rats), Non (fecal bacteria supernatant of Non-T2DM group rats), and Con (fecal bacteria supernatant of control group rats). Another seventy-nine SPF-grade SD rats were separated into normal saline (NS) and antibiotics (ABX) groups and given normal saline and antibiotics solutions, respectively. In addition, the ABX group rats were randomly separated into ABX-ord (fed with a 4-week ordinary diet), ABX-fat (fed with a 4-week high-fat diet and STZ ip), FMT-Diab (with transplanted fecal bacteria supernatant Diab and fed with a 4-week high-fat diet and STZ ip), FMT-Non (with transplanted fecal bacteria supernatant Non and fed with a 4-week high-fat diet and STZ ip), and FMT-Con (with transplanted fecal bacteria supernatant Con and fed with a 4-week high-fat diet and STZ ip) groups. Furthermore, the NS group was randomly divided into NS-ord (fed with a 4-week ordinary diet) and NS-fat (fed with a 4-week high-fat diet and STZ ip) groups. After this, the short-chain fatty acids (SCFAs) in the feces were detected using gas chromatography, and the gut microbiota were detected using 16S rRNA gene sequencing. Finally, G protein-coupled receptor 41 (GPR41) and GPR43 were detected by western blot and quantitative real-time polymerase chain reaction.ResultsG__Ruminococcus_gnavus_group were more abundant in the FMT-Diab group compared to the ABX-fat and FMT-Non groups. The levels of blood glucose, serum insulin, total cholesterol, triglycerides, and low-density lipoprotein cholesterol were also higher in the FMT-Diab group compared to those of the ABX-fat group. Compared to the ABX-fat group, both the FMT-Diab and FMT-Non groups had higher contents of acetic and butyric acid, and the expression of GPR41/43 were significantly higher as well.ConclusionsG__Ruminococcus_gnavus_group might make rats more susceptible to T2DM; T2DM-susceptible flora transplantation increased the susceptibility to T2DM in rats. Additionally, gut microbiota-SCFAs-GPR41/43 may play a role in the development of T2DM. Lowering blood glucose by regulating gut microbiota may therefore become a new strategy for the treatment of T2DM in humans.

Two Important Players for Type 2 Diabetes Mellitus: Metrnl and Asprosin.

The prevalence of diabetes mellitus (DM) is rapidly increasing worldwide. Metrnl and asprosin are the new adipomyokins that can increase glucose tolerance and affect insulin resistance. Based on this information, we aimed to identify the possible relationship between T2DM and asprosin, Metrnl levels and insulin resistance. Our study consisted of a group of 60 patients (female: 30/male: 30) who were newly diagnosed with T2DM and did not take any medications and a control group of 60 healthy (female: 31 - male: 29) individuals. We found that serum Metrnl levels were significantly lower in the diabetic group than in the control group (p < 0.01). In contrast, serum asprosin levels were significantly higher in the diabetic group compared to the control group (p < 0.01). We found a positive correlation between asprosin levels and HOMA-IR, insulin, BMI, and triglyceride levels in the patient group. On the contrary, we found a negative correlation between Metrnl levels and HOMA-IR, insulin, triglyceride, glucose levels. In the literature review, we could not find a comparison study on the relationship between T2DM, Metrnl, asprosin levels, and HOMA-IR in humans. As far as we know, this study will be the first report in which both adipokine/adipomyokine are compared and associated with HOMA-IR. Asprosin levels in patients with T2DM are higher than healthy people, and Metrnl levels are lower. These two molecules (Metrnl and asprosin) have the ability to be an early warning signal of insulin resistance for T2DM.

