T2DM Model Research Articles

Metabolic changes during pregnancy in glucose-intolerant NZO mice: A polygenic model with prediabetic metabolism.

Gestational diabetes mellitus (GDM) is a complex metabolic disease involving genetic and environmental factors. Recent studies have underlined its heterogeneity, so it is reasonable to divide patients into subpopulations depending on whether an insulin secretion or sensitivity defect is predominant. Since testing for GDM is usually performed in the second trimester, misinterpretation of prediabetes as gestational diabetes may occur. As with type 2 diabetes (T2DM), rodent models are needed for both GDM and prediabetes, but few do exist. Here, we compared the metabolic changes in pregnant normal NMRI mice with those in New Zealand obese (NZO) mice. Male animals of this strain are an established model of T2DM, whereas female mice of this strain are protected from hyperglycemia and β‐cell death. We demonstrate that female NZO mice exhibited impaired glucose tolerance, preconceptional hyperinsulinemia, and hyperglucagonemia without any signs of manifest diabetes. The NZO model showed, compared with the NMRI control strain, a reduced proliferative response of the Langerhans islets during pregnancy (3.7 ± 0.4 vs. 7.2 ± 0.8% Ki‐67‐positive nuclei, p = .004). However, oral glucose tolerance tests revealed improved stimulation of insulin secretion in both strains. But this adaption was not sufficient to prevent impaired glucose tolerance in NZO mice compared with the NMRI control (p = .0002). Interestingly, glucose‐stimulated insulin secretion was blunted in isolated primary NZO islets in perifusion experiments. In summary, the NZO mouse reflects important characteristics of human GDM and prediabetes in pregnancy and serves as a model for subpopulations with early alterations in glucose metabolism and primary insulin secretion defect.

A novel metformin derivative showed improvement of lipid metabolism in obese rats with type 2 diabetes.

In this study, we investigated the lipid metabolism regulatory activity of a novel metformin derivative (MD568) and its potential mechanism of action in obese rats with type 2 diabetes mellitus (T2 DM). Previous gene chip analysis of 3T3-L1 cells have shown that MD568 regulates the transcription of genes involved in the peroxisome proliferator-activated receptor (PPAR) signalling pathway, fatty acid metabolism, and glycerolipid metabolism. In this study, obese T2 DM rats were treated with MD568 (200mg/kg) for 8weeks. Results showed that MD568 significantly reduced the body weight gain, plasma glucose, insulin, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels. MD568 treatment also improved the insulin resistance of obese T2 DM model rats. In particular, in white adipose tissue, MD568 inhibited the excessive volume increment of adipose cells by down-regulating the protein levels of CCAAT/enhancer-binding protein-α (C/EBP-α) and PPAR-γ, as well as the transcription of their target lipid metabolism-related genes. In the liver, MD568 inhibited hepatic fatty lesions and interfered with hepatic gluconeogenesis by regulating the expression of lipid metabolism-related genes and glycogen-related kinases. In conclusion, our results suggest that the newly synthesized MD568 affects the maintenance of lipid homeostasis in obese type 2 diabetic rats.

Bioenergetic functions in subpopulations of heart mitochondria are preserved in a non-obese type 2 diabetes rat model (Goto-Kakizaki)

A distinct bioenergetic impairment of heart mitochondrial subpopulations in diabetic cardiomyopathy is associated with obesity; however, many type 2 diabetic (T2DM) patients with high-risk for cardiovascular disease are not obese. In the absence of obesity, it is unclear whether bioenergetic function in the subpopulations of mitochondria is affected in heart with T2DM. To address this issue, a rat model of non-obese T2DM was used to study heart mitochondrial energy metabolism, measuring bioenergetics and enzyme activities of the electron transport chain (ETC). Oxidative phosphorylation in the presence of substrates for ETC and ETC activities in both populations of heart mitochondria in T2DM rats were unchanged. Despite the preservation of mitochondrial function, aconitase activity in T2DM heart was reduced, suggesting oxidative stress in mitochondria. Our study indicate that metabolic function of heart mitochondria is unchanged in the face of oxidative stress and point to a critical role of obesity in T2DM cardiomyopathy.

Protective effects of losartan on some type 2 diabetes mellitus-induced complications in Wistar and spontaneously hypertensive rats.

Diabetes mellitus type 2 (T2DM) is characterized by resistance of insulin receptors and/or inadequate insulin secretion resulting in metabolic and structural complications including vascular diseases, arterial hypertension and different behavioral alterations. We aimed to study the effects of the antihypertensive angiotensin AT1 receptor antagonist losartan on the T2DM-induced changes of exploratory behavior, anxiety, nociception and short term memory in normotensive Wistar and spontaneously hypertensive rats (SHRs). The experimental model of T2DM induced by a combination of high fat diet and streptozotocin, decreased exploratory activity and increased the level of carbonylated proteins in selected brain structures in both strains; as well it increased corticosterone level, pain threshold, anxiety-like behavior, and decline short term memory only in SHRs. Losartan treatment alleviated some of the T2DM- induced metabolic complications, abolished the T2DM-induced hypo activity, and normalized the corticosterone level, carbonylated proteins in brain, nociception and memory. Losartan did not exert effect on the anxiety behavior in both strains. We showed that T2DM exerted more pronounced negative effects on the rats with comorbid hypertension as compared to normotensive rats. Overall effects on the studied behavioral parameters are related to decreased exploration of the new environment, increased anxiety-like behavior, and decline in short-term memory. The systemic sub-chronic treatment with an angiotensin AT1 receptor antagonist losartan ameliorated most of these complications.

Combined effects of metformin and photobiomodulation improve the proliferation phase of wound healing in type 2 diabetic rats

We determined the impact of Photobiomodulation (PBM) and metformin administration alone and combined on the inflammation and proliferation steps of wound healing of incisions in type two diabetes mellitus (T2DM) rats. 40 rats were divided into 4 groups (n = 10 each group). A non-genetic model of T2DM was induced in all rats, and an incision was made on each rat. There were 4 groups as follows: Group 1 was control group. Group 2 received PBM alone (890 nm, 80 Hz, 0.324 J/cm2, daily). Group 3 received metformin alone (50 mg/kg, i.p., daily) and the fourth group received combination of PBM + metformin. At inflammation (day 4) and proliferation (day 7) steps, tensiometerical, stereological, and immunohistochemical examinations were performed. PBM and PBM + metformin treatments significantly increased wound strength at inflammation and proliferation steps of wound healing respectively. PBM, metformin, and PBM + metformin groups significantly decreased inflammatory cells at inflammation and proliferation steps of wound healing. PBM, metformin, and PBM + metformin groups significantly improved granulation tissue formation by increasing fibroblasts, and new blood vessel formation at inflammation and proliferation steps of wound healing. Metformin significantly increased M2 macrophages than other treatment groups at inflammation and proliferation steps of wound healing. Simultaneously, PBM significantly decreased M2 macrophages than control group. We concluded PBM and PBM + metformin treatments significantly hastened repair at the inflammation and proliferation steps of repairing skin injury in a non-genetic model of T2 DM. PBM + metformin showed a synergistic impact. There were not a positive relation between M2 macrophage number and wound strength in the studied groups. The details of the molecular mechanisms of PBM, and PBM + metformin treatments of repairing wounds in animals, and treatment of DFUs of patients with T2 DM should be elucidated by further research.

The potential roles of chitosan oligosaccharide in prevention of kidney injury in obese and diabetic conditions.

Obesity is closely associated with insulin resistance (IR). The most likely links between the two are obesity-mediated systemic low-grade chronic inflammation, endoplasmic reticulum stress and mitochondrial dysfunction, which are all known to contribute to the development of type 2 diabetes (T2DM) and eventually diabetic nephropathy (DN). Chitosan oligosaccharide (COS) is an oligomer of chitosan prepared by the deacetylation of chitin commonly found in exoskeletons of crustaceans such as shrimp and crab as well as the cell walls of fungi. COS has various biological effects including lipid lowering, anti-inflammation, anti-diabetes, and anti-oxidant effects. Therefore, COS is a potential new therapeutic agent for treatment of the obesity-induced DN condition. It is an abundant natural polymer and therefore freely available. This review includes information regarding the relationship between obesity, IR, T2DM, and DN as well as the potential usefulness of COS in controlling lipid and cholesterol metabolism, T2DM and kidney injury models in both in vivo and in vitro studies. However, evidence is limited regarding the effect of COS on the DN model. Further studies, especially in obesity-induced DN, are needed to support the mechanisms proposed in this review.

Nutritional Models of Type 2 Diabetes Mellitus.

In order to better understand the events that precede and precipitate the onset of type 2 diabetes (T2DM), several nutritional animal models have been developed. These models are generated by manipulating the diet of either the animal itself, or its mother during her pregnancy, and in comparison to traditional genetic and knock out models, have the advantage that they more accurately reflect the etiology of human T2DM. This chapter will discuss some of the most widely used nutritional models of T2DM: Diet-induced obesity (DIO) in adult rodents, and studies of offspring of mothers fed a low-protein, high-fat and/or high-sugar diet during pregnancy and/or lactation. Several common mechanisms have been identified through which these nutritional manipulations can lead to metabolic disease, including pancreatic beta-cell dysfunction, impaired insulin signaling in skeletal muscle, and the excess accumulation of visceral adipose tissue and consequent deposition of nonesterified fatty acids in peripheral tissues. In addition, there is an emerging concept that obesity/poor quality diets result in increased production and release of pro-inflammatory cytokines from adipose tissue leading to a state of chronic low-grade inflammation, and that this is likely to represent an important link between obesity/diet and metabolic dysfunction. The following chapter will discuss the most common nutritional models of T2DM in experimental animals, their application, and relationship to human etiology, and will highlight the important insights these models have provided into the pathogenesis of T2DM.

MicroRNA-96 regulates pancreatic β cell function under the pathological condition of diabetes mellitus through targeting Foxo1 and Sox6

To elucidate the potential function of microRNA-96 in protecting pancreatic β cell function under the pathological condition of T2DM and the underlying mechanism. Relative levels of microRNA-96 and genes associated with β cell function in the in vivo and in vitro T2DM and obesity models were detected by qRT-PCR. Insulin functions, including fasting blood glucose, plasma insulin, HOMA-IR, HOMA-%b, glucose tolerance and insulin tolerance, were assessed in microRNA-96 KO mice and wild-type mice fed with normal diet or high-fat diet. Downstream targets of microRNA-96 were verified by dual-luciferase reporter gene assay. Finally, regulatory effects of microRNA-96 on proliferation and apoptosis of MIN6 cells were determined. MicroRNA-96 was upregulated in mice fed with high-fat diet, db/db mice, high-level glucose-treated cells, TNF-α-treated cells, pancreatic cells isolated from the obesity and T2DM patients. Increased fasting blood glucose and HOMA-IR, as well as decreased plasma insulin and HOMA-%b were observed in microRNA-96 KO mice. IPGTT and IPITT results indicated that knockout of microRNA-96 led to pancreatic β cell dysfunction under the pathological condition of T2DM. Dual-luciferase reporter gene assay confirmed that microRNA-96 could bind Foxo1 and Sox6. MicroRNA-96 negatively regulated Foxo1 and Sox6 levels. Moreover, overexpression of microRNA-96 promoted proliferative ability and inhibited apoptosis in MIN6 cells. Relative levels of Pdx1, Nkx6.1, Cyclin D1 and Cyclin E1 were upregulated in MIN6 cells overexpressing microRNA-96. Opposite results were obtained after knockdown of microRNA-96 in MIN6 cells. MicroRNA-96 is upregulated in pancreatic β cells under the pathological condition of T2DM. Overexpression of microRNA-96 promotes proliferative ability and inhibits apoptosis in pancreatic β cells through targeting Foxo1 and Sox6.

Abstract 531: Urolithin a Suppress Cardiac Fibrosis via Autophagy Pathway in the Diabetic Cardiomyopathy

Objective: The cardiovascular protective effect of Urolithins remains poorly understood, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which is found in the pomegranate fruit. We identified Urolithin A (UA) as a natural compound that induces mitophagy and protects against diabetic cardiomyopathy both in vivo and in vitro. Healthy male C57BL/6 mice were fed with a High-fat diet for 6 months combined with a small dose of STZ injection to establish the T2DM model. Compared with the control, the diabetic mice suffered from cardiac dysfunction characterized by decrease EF, FS and E/A ratio, which was reversed with UA treatment. Masson staining and collagen marker Immunoblots showed that cardiac fibrosis was also decreased with UA treatment in the diabetic mice both in vivo and in vitro. Interestingly, we found UA significantly activated mitophagy and increased the co-localization of Myto-tracker and Lysotracker. However, we found UA increased Drp1 expression but not PINK1 or Parkin phosphorylation indicating a non-canonical mitophagy pathway. We treated the cardiac fibroblast with Drp1 siRNA and found the protective effect of UA against cardiac fibrosis was abolished. Conclusion: UA protected against diabetic cardiomyopathy by activating mitophagy vias a non-canonical pathway. Keywords: Diabetic cardiomyopathy; Cardiac fibrosis; Urolithin A; Autophagy; Mitophagy

Efficacy and adverse reaction to different doses of atorvastatin in the treatment of type II diabetes mellitus

Background: Type II diabetes mellitus (T2DM), a persistent metabolic disorder, is primarily characterized by insulin resistance, relative insulin deficiency and dyslipidemia. Here, we aimed to investigate whether different doses of atorvastatin (ATV) affect rats with T2DM. A total of 110 Sprague–Dawley rats were successfully established as T2DM models. Methods: First, the total cholesterol, triglyceride (TG), high-/low-/very-low-density lipoprotein cholesterol (HDL-c/LDL-c/VLDL-c), alanine transaminase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr), apolipoprotein Al (ApoA1) and apolipoprotein B (ApoB) levels in rat serum were analyzed. In addition, cholesteryl ester transfer protein (CETP) and retinol-binding protein 4 (RBP4) were also measured. Then, the incidence of adverse reactions was noted. Finally, the pathological study of liver and pancreatic tissues was performed. Results: Rats administered ATV at the doses of 40 and 80 mg/(kg·day) showed down-regulated TG, LDL-c, ApoB, CETP and RBP4 levels yet up-regulated HDL-c and ApoAl levels. Rats administered ATV at a dose of 80 mg/(kg·day) exhibited a higher incidence of adverse reactions and higher ALT and AST levels but lower BUN and Cr levels, which might affect liver and kidney function. Rats administered ATV at the doses of 40 and 80 mg/(kg·day) demonstrated significantly improved liver injury and pancreatic injury induced by T2DM. Conclusion: These data revealed that ATV could improve the lipid metabolism in T2DM rats and 40 mg/(kg·day) may serve as the optimal dose for the reduction of lipid levels and the incidence of adverse effects.

Therapy of empagliflozin plus metformin on T2DM mice shows no higher amelioration for glucose and lipid metabolism than empagliflozin monotherapy

AimsThis study was designed to compare the effects of empagliflozin monotherapy and its combination with metformin on glucose and lipid modulations in T2DM mice. Main methodsNine-week-old male C57BLKS/J db/db mice (n = 32) were used as T2DM model, and their age-matched C57BLKS/J db/m mice (n = 8) were used as normal control. A total of 32 db/db mice were randomly divided into four groups (n = 8/group): the DMT1 group, treated with metformin (250 mg/kg/day); the DMT2 group, treated with metformin (250 mg/kg/day) plus empagliflozin (10 mg/kg/day); the DMT3 group, treated with empagliflozin (10 mg/kg/day); the T2DM control group (DM), received 0.5% Natrosol. The db/m mice received same administration as DM group. Key findingsAfter four-week treatments, compared with T2DM control (DM), the empagliflozin or its combination with metformin dramatically increased the levels of plasma HDL-C (139.6% and 154.9%, respectively), with significant decrease in plasma TC (22.9% and 13.7%, respectively) and plasma TG (26% and 19.7%, respectively) and in hepatic TG (30.3% and 28.6%, respectively). The protein expressions of SREBP1c (75.3% and 54.0%, respectively) and APOC-III (51.2% and 50.2%, respectively) were reduced, while CPT1A (304.0% and 221.4%, respectively) and ApoA1 levels (90.0% and 85.3%, respectively) were enhanced. Although both interventions improve above-mentioned lipid homeostasis, there were no statistic differences between two groups (p > 0.05). SignificanceOur study demonstrated that current dose of combination therapy may have no higher amelioration than empagliflozin monotherapy for glucose and lipid metabolism in male T2DM mice when it followed a treatment shorter than that expected during clinical treatment.

1172-P: GLUT4-Overexpressing Engineered Muscle Tissue Implants as a Potential Novel Therapy for Type 2 Diabetes: Lessons from Diabetic Mice

In spite of current therapy protocols many T2DM patients fail to achieve blood glucose homeostasis goals. Insulin resistance in T2DM is associated with impaired GLUT4 function and cellular content. Thus, our aim was to improve overall glucose homeostasis by constructing engineered muscle tissue, using genetically modified skeletal muscle cells that over-express the GLUT4 transporter (OEG4). The OEG4 cells were grafted on biodegradable scaffolds and cultured to allow the formation of engineered muscle tissue constructs (EMC). Using an in-vitro 2-deoxyglucos (DOG) uptake assay, the OEG4-EMCs showed a 1.8-fold increase in DOG uptake with insulin stimulation, compared to unmodified controls. For in-vivo efficacy evaluation OEG4-EMCs and empty constructs, not seeded with cells, as control were implanted in the abdominal wall of immunodeficient recombination-activating gene 1 (Rag1)/MKR mice model of T2DM. Following i.p glucose tolerance test mice implanted with OEG4-EMCs had significantly (p<0.05) reduced maximal blood glucose levels (185+/-14.8 mg/dL), compared to diabetic controls group (294+/-23 mg/dL) and similar to nondiabetic mice (188+/-8.1 mg/dL). In addition, glucose levels returned to basal levels faster than in the control group. Since, EMC implants improved diabetic mice overall glucose homeostasis our data support the potential of such implants as novel therapeutic mode for T2DM therapy. Disclosure M. Beckerman: None. E. Karnieli: None. C. Harel: None. A. Klip: None. P.J. Bilan: None. E. Gallagher: None. D. LeRoith: Advisory Panel; Self; AstraZeneca, MannKind Corporation. S. Levenberg: None. Funding Rina and Avner Schneur Charitable Giving Fund

1791-P: A New Antidiabetic Monomers Composition against Insulin Resistance via Modulation of Bacteria-Cometabolism-Inflammation-Diabetes Axis

Intestinal flora disturbance can cause chronic inflammation, which leads to metabolic disorders such as obesity and insulin resistance. Insulin resistance is the main pathogenesis of T2DM. Recent studies indicated that changes of host-microbiome metabolic axis also play an important role in the pathogenic process. Based on previous experiments and literatures, Baicalin, Berberine, Puerarin, Paeoniflorin, Mangiferin, Ginsenoside Rb1 and other effective hypoglycemic compounds were combined to be a new antidiabetic monomers composition (AMC). C57BL/6J mice were used to establish T2DM models with high-fat diet (HFD). The mice in AMC group were observed with an effective weight loss, reduced blood glucose, lower insulin level and content of cholesterol and LDL, and increased metabolic rate and energy consumption compared with HFD group, and impaired glucose tolerance was also alleviated treated with AMC. Further studies showed that AMC improved the disordered of intestinal flora, especially the increase of beneficial bacteria such as Akkermansia, and the decrease of harmful bacteria such as Bacteroides and Collinsella. Afterwards, host-microbial metabolome, inducing inflammatory response, such as Ethylmethylacetic acid and Hydroxyphenyllactic acid reduced. As a result, the level of inflammation in the body decreased as well, and the suppressed signaling pathways related to insulin resistance alleviated. In conclusion, we explored the potential mechanism of AMC against insulin resistance via modulation of bacteria-cometabolism-inflammation-diabetes axis. Disclosure L. Han: None. L. Zhao: None. M. Zhang: None. S. Di: None. Z. Gao: None. X. Wang: None. H. Wu: None. W. Jia: None. X. Tong: None. Funding National Natural Science Foundation of China (81704067, 81430097)

Enhanced Platelet Response to Clopidogrel in Zucker Diabetic Fatty Rats due to Impaired Clopidogrel Inactivation by Carboxylesterase 1 and Increased Exposure to Active Metabolite.

Clopidogrel (Clop), a thienopyridine antiplatelet prodrug, is metabolized by cytochrome P450s (CYPs) to an active metabolite, Clop-AM, and hydrolyzed by carboxylesterase (CES)1 to the inactive Clop-acid. Patients with type 2 diabetes (T2DM) tend to have a poor response to Clop due to reduced generation of Clop-AM. Whether a similar response occurs in the Zucker diabetic fatty (ZDF) rat, a commonly used animal model of T2DM, has not been explored. In this work, we compared ZDF and control rats for hepatic CES1- and CYP-mediated Clop metabolism; pharmacokinetics of Clop, Clop-AM, and Clop-acid; and the antiplatelet efficacy of Clop. In contrast to clinical findings, Clop-treated ZDF rats displayed significantly less (50%) maximum platelet aggregation at 4 hours than control rats; the enhanced efficacy was accompanied by higher formation of Clop-AM and lower formation of Clop-acid. In vitro studies showed that hepatic levels of CES1 protein and activity and Ces1e mRNA were significantly lower in ZDF than in control rats, as were the mRNA levels of CYP2B1/2, CYP2C11, and CYP3A2, and levels of CYP2B6-, CYP2C19-, and CYP3A4-related proteins and enzymatic activities in liver microsomes of ZDF rats. Interestingly, liver microsomes of ZDF rats produced higher levels of Clop-AM than that of control rats despite their lower CYP levels, although the addition of fluoride ion, an esterase inhibitor, enhanced Clop-AM formation in control rats more than in ZDF rats. These results suggest that the reduction in CES1-based Clop inactivation indirectly enhances Clop efficacy in ZDF rats by making more Clop available for CYP-mediated Clop-AM formation.

The Role of Black Soybean and Purple Sweet Potato Active Compound on Advanced Glycation End-Product in Streptozotocin-Induced Type 2 Diabetes Mellitus Rat

Diabetic nephropathy is one of the diabetes complications attacking kidney leading to kidney damage. Hyperglycemia accompanying DM causes the increase of Ad-vanced Glycation End-Product (AGE) and Receptor Advanced Glycation End-Product (RAGE) activity, then develop kidney damage and other diabetes compli-cations. The study aimed to investigate the effect of black soybean, purple sweet potato, or their combination on the expression of AGE, RAGE, and kidney necro-sis T2DM model rats. The rats were given with high-calorie diet for five weeks and then injected with a low dose of streptozotocin (30 m/kg Body Weight) in intraperitoneal. DM rats were divided into: normal, K- (T2DM), K+ (T2DM + glibenclamide 0.6 mg/kg body weight), P1 (T2DM + black soybean), P2 (T2DM + purple sweet potato), and P3-5 Combination 1-3 (T2DM + combination of black soybean and purple sweet potato in ratio of 1 : 3, 2 : 2, and 3 : 1). DM rats were then given the treatments for thirty days. The effect of black soybean, purple sweet potato, or the combination of both was evaluated through the expression of AGE, RAGE, and necrosis of renal tubules. The changes in renal tubules histological characteristics were evaluated using hematoxylin-eosin (HE) staining. Immuno-histochemistry analysis of renal tubules was to evaluate AGE-RAGE expression after the treatments. The research results indicated that there was a significant dif-ference from the combination of black soybean and purple sweet potato in reduc-ing AGE, RAGE, and renal tubules necrosis. The BSB and PSP combination ratio of 1:1 was able to improve renal tubules, decrease the expression of AGE and RAGE towards near normal. The combination of black soybean and purple sweet potato could be used as one of the alternatives to improve kidney damage in dia-betic nephropathy.

PPAR-δ Activation Ameliorates Diabetes-Induced Cognitive Dysfunction by Modulating Integrin-linked Kinase and AMPA Receptor Function

An estimated 9% of the American population experiences type II diabetes mellitus (T2DM) due to diet or genetic predisposition. Recent reports indicate that patients with T2DM are at increased risk for cognitive dysfunctions, as observed in conditions like Alzheimer’s disease (AD). In addition, AD is the leading cause of dementia, highlighting the urgency of developing novel therapeutic targets for T2DM-induced cognitive deficits. The peroxisome proliferator activated receptor-δ (PPAR-δ) is highly expressed in the brain and has been shown to play an important role in spatial memory and hippocampal neurogenesis. However, the effect of PPAR-δ agonists on T2DM-induced cognitive impairment has not been explored. In this study, the effects of GW0742 (a selective PPAR-δ agonist) on hippocampal synaptic transmission, plasticity, and spatial memory were investigated in the db/db mouse model of T2DM. Oral administration of GW0742 for 2 weeks significantly improved hippocampal long-term potentiation. In addition, GW0742 effectively prevented deficits in hippocampal dependent spatial memory in db/db mice. PPAR-δ–mediated improvements in synaptic plasticity and behavior were accompanied by a significant recovery in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–mediated synaptic transmission. Our findings suggest that activation of PPAR-δ might ameliorate T2DM-induced impairments in hippocampal synaptic plasticity and memory.

Impaired Dilator Reactivity of Middle Cerebral Arteries in Goto‐Kakizaki Rats with Type II Diabetes Mellitus

Type II diabetes mellitus (T2DM) is a highly prevalent disease and is associated with the development of cerebrovascular disease. The objective of the study was to determine whether alterations to the regulation of cerebral vascular tone exist in a non‐obese model of T2DM and to determine the mechanistic contributors to changes in this response. Middle cerebral arteries (MCA) from 17–18‐wk‐old male Wistar Kyoto (WKY) and Goto‐Kakizaki (GK) were isolated and cannulated with glass micropipettes. Vascular reactivity was assessed in response to challenge with acetylcholine (ACh), sodium nitroprusside (SNP), reductions in Po2, 5‐HT, and increased intraluminal pressure. Vessels were treated with the competitive nitric oxide synthase (NOS) inhibitor L‐NAME, the cyclooxygenase inhibitor indomethacin, and the cell‐permeable superoxide dismutase (SOD) mimetic TEMPOL to support interpretation of mechanistic contributors to changes in vessel reactivity. Similar measurements of vascular reactivity to methacholine (MCh), phenylephrine, SNP, and reductions in PO2 were measured in aortic ring preparations, along with measurements of vascular NO production and metabolites of arachidonic acid. There was an impairment of vessel dilation within the MCA and aorta of GK in response to ACh/MCh and hypoxia but not SNP. Decreased vascular NO release and ratio of PGI2/TxA2 were measured within the aorta in response to hypoxia, and increasing MCh concentration. No change was seen in the constrictor response to either 5‐HT or phenylephrine within the MCA or aorta respectively or in the myogenic activation of the MCA. Treatment with L‐NAME severely blunted the dilator reactivity of both the MCA and aorta, while TEMPOL showed mild improvements in GK, and indomethacin yielded improved dilator reactivity to MCh in GK but blunted it in WKY. These results suggest that the vasodilator reactivity of the MCA and aorta of GK in response to endothelium‐dependent dilator stimuli is impaired vs. WKY. This may be due to decreased NO bioavailability and altered arachidonic acid metabolism as a result of a pro‐oxidant pro‐inflammatory condition present in T2DM. The lack of change to the constrictor response of MCA and aorta in GK suggests a lack of structural remodeling as a result of T2DM at this age.Support or Funding InformationAmerican Heart Association and National Institutes of Health (USA); Canadian Institutes for Health Research and Natural Sciences and Engineering Research Council (Canada)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The prevalence and associated factors of type 2 diabetes in rural areas of Ningbo, China

This study aimed to investigate the prevalence of T2DM and its risk factors in rural areas in Yinzhou District of Ningbo, China. A cross-sectional study with 4832 participants aged 18 years or older was conducted during the period of March 2013 to May 2013. Among the participants, 4760 completed a self-administered survey and physical examinations. Data collected included demographic characteristics, lifestyle, medical history, anthropometric measurements, and clinical assessment. After an overnight fasting of at least 10 h, participants also underwent an oral glucose tolerance test (OGTT) for diagnosing T2DM. Logistic regression analysis was performed to determine the risk factors associated with T2DM. The area under the receiver operating characteristic curve (AUROC) was used to assess the prediction ability of the models. The age-standardized prevalence of T2DM was 7.86% (95% confidence interval (95% CI = 7.10–8.62%), and the crude prevalence was 15.36%. In multivariate logistic regression models, age (≥ 65), obesity, and hypertension were the common risk factors of T2DM for both males and females. The AUROC of the T2DM model was 0.735 (95% CI = 0.709–0.762), indicating the accuracy of the model in predicting T2DM. Old age, obesity, hypertension, and elevated triglycerides and LDL-C were the risk factors for T2DM. And the predictive power of ROC curve we established for predicting T2DM had a good accuracy. Therefore, diabetes health education and early screening programs should be developed and strengthened for the prevention of T2DM in rural areas.

GLP-1 mediated improvement of the glucose tolerance in the T2DM GK rat model after massive jejunal resection

ObjectiveThe aim of this study was to clarify the role of the middle gut in the entero-pancreatic axis modification that leads to glucose improvement in the Goto-Kakizaki (GK) rat as a non-obese T2DM model. BackgroundBariatric surgery is considered an assured solution for type 2 Diabetes (T2DM). Enterohormones such as ghrelin, gastric inhibitory polypeptide and mainly glucagon-like peptide-1 (GLP-1) were recognized as key players in the physiophathological mechanisms associated with entero-pancreatic axis regulation and glucose tolerance improvement. However, the influence of anatomical arrangements post-bariatric surgery on this axis is still debatable. MethodTo this purpose, 50% of small intestine resections were performed on GK rats (n = 6), preserving the proximal half of the jejunum and the ileum (IR50). Phenotypic and functional changes, such as performance in oral glucose tolerance tests, ileal release of GLP-1, beta-cell sensitivity to GLP-1, beta-cell mass, and turnover were characterized in IR50 and the surgical control group (Sham). ResultsThe glucose tolerance was improved and ileal release of GLP-1 was enhanced four weeks after IR50 versus the control group rats. Beta-cell mass, beta-cell proliferation, and beta-cell sensitivity to GLP-1 were also increased in the pancreas of IR50 versus the control group rats. Conclusionthe jejunal exclusion increases beta-cell-mass and improves glucose tolerance by increasing in GLP-1 expression and number of receptors via the entero-pancreatic axis.

P38 MAPK Inhibitor (SB203580) and Metformin Reduces Aortic Protein Carbonyl and Inflammation in Non-obese Type 2 Diabetic Rats.

Microvascular and macrovascular diseases are the main causes of morbidity in type 2 diabetes patients through chronic hyperglycaemic condition via oxidative stress and inflammation. Reactive oxygen species (ROS) activate p38 MAPK phosphorylation and inflammation which enhances protein modification by carbonylation. The use of metformin and a p38 MAPK inhibitor is hypothesised to reduce ROS production and inflammation but effects of metformin and p38 MAPK inhibitor (SB203580) on ROS production and inflammation in vascular type 2 diabetes mellitus non-obese (T2DM) have not been investigated. The Goto-Kakizaki rat T2DM model was divided into three groups as T2DM, T2DM treated with 15mg/kg bw metformin and T2DM treated with 2mg/kg bw SB203580 for 4weeks. Rat aortas were isolated and protein carbonyl (PC) contents were measured by spectrophotometric DNPH assay. Aortic IL-1ß level was determined by ELISA. Results showed that aortic PC contents in the T2DM group were significantly higher than in non-diabetic rats. Treatment with metformin or SB203580 significantly reduced PC contents while only metformin significantly reduced IL-1ß levels. Findings indicated that metformin reduced ROS production and inflammation in diabetic vessels and possibly reduce vascular complications in non-obese T2DM.