Improved Glucose Intolerance Research Articles

The sodium-glucose co-transporter 2 inhibitor tofogliflozin suppresses atherosclerosis through glucose lowering in ApoE-deficient mice with streptozotocin-induced diabetes.

Epidemiological and animal studies have revealed that sodium‐glucose cotransporter 2 (SGLT2) inhibitors suppress cardiovascular events in subjects with type 2 diabetes and atherosclerosis in animal models of diabetes. However, it still remains unclear if the anti‐atherosclerotic effect of SGLT2 inhibitors is entirely dependent on their glucose‐lowering effect. Tofogliflozin, a highly specific SGLT2 inhibitor, was administrated to apolipoprotein‐E‐deficient (ApoEKO) with streptozotocin (STZ)‐induced diabetes and nondiabetic ApoEKO mice. After 6 weeks, samples were collected to investigate the histological changes and peritoneal macrophage inflammatory cytokine levels. Tofogliflozin suppressed atherosclerosis in the diabetic ApoEKO mice. The atherosclerosis lesion areas and accumulation of macrophages in these areas were reduced by tofogliflozin treatment. The expression levels of interleukin (IL)‐1β and IL‐6 in the peritoneal macrophages were significantly suppressed in the tofogliflozin‐treated diabetic ApoEKO mice. Tofogliflozin treatment failed to inhibit atherosclerosis in the nondiabetic ApoEKO mice. No significant difference in the anti‐atherosclerotic effects of insulin and tofogliflozin was observed between diabetic ApoEKO mice with equivalent degrees of glycemic control achieved with the two treatments. Insulin treatment significantly reduced the IL‐1β and IL‐6 expression levels in the peritoneal macrophages of the diabetic ApoEKO mice. Significant decrease of the LPS‐stimulated IL‐1β concentrations was also observed in the conditioned medium of the peritoneal macrophages collected from insulin‐ and tofogliflozin‐treated diabetic ApoEKO mice. These results suggest that tofogliflozin suppresses atherosclerosis by improving glucose intolerance associated with inhibition of inflammation. Tofogliflozin suppresses atherosclerosis in ApoEKO mice with STZ‐induced diabetes via its glucose‐lowering effect.

1426-P: Increased Insulin Secretion and Glucose Effectiveness Result in Improved Glucose Tolerance in Obese Subjects Two Months after Gastric Bypass and Sleeve

The early effects of bariatric surgery on insulin secretion and action in obese subjects with type 2 diabetes (T2D) remains poorly investigated. Here we assessed the mechanisms resulting in improved glucose intolerance using the oral minimal model approach. An oral glucose tolerance test was performed before and 2 months after bariatric surgery in 16 obese T2D subjects (9 bypass, 7 gastric sleeve) and in 8 healthy control subjects. For each visit, body mass index (BMI) was measured, and the oral glucose and the insulin and C-peptide minimal models were used to estimate insulin sensitivity (SI) , glucose effectiveness (GE) , total β-cell responsiveness (Φtot) , disposition index (DI) and total hepatic insulin extraction (HE) . Bariatric surgery resulted in a significant reduction (similar between bypass and sleeve groups) in BMI by 14% (from 42±5 to 36±4 kg/m2) . Glucose tolerance increased comparably after bypass and sleeve, but remained impaired compared to the control group (Figure 1) : GE, Φtot, DI and HE were equally increased following bariatric surgery, whereas insulin action (SI) remained unaltered in the two groups. These results suggest that improved glucose tolerance in obese T2D subjects 2 months after bariatric surgery is attributable mainly to an increase in insulin secretion and glucose effectiveness rather than an improvement in insulin action. Disclosure R. Visentin: Research Support; Becton, Dickinson and Company, MannKind Corporation, Sanofi-Aventis Deutschland GmbH. K. Brodersen: None. N. Moller: None. C. Dalla Man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. M.F. Nielsen: None. Funding Novo Nordisk Foundation

Exogenous thyroxine increases GLUT4 translocation to the membrane in cardiomyocytes in insulin resistant OLETF rats Dora A Mendez1, Jose G. Soñanez‐Organis2, Guillermo Vasquez‐Anaya1, Daisuke Nakano3, Akira Nishiyama3, Rudy M Ortiz11Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA 2Division of Science and Engineering, Department of Chemical Biological and Agropecuary Sciences, University of Sonora,