Vitamin D and Insulin Resistance in Polycystic Ovarian Syndrome and Congenital Adrenal Hyperplasia-a Commentary and Natural Expansion

In our previous focused review, the journal emphasized Type 2 diabetes (T2DM), excluding intimately associated disorders that should be considered integral components of the insulin resistance (IR) syndrome e.g., polycystic ovarian syndrome (PCOS), congenital adrenal hyperplasia (CAH), and gout [1]. In this expansion I’ll highlight potential roles of vitamin D in PCOS and CAH. Before discussing these areas, I shall briefly summarize key points from our review: • Low vitamin D levels are strongly and independently associated with IR, impaired insulin secretion, and higher incident T2DM risk, especially in people already at increased risk. • In several species the association of hypovitaminosis D with incident T2DM risk is apparently causal. • Causality of hypovitaminosis D in incident T2DM in humans is not established due to conflicting results of interventional trials and mendelian randomization studies on both incidence and glycemic control indices. Interventional trials varied idely in terms of dosage, preparations used, duration, and demographics. • Low vitamin D status (VDS) is strongly correlated with risk for several micro- and macrovascular T2DM complications including: peripheral neuropathy, erectile dysfunction (ED), retinopathy, kidney disease, and all-cause mortality, but not gastroparesis. The association between serum vitamin D level and diabetic cardiac neuropathy risk is U-shaped. • Interventional studies in people with diabetic kidney disease reported significant therapeutic benefit when combining vitamin D analogues with renin angiotensin aldosterone system (RAAS) inhibitors. Causality of low VDS in T2DM omplications, except for renal damage, remains unconfirmed. • In people with prediabetes (unselected for hypovitaminosis D), vitamin D3 supplementation at 4000 IU/ day did not significantly lower risk of incident diabetes in the much much-anticipated D2d trial [2].

Pancreatic Islets Accumulate Cadmium in a Rodent Model of Cadmium-Induced Hyperglycemia.

Cadmium (Cd) is an anthropogenic as well as a naturally occurring toxicant associated with prediabetes and T2DM in humans and experimental models of Cd exposure. However, relatively few studies have examined the mechanism(s) of Cd-induced hyperglycemia. The purpose of this study was to examine the role of pancreatic islets in Cd-induced hyperglycemia. Male Sprague–Dawley rats were given daily subcutaneous doses of Cd at 0.6 mg/kg over 12 weeks. There was a resulting time-dependent increase in fasting blood glucose and altered insulin release in vitro. Islets isolated from control (saline-treated) and Cd-treated animals were incubated in low (0.5 mg/mL) or high (3 mg/mL) glucose conditions. Islets from 12 week Cd-treated animals had significantly less glucose-stimulated insulin release compared to islets from saline-treated control animals. The actual Cd content of isolated islets was 5 fold higher than the whole pancreas (endocrine + exocrine) and roughly 70% of that present in the renal cortex. Interestingly, islets isolated from Cd-treated animals and incubated in high glucose conditions contained significantly less Cd and zinc than those incubated in low glucose. These results show that within whole pancreatic tissue, Cd selectively accumulates in pancreatic islets and causes altered islet function that likely contributes to dysglycemia.

Fat storage-inducing transmembrane protein 2 (FIT2) is less abundant in type 2 diabetes, and regulates triglyceride accumulation and insulin sensitivity in adipocytes.

Fat storage-inducing transmembrane protein 2 (FIT2) aids in partitioning of cellular triacylglycerol into lipid droplets. A genome-wide association study reported FITM2-R3H domain containing like-HNF4A locus to be associated with type 2 diabetes (T2DM) in East Asian populations. Mice with adipose tissue (AT)-specific FIT2 knockout exhibited lipodystrophic features, with reduced AT mass, insulin resistance, and greater inflammation in AT when fed a high-fat diet. The role of FIT2 in regulating human adipocyte function is not known. Here, we found FIT2 protein abundance is lower in subcutaneous and omental AT obtained from patients with T2DM compared with nondiabetic control subjects. Partial loss of FIT2 protein in primary human adipocytes attenuated their lipid storage capacity and induced insulin resistance. After palmitate treatment, triacylglycerol accumulation, insulin-induced Akt (Ser-473) phosphorylation, and insulin-stimulated glucose uptake were significantly reduced in FIT2 knockdown adipocytes compared with control cells. Gene expression of proinflammatory cytokines IL-18 and IL-6 and phosphorylation of the endoplasmic reticulum stress marker inositol-requiring enzyme 1α were greater in FIT2 knockdown adipocytes than in control cells. Our results show for the first time that FIT2 is associated with T2DM in humans and plays an integral role in maintaining metabolically healthy AT function.-Agrawal, M., Yeo, C. R., Shabbir, A., Chhay, V., Silver, D. L., Magkos, F., Vidal-Puig, A., Toh, S.-A. Fat storage-inducing transmembrane protein 2 (FIT2) is less abundant in type 2 diabetes, and regulates triglyceride accumulation and insulin sensitivity in adipocytes.

The Nile Rat (Arvicanthis niloticus) as a Superior Carbohydrate-Sensitive Model for Type 2 Diabetes Mellitus (T2DM).

Type II diabetes mellitus (T2DM) is a multifactorial disease involving complex genetic and environmental interactions. No single animal model has so far mirrored all the characteristics or complications of diabetes in humans. Since this disease represents a chronic nutritional insult based on a diet bearing a high glycemic load, the ideal model should recapitulate the underlying dietary issues. Most rodent models have three shortcomings: (1) they are genetically or chemically modified to produce diabetes; (2) unlike humans, most require high-fat feeding; (3) and they take too long to develop diabetes. By contrast, Nile rats develop diabetes rapidly (8–10 weeks) with high-carbohydrate (hiCHO) diets, similar to humans, and are protected by high fat (with low glycemic load) intake. This review describes diabetes progression in the Nile rat, including various aspects of breeding, feeding, and handling for best experimental outcomes. The diabetes is characterized by a striking genetic permissiveness influencing hyperphagia and hyperinsulinemia; random blood glucose is the best index of disease progression; and kidney failure with chronic morbidity and death are outcomes, all of which mimic uncontrolled T2DM in humans. Non-alcoholic fatty liver disease (NAFLD), also described in diabetic humans, results from hepatic triglyceride and cholesterol accumulation associated with rising blood glucose. Protection is afforded by low glycemic load diets rich in certain fibers or polyphenols. Accordingly, the Nile rat provides a unique opportunity to identify the nutritional factors and underlying genetic and molecular mechanisms that characterize human T2DM.

Chronic Osteomyelitis Increases the Incidence of Type 2 Diabetes in Humans and Mice.

Background: To compare the risk of type 2 diabetes (T2DM) between patients with and without chronic osteomyelitis (COM), both in humans and in mice, and to explore risk factors in COM patients who developed T2DM.Methods: One hundred seven patients with COM and 114 patients without COM were consecutively enrolled and retrospectively analysed. Clinical data concerning the time to develop diabetes, glucose metabolism, lipid metabolism, inflammatory factors, mental health and frequency of specialist visits were collected. A mouse model of osteomyelitis was used to verify the presence of impaired glucose metabolism and depression. All data were processed by SPSS.Results: The incidence of T2DM was 2.37-fold higher in patients with COM than in those without. In COM patients, subjects with T2DM (DDM) had higher BMI, less exercise and more frequent visits to specialists than those without (Con). Glucose and lipid metabolism were worse in patients with DDM. Patients with DDM had higher levels of white blood cells (12.9±2.1×109/L vs. 11.7±2.2×109/L, p=0.027), CRP (28.4±4.5 mg/L vs. 22.0±4.8 mg/L, p<0.001), TNF-α (13.5±5.0 pg/mL vs. 9.4±2.6 pg/mL, p= 0.003) and IL-6 (12.9±3.2 pg/mL vs. 9.2±2.7 pg/mL, p<0.001). Significantly increased fasting blood glucose concentrations and impairment of oral glucose tolerance tests were also observed in mice modelling osteomyelitis, which were accompanied by elevated TNF-α and IL-6 levels. Furthermore, the proportion of depression (63.2% vs. 35.2%, p=0.003) and severe anxiety (31.6% vs. 9.1%, p=0.002) were significantly higher in the DDM group. Osteomyelitis mice showed obvious depressive-like behaviours. The levels of TNF-α, IL-6, CRP, BMI, and LDL; lack of exercise; SAS; HAQ; and SF36 assessment were risk factors for the development of T2DM in COM patients.Conclusions: Chronic osteomyelitis increased the incidence of T2DM in both humans and mice. Inflammation, mental illness and lack of exercise were risk factors for the occurrence of T2DM in osteomyelitis. Comprehensive consideration of patient history, including metabolism and mental health, is needed in planning future treatment.

Surgical cure for type 2 diabetes by foregut or hindgut operations: a myth or reality? A systematic review.

Bariatric surgery results in remission of type 2 diabetes mellitus in a significant proportion of patients. Animal research has proposed the foregut and hindgut hypotheses as possible mechanisms of remission of T2DM independent of weight loss. These hypotheses have formed the basis of investigational procedures designed to treat T2DM in non-obese (in addition to obese) patients. The aim of this study was to review the procedures that utilise the foregut and hindgut hypotheses to treat T2DM in humans. A systematic review was conducted to identify the investigational procedures performed in humans that are based on the foregut and hindgut hypotheses and then to assess their outcomes. Twenty-four studies reported novel procedures to treat T2DM in humans; only ten utilised glycated haemoglobin A1c (HbA1c) in their definition of remission. Reported remission rates were 20-40% for duodenal-jejunal bypass (DJB), 73-93% for duodenal-jejunal bypass with sleeve gastrectomy (DJB-SG), 62.5-100% for duodenal-jejunal bypass sleeve (DJBS) and 47-95.7% for ileal interposition with sleeve gastrectomy (II-SG). When using a predetermined level of HbA1c to define remission, the remission rates were lower (27, 63, 0 and 65%) for DJB, DJB-SG, DJBS and II-SG. The outcomes of the foregut- and hindgut-based procedures are not better than the outcomes of just one of their components, namely sleeve gastrectomy. The complexity of these procedures in addition to their comparable outcomes to a simpler operation questions their utility.

Sexual dimorphism in mesenteric arterial function of a novel rat model of type 2 diabetes, UC Davis‐Type 2 Diabetes Mellitus (UCD‐T2DM)

This is the first study to characterize the vascular functions in a well characterized and validated polygenic rat model of type 2 diabetes (UC Davis‐Type 2 Diabetes Mellitus, UCD‐T2DM), exhibiting etiology more similar to clinical T2DM in humans than other rodent models. The objectives of this study were to investigate whether 1) the endothelium‐dependent and ‐independent vasodilation in mesenteric arteries (MA) are impaired, 2) sex differences exist in the development of abnormal vascular responses, and 3) the relative contributions of endothelium derived relaxing factors in modulating vascular reactivity of MA is altered in UCD‐T2DM Rats.Endothelium‐dependent vasodilation to acetylcholine (ACh, 10−8 to 10−5 M) in pre‐contracted arteries with phenylephrine (PE, 2 μM) was measured before and after pre‐treatment with indomethacin (cyclooxygenase inhibitor, 10 μM), L‐NAME (nitric oxide synthase inhibitor, 200 μM), or barium chloride (KIR blocker, 100 μM) plus ouabain (Na+‐K+‐ATPase inhibitor, 10 μM). Vascular responses to sodium nitroprusside (SNP) (endothelium‐independent vasodilator, 10−9 to 10−5 M) and contractile agents such as PE (10−7 to 3×10−5 M) or endothelin‐1 (ET‐1, 10−10 to 10−7 M) were also determined.Both ACh‐ and SNP‐induced relaxation were significantly impaired in MA of diabetic rats, regardless of sex. However, the extent of impairment was greater in female diabetic rats compared to male diabetic animals. Diabetes also significantly increased sensitivity to PE or ET‐1 in females compared to males. Finally, the relative importance of endothelium‐derived hyperpolarizing factor (EDHF) to vascular regulation was lost in diabetic rats, regardless of sex.These data, for the first time, show that the endothelial function in MA of UCD‐T2DM Rats is impaired in both sexes, possibly due to the loss of EDHF, initially a major vasodilatory factor. Furthermore, we showed a greater predisposition of MA to injury in diabetic female rats, in part due to a higher sensitivity of female arteries to contractile agents.

β-Cell Identity in Type 2 Diabetes: Lost or Found?

Type 2 diabetes (T2DM) is characterized by deficits of β-cell mass and function. The deficit in β-cell mass in patients with T2DM is up to ∼65% compared with those without diabetes (1). This deficit in β-cell mass has been attributed to increased β-cell apoptosis (1) due to endoplasmic reticulum stress mediated by protein misfolding due to the accumulation of toxic oligomers of islet amyloid polypeptide (2) and/or gluco- or lipotoxicity (3) and disruption of the mitochondrial network (4). Alternatively, decreased β-cell mass in T2DM may reflect insufficient expansion of β-cell mass during fetal and neonatal life (5) or a failure to adaptively regenerate β-cells in response to β-cell loss. Recent studies have shown that loss of β-cell identity by de-differentiation may contribute to the measured β-cell deficit in mouse models of T2DM characterized by impaired leptin signaling, a finding not yet confirmed in humans with T2DM (6). In this issue of Diabetes , Spijker et al. (7) present data highlighting the loss of β-cell identity in T2DM in humans and nonhuman primates. The authors confirm an increased ratio of α-cells to β-cells reported previously (8) and predicted by the selective loss of β-cells in T2DM. They also confirm an increased frequency of cells coexpressing insulin and glucagon in T2DM (0.52 ± 0.18% vs. 4.05 ± 1.37%; nondiabetic donors vs. T2DM; P < 0.01), as previously reported (0.4 ± 0.1% vs. 3.2 …

Type 2 diabetes critically redefined for nonhuman primates (854.9)

Nonhuman primates (NHPs) naturally develop type 2 diabetes (T2DM) with extraordinary concomitance to T2DM in humans. In order to determine valid criteria for the onset of T2DM in NHPs, a colony of 326 adult NHPs (232 male and 94 female; rhesus monkeys, Macaca mulatta) was studied prospectively, including fasting plasma glucose (FPG), glucose tolerance, HbA1c, insulin, lipid profiles, β‐cell function and insulin sensitivity. A subset of 105 metabolically healthy NHPs was used to establish normal/baseline fasting levels, with normal FPG, 57.3±6.6 mg/dl comparable to ~85 mg/dl in humans and normal HbA1c level, 4.2±0.3 comparable to ~5.5 in humans, thus, 37% and 27% lower than for humans. 112 monkeys developed diabetes while under study and showed the necessity of redefining the onset of T2DM for rhesus, specifically at a fasting glucose of 100 mg/dl or 5.6 mmol/l. Monkeys with a fasting glucose &gt;70 mg/dl were in the progression toward diabetes, and 80‐99 mg/dl was redefined as prediabetes, a level that coincided with sharp changes in β‐cell responses to glucose, and in fasting insulin levels. HbA1c was highly correlated with fasting glucose (r=0.852, p&lt;0.001), with a T2DM diagnostic level of &gt; 5.5% for rhesus. NHPs provide the optimal animal model for studies of the in vivo and molecular pathophysiology of T2DM, and these new diagnostic criteria are essential to improved translation to humans.

Low‐glycemic index diets prevent type 2 diabetes in the Nile rat

The Nile rat (NR) is a novel model for type 2 diabetes (T2DM) and metabolic syndrome sensitive to metabolic stress from simple carbohydrates (CHO). Three experiments assessed the effects of a low‐glycemic index CHO (green lentils, GL) on T2DM. Expt 1 compared a GL diet directly with a semipurified hiCHO diet having identical %En from CHO:fat:protein (70:10:20). Expt 2 assessed reversibility of hyperglycemia by comparing a modCHO‐GL diet (45:25:30) to diabetogenic semipurified hiCHO (70:10:20) or lab chow (#5020) diets in 3 separate studies. Expt 3 examined young Nile rats “primed” from weaning for 7wks with the modCHO‐GL diet (45:25:30) before being challenged with stressful semipurified hiCHO (70:10:20) or modCHO (40:40:20) diets based on glucose and starch. 1. Compared to the hiCHO semipurified diet with the same macronutrient composition, the GL diet induced significantly less diabetes. 2. GL substantially reversed hyperglycemia, especially in young (&lt;4mo) diabetic rats. 3.”Priming” rats with GL prior to hiCHO resulted in less severe diabetes compared to previous studies without priming. Positive influences on other metabolic parameters such as liver and kidney weight and plasma lipids also were observed. Since the NR mimics T2DM in humans, GL or components therein may represent a potentially useful adjunct for T2DM control in humans.Funding source: Foster Biomed Res Lab and the Malaysian Palm Oil Board

Abstract 19265: Adipose Tissue Overexpression of a Constitutively Active Isoform of Chrebp Protects Against Obesity and Insulin Resistance in Mice

Obesity is associated with increased risk for T2DM and CVD in humans, and nutrients typically consumed in excess in the Western diet, such as various saturated fats, cholesterol, and simple sugars, are thought to regulate the activity of metabolic genes that modulate risk for obesity and insulin resistance. The glucose-sensing transcription factor carbohydrate response element binding protein (ChREBP) has been shown to regulate hepatic intracellular glucose and lipid homeostasis independent of the effects of insulin. Recent publications have reported that white adipose tissue (WAT) and brown adipose tissue (BAT) depots also highly express ChREBP, that ChREBP expression is upregulated during adipocyte differentiation, and that increased ChREBP activation in adipocytes is associated with obesity, but not insulin resistance, in the context of adipose tissue-specific GLUT4 overexpression in mice. However, independent modulation of ChREBP expression in adipose tissue has not yet been achieved. To better understand the impact of adipocyte-specific ChREBP activity on intracellular and whole-body metabolism, we have generated a novel transgenic mouse model that overexpresses a constitutively active ChREBP (caChREBP) isoform in adipose tissue (ap2-Cre;eGFPflox-caChREBP mice). When fed either standard chow diet or Western-type diet (WD) for 10 weeks, total fat mass, but not lean mass, was significantly decreased in male ap2-Cre;eGFPflox-caChREBP mice versus ap2-Cre littermate controls. Both glucose tolerance testing and insulin tolerance testing revealed no differences between groups of chow-fed mice, but significantly improved insulin sensitivity in WD-fed male ap2-Cre;eGFPflox-caChREBP mice. RER during the daily active cycle was increased in WD-fed ap2-Cre;eGFPflox-caChREBP mice, implying greater utilization of carbohydrate for energy expenditure. Transgenic overexpression of caChREBP resulted in increased expression of lipogenic genes, but not genes involved in adipocyte differentiation, in gonadal fat. Taken together, these data indicate that upregulation of ChREBP activity in adipose tissue may defend against WD-induced obesity and insulin resistance, despite increased adipocyte expression of lipogenic genes.

Development and characterization of a novel rat model of type 2 diabetes mellitus: the UC Davis type 2 diabetes mellitus UCD-T2DM rat.

The prevalence of type 2 diabetes (T2DM) is increasing, creating a need for T2DM animal models for the study of disease pathogenesis, prevention, and treatment. The purpose of this project was to develop a rat model of T2DM that more closely models the pathophysiology of T2DM in humans. The model was created by crossing obese Sprague-Dawley rats with insulin resistance resulting from polygenic adult-onset obesity with Zucker diabetic fatty-lean rats that have a defect in pancreatic beta-cell function but normal leptin signaling. We have characterized the model with respect to diabetes incidence; age of onset; longitudinal measurements of glucose, insulin, and lipids; and glucose tolerance. Longitudinal fasting glucose and insulin data demonstrated progressive hyperglycemia (with fasting and fed glucose concentrations >250 and >450 mg/dl, respectively) after onset along with hyperinsulinemia resulting from insulin resistance at onset followed by a progressive decline in circulating insulin concentrations, indicative of beta-cell decompensation. The incidence of diabetes in male and female rats was 92 and 43%, respectively, with an average age of onset of 6 mo in males and 9.5 mo in females. Results from intravenous glucose tolerance tests, pancreas immunohistochemistry, and islet insulin content further support a role for beta-cell dysfunction in the pathophysiology of T2DM in this model. Diabetic animals also exhibit glycosuria, polyuria, and hyperphagia. Thus diabetes in the UC Davis-T2DM rat is more similar to clinical T2DM in humans than in other existing rat models and provides a useful model for future studies of the pathophysiology, treatment, and prevention of T2DM.