During insulin resistance the heart undergoes a metabolic shift in which fatty acids (FA) accounts for about 99% of the ATP production. This metabolic shift is indicative of impaired glucose metabolism. A shift in FA metabolism with impaired glucose tolerance can cause an increase in reactive oxygen species (ROS) and lipotoxicity ultimately leading to impaired mitochondrial function. Thyroid hormones (TH) may improve glucose intolerance by increasing glucose reabsorption and metabolism in peripheral tissues but its effects on cardiac tissue during insulin resistance is not well known. The glucose transport protein, GLUT4, is a downstream target of the TH response element (TRE) indicating a possible mechanism by which THs regulate glucose metabolism. Non‐classical TH signaling may also phosphorylate protein kinase B (Akt) and increase activity of phosphoinositide‐3‐kinase (PI3K), which are two key regulators in insulin‐mediated glucose uptake. Insulin resistant, Otsuka Long Evans Tokushima Fatty (OLETF) rats were used to assess the effects of exogenous thyroxine (T4) on glucose metabolism in cardiac tissue. Rats were assigned to four groups: 1) lean, Long Evans Tokushima Otsuka (LETO; n=6), 2) LETO + T4 (8 μg/100g BM/d × 5 wks; n=7), 3) untreated OLETF (n=6), and 4) OLETF + T4 (n=7). T4 increased GLUT4 gene expression by 85% (p<0.05) in OLETF and increased GLUT4 protein translocation to the membrane by 328% (p<0.05). Additionally, T4 increased phosphofructokinase‐1 (PFK‐1) gene expression, the rate limiting step in glycolysis, by 98% (p<0.05) in OLETF. T4 increased AKT and p‐AKT by 177% and 134% (p<0.05), respectively, in LETO, but not in OLETF. The results suggest that increased T4 has the potential to increase glucose reabsorption and metabolism in the heart of insulin resistant rats to help restore impaired substrate metabolism.

Combination of Aerobic Training and Cocoa Flavanols as Effective Therapies to Reduce Metabolic and Inflammatory Disruptions in Insulin-Resistant Rats: The Exercise, Cocoa, and Diabetes Study.

We aimed to investigate the combined effects of aerobic exercise (EXE) and cocoa flavanol (COCOA) supplementation on performance, metabolic parameters, and inflammatory and lipid profiles in obese insulin-resistant rats. Therefore, 32 male Wistar rats (230-250g) were fed a high-fat diet and a fructose-rich beverage for 30days to induce insulin resistance. Next, the rats were randomized into four groups, orally administered placebo solution or COCOA supplementation (45mg·kg-1), and either remained sedentary or were subjected to EXE on a treadmill at 60% peak velocity for 30min, for 8 weeks. Blood samples and peripheral tissues were collected and processed to analyze metabolic and inflammatory parameters, lipid profiles, and morphological parameters. Supplementation with COCOA and EXE improved physical performance and attenuated body mass gain, adipose index, and adipocyte area. When analyzed as individual interventions, supplementation with COCOA and EXE improved glucose intolerance and the lipid profile reduced the concentrations of leptin, glucose, and insulin, and reduced homeostasis assessment index (all effects were p < .001 for both interventions), while ameliorated some inflammatory mediators in examined tissues. In skeletal muscles, both COCOA supplementation and EXE increased the expression of glucose transporter (p < .001 and p < .001), and combined intervention showed additive effects (p < .001 vs. COCOA alone or EXE alone). Thus, combining COCOA with EXE represents an effective nonpharmacological strategy to treat insulin resistance; it could prevent Type 2 diabetes mellitus by improving physical performance, glucose metabolism, neuroendocrine control, and lipid and inflammatory mediators in the liver, pancreas, adipose tissue, and skeletal muscle in obese male insulin-resistant rats.

Empagliflozin Alleviates Left Ventricle Hypertrophy in High-Fat-Fed Mice by Modulating Renin Angiotensin Pathway.

Aims. The cardiobenefits of empagliflozin are multidimensional, and some mechanisms are still unclear. The aim of the present study was to evaluate the effect of treatment with empagliflozin on biometric parameters and gene expression in the local cardiac RAS, oxidative stress, and endoplasmic reticulum pathways in a mouse model. Main Methods. Forty male C57BL/6 mice were fed with control (C) or high-fat (HF) diets for 10 weeks. After that, the groups were redistributed according to the treatment with empagliflozin—CE or HFE. The empagliflozin was administered via food for 5 weeks (10 mg/kg/day). We performed biochemical analyses, blood pressure monitoring, oral glucose tolerance test, left ventricle (LV) stereology, RT-qPCR for genes related to classical and counterregulatory local RAS, oxidative stress, and endoplasmic reticulum stress. Key Findings. In comparison to HF, HFE decreased body mass and improved glucose intolerance and insulin resistance. The cardiac parameters were enhanced after treatment as expressed by decrease in plasma cholesterol, plasma uric acid, and systolic blood pressure. In addition, LV analysis showed that empagliflozin reduces cardiomyocyte area and LV thickness. The local RAS had less activity of the classical pathway and positive effects on the counterregulatory pathway. Empagliflozin treatment also decreased oxidative stress and endoplasmic reticulum stress-related genes. Significance. Our results suggests that empagliflozin modulates the local RAS pathway towards alleviation of oxidative stress and ER stress in the LV, which may be a route to its effects on improved cardiac remodeling.

Consumption of barley flour increases gut fermentation and improves glucose intolerance via the short-chain fatty acid receptor GPR43 in obese male mice.

Barley consumption is expected to increase insulin sensitivity by increasing the level of short-chain fatty acids (SCFAs) and promoting the secretion of GLP-1. However, the involvement of GPR43, a receptor for SCFAs, has not been investigated. Therefore, we evaluated whether the inhibitory effect of β-glucan-rich barley intake on blood glucose rise is mediated by GPR43 signalling via an increase of SCFAs. C57BL/6J mice and GPR43-knockout mice were fed high-fat diets with either cellulose (HC) or β-glucan-rich barley flour (HB) for 12 weeks. The level of SCFAs in cecum contents was measured and the concentration of GLP-1 in the portal vein was determined. The supernatant of the cecum contents of C57BL/6J mice was added to GLUTag cells, and then the changes to GLP-1 and intracellular Ca2+ concentrations determined. The same parameters were measured using cells in which GPR43 was knocked down by siRNA. C57BL/6J mice fed HB diets showed a suppressed glucose rise compared to those on the HC diet. Cecum SCFAs and GLP-1 concentration in the portal vein were also increased by the HB diet. When an aqueous solution from the cecum content of mice fed a HB diet was added to GLUTag cells, GLP-1 secretion and intracellular Ca2+ concentration were increased. These phenomena were not observed in cells with knockdown of GPR43. In GPR43 knockout mice an increase of GLP-1 in the portal vein and suppression of blood glucose elevation was attenuated, despite increased SCFAs brought on by the HB diet. In conclusion, GPR43 activation in the intestinal tract via increased SCFAs is required for the glucose intolerance-improving effect of barley consumption.

Smad3 deficiency improves islet-based therapy for diabetes and diabetic kidney injury by promoting β cell proliferation via the E2F3-dependent mechanism.

Rationale: Poor β cell proliferation is one of the detrimental factors hindering islet cell replacement therapy for patients with diabetes. Smad3 is an important transcriptional factor of TGF-β signaling and has been shown to promote diabetes by inhibiting β cell proliferation. Therefore, we hypothesize that Smad3-deficient islets may be a novel cell replacement therapy for diabetes.Methods: We examined this hypothesis in streptozocin-induced type-1 diabetic mice and type-2 diabetic db/db mice by transplanting Smad3 knockout (KO) and wild type (WT) islets under the renal capsule, respectively. The effects of Smad3KO versus WT islet replacement therapy on diabetes and diabetic kidney injury were examined. In addition, RNA-seq was applied to identify the downstream target gene underlying Smad3-regulated β cell proliferation in Smad3KO-db/db versus Smad3WT-db/db mouse islets.Results: Compared to Smad3WT islet therapy, treatment with Smad3KO islets produced a much better therapeutic effect on both type-1 and type-2 diabetes by significantly lowering serum levels of blood glucose and HbA1c and protected against diabetic kidney injuries by preventing an increase in serum creatinine and the development of proteinuria, mesangial matrix expansion, and fibrosis. These were associated with a significant increase in grafted β cell proliferation and blood insulin levels, resulting in improved glucose intolerance. Mechanistically, RNA-seq revealed that compared with Smad3WT-db/db mouse islets, deletion of Smad3 from db/db mouse islets markedly upregulated E2F3, a pivotal regulator of cell cycle G1/S entry. Further studies found that Smad3 could bind to the promoter of E2F3, and thus inhibit β cell proliferation via an E2F3-dependent mechanism as silencing E2F3 abrogated the proliferative effect on Smad3KO β cells.Conclusion: Smad3-deficient islet replacement therapy can significantly improve both type-1 and type-2 diabetes and protect against diabetic kidney injury, which is mediated by a novel mechanism of E2F3-dependent β cell proliferation.

Effect of Electroacupuncture on Reproductive Disorders and Insulin Resistance in a Murine Polycystic Ovary Syndrome Model.

Polycystic ovarian syndrome (PCOS) is a common, complex, and heterogeneous endocrine and metabolic disorder. There is no standardized treatment, and it therefore requires individualized therapies according to the symptoms and pathogenesis of each patient. The present study aimed to determine the effect of electroacupuncture at the acupoints Zusanli (ST36), Sanyinjiao (SP6), and Neiguan (PC6) on reproductive disorders and insulin resistance in a murine model of PCOS induced by dehydroepiandrosterone (DHEA). Vaginal smear analysis was used to determine mice estrous cycle; intraperitoneal glucose and insulin tolerance tests were adopted to analyze metabolic characteristics; enzyme-linked immunosorbent assay was used to measure hormone levels; gene expression was quantified with real-time PCR; hematoxylin and eosin staining was used to observe ovarian morphology. We observed disordered estrous cycle, polycystic ovarian morphology, and higher levels of homeostasis model assessment-insulin resistance (HOMA-IR) and testosterone (T), indicating successful modeling of PCOS. DHEA increased levels of estrogen (E2), progesterone (P), testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), and EA treatment restored them to levels seen in the control group. EA reduced the days in estrus caused by DHEA, improved the abnormal sex hormone receptor genes, and attenuated the DHEA-induced histomorphological changes in mouse ovaries. The average expressions of the androgen receptor (AR), estrogen receptor (ER), luteinizing hormone receptor (LHR), and follicle-stimulating hormone receptor (FSHR) genes in the ovary greatly increased after DHEA treatment and significantly decreased in the DHEA + EA group. After EA treatment, the cystic follicle (CF) number was reduced and corpora lutea (CL) increased in the DHEA + EA group compared to the DHEA group. EA improved glucose intolerance and insulin intolerance. Statistical analysis of intraperitoneal glucose tolerance test-area under curve (IPGTT-AUC) glucose levels revealed a significant decrease in DHEA group mice compared to the control and DHEA + EA groups. EA was found to restore fasting blood glucose, fasting serum insulin, and HOMA-IR. In summary, our study suggests that EA has a remarkable effect in the DHEA-induced murine PCOS model. Management of EA could improve estrous cycle, hormonal disorders, abnormal sex hormone receptors in ovaries, ovary morphology, and insulin resistance in PCOS mice.

Aerobic Physical Exercise Improves Exercise Tolerance and Fasting Glycemia Independent of Body Weight Change in Obese Females.

Obesity is associated with increased risk of several chronic diseases and the loss of disease-free years, which has increased the focus of much research for the discovery of therapy to combat it. Under healthy conditions, women tend to store more fat in subcutaneous deposits. However, this sexual dimorphism tends to be lost in the presence of comorbidities, such as type 2 diabetes mellitus (T2DM). Aerobic physical exercise (APE) has been applied in the management of obesity, however, is still necessary to better understand the effects of APE in obese female. Thus, we investigated the effect of APE on body weight, adiposity, exercise tolerance and glucose metabolism in female ob/ob mice. Eight-weeks-old female wild-type C57BL/6J and leptin-deficient ob/ob mice (Lepob) were distributed into three groups: wild-type sedentary group (Wt; n = 6), leptin-deficient sedentary group (LepobS; n = 5) and leptin-deficient trained group (LepobT; n = 8). The LepobT mice were subjected to 8 weeks of aerobic physical exercise (APE) at 60% of the maximum velocity achieved in the running capacity test. The APE had no effect in attenuating body weight gain, and did not reduce subcutaneous and retroperitoneal white adipose tissue (SC-WAT and RP-WAT, respectively) and interscapular brown adipose tissue (iBAT) weights. The APE neither improved glucose intolerance nor insulin resistance in the LepobT group. Also, the APE did not reduce the diameter or the area of RP-WAT adipocytes, but the APE reduced the diameter and the area of SC-WAT adipocytes, which was associated with lower fasting glycemia and islet/pancreas area ratio in the LepobT group. In addition, the APE increased exercise tolerance and this response was also associated with lower fasting glycemia in the LepobT group. In conclusion, starting APE at a later age with a more severe degree of obesity did not attenuate the excessive body weight gain, however the APE promoted benefits that can improve the female health, and for this reason it should be recommended as a non-pharmacological therapy for obesity.

Effects of L-arabinose by hypoglycemic and modulating gut microbiome in a high-fat diet- and streptozotocin-induced mouse model of type 2 diabetes mellitus.

L-arabinose is a good and healthy food additive. This study was conducted to investigate the effect of L-arabinose in a mouse model of type 2 diabetes mellitus (T2DM) induced by exposure to a high-fat diet (HFD) and streptozotocin (STZ). The model mice received L-arabinose at 20 and 60mg (kg body weight [bw])-1 d-1 , metformin at 300mg (kg bw)-1 d-1 (positive control) or sterile water (control) via oral gavage. Compared with the model group, mice treated with L-arabinose exhibited attenuated symptoms of diabetes mellitus, including a slower rate of body weight loss, increased homeostasis model assessment of β-cell function index levels, decreased blood glucose, alleviation of steatosis, and repair of pancreatic islet cells. L-arabinose also exerted an anti-inflammatory effect and partially mitigated dyslipidemia. A 16S-rRNA sequence analysis of the gut microbiota revealed that at the phylum level, treatment with L-arabinose significantly reduced the ratio of Firmicutes to Bacteroidetes due to a decreased relative abundance of Firmicutes; at the genus level, it reversed the increase in the relative abundance of Allobaculum and the decrease abundance of Oscillospira caused by exposure to an HFD and STZ. And the model mice received L-arabinose at 20mg (kg bw)-1 d-1 had a better effect on improving T2DM than the high-dose group supplemented L-arabinose at 60mg (kg bw)-1 d-1 . These results strongly suggest L-arabinose as an excellent candidate supplement to prevent or treat T2DM. PRACTICAL APPLICATIONS: L-arabinose, xylitol and sucralose are well-known substitutes for sucrose. L-arabinose has been reported to have beneficial effects on hyperglycemia, glycemic index, and fat accumulation. In this study, we found that low-dose (20mg (kg bw)-1 d-1 ) supplementation of L-arabinose significantly improved glucose intolerance and gut microbiota incoordination in T2DM caused by HFD and STZ.

Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist.

The weight loss following Semaglutide treatment, a GLP-1 receptor agonist, might be responsible for some effects observed on the nonalcoholic fatty liver disease of obese mice. Two groups of C57BL/6 male mice (n = 30/group) were fed the diets Control (C) or high-fat (HF) for 16 weeks. Then, separated into six new groups for an additional four weeks (n = 10/group) and treated with Semaglutide (S, 40 µg/kg) or paired feeding (PF) with S groups (C; C-S; C-PF; HF; HF-S; HF-PF). Semaglutide reduced energy consumption leading to weight loss. Simultaneously it improved glucose intolerance, glycated hemoglobin, insulin resistance/sensitivity, plasma lipids, and gastric inhibitory polypeptide. Semaglutide and paired feeding mitigated liver steatosis and adipose differentiation-related protein (Plin2) expression. Semaglutide also improved hormones and adipokines, reduced lipogenesis and inflammation, and increased beta-oxidation. Semaglutide lessened liver glucose uptake and endoplasmic reticulum (ER) stress. Among the 14 genes analyzed, 13 were modified by Semaglutide (93 %, six genes were changed exclusively by Semaglutide, and seven other genes were affected by the combination of Semaglutide and paired feeding). In seven genes, the paired diet showed no effect (50% of the genes tested). No marker was affected exclusively by paired feeding. Semaglutide and the consequent weight loss reduced obese mice liver inflammation, insulin resistance, and ER stress. However, weight loss alone did show few or no action on some significant study findings, like liver steatosis, leptin, insulin, resistin, and amylin. Furthermore, hepatic inflammation mediated by MCP-1 and partially by TNF-alpha and IL6 were also not reduced by weight loss. Furthermore, weight loss alone did not lessen hepatic lipogenesis as determined by the findings of SREBP-1c, CHREBP, PPAR-alpha, and SIRT1. Semaglutide was implicated in improving glucose uptake and lessening ER stress by reducing GADD45, independent of weight loss.

Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus.

Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic β-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional β-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit β-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of β-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic β-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet β-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.

Thyroid hormones and the potential for regulating glucose metabolism in cardiomyocytes during insulin resistance and T2DM.

In order for the heart to maintain its continuous mechanical work and provide the systolic movement to uphold coronary blood flow, substantial synthesis of adenosine triphosphate (ATP) is required. Under normal conditions cardiac tissue utilizes roughly 70% fatty acids (FA), and 30% glucose for the production of ATP; however, during impaired metabolic conditions like insulin resistance and diabetes glucose metabolism is dysregulated and FA account for 99% of energy production. One of the major consequences of a shift in FA metabolism in cardiac tissue is an increase in reactive oxygen species (ROS) and lipotoxicity, which ultimately lead to mitochondrial dysfunction. Thyroid hormones (TH) have direct effects on cardiac function and glucose metabolism during impaired metabolic conditions suggesting that TH may improve glucose metabolism in an insulin resistant condition. None‐classical TH signaling in the heart has shown to phosphorylate protein kinase B (Akt) and increase activity of phosphoinositide‐3‐kinase (PI3K), which are critical mediators in the insulin‐stimulated glucose uptake pathway. Studies on peripheral tissues such as skeletal muscle and adipocytes have demonstrated TH treatment improved glucose intolerance in a diabetic model and increased insulin‐regulated glucose transporter (GLUT4) mRNA levels. GLUT4 is a downstream target of thyroid response element (TRE), which demonstrates that THs regulate glucose via GLUT4. Elevated 3,5,3′‐triiodothyronine (T3) increased glucose oxidation rate and decreased the glycolytic intermediate, fructose 6‐phosphate (F6P) in cardiomyocytes, in addition to increasing mitochondrial biogenesis and pyruvate transport across the mitochondrial membrane. These findings along with a few other studies on T3 treatment in cardiac tissue suggest TH may improve glucose metabolism in an insulin resistant model and ameliorate the effects of diabetes and metabolic syndrome. This review highlights the potential benefits of exogenous TH on ameliorating metabolic dysfunction in the heart.

Vascepa protects against high-fat diet-induced glucose intolerance, insulin resistance, and impaired β-cell function

SummaryOmega-3 fatty acid prescription drugs, Vascepa (≥96% eicosapentaenoic acid [EPA] ethyl ester) and Lovaza (46.5% EPA and 37.5% docosahexaenoic acid ethyl ester) are known therapeutic regimens to treat hypertriglyceridemia. However, their impact on glucose homeostasis, progression to type 2 diabetes, and pancreatic beta cell function are not well understood. In the present study, mice were treated with Vascepa or Lovaza for one week prior to six weeks of high-fat diet feeding. Vascepa but not Lovaza led to reduced insulin resistance, reduced fasting insulin and glucose, and improved glucose intolerance. Vascepa improved beta cell function, reduced liver triglycerides with enhanced expression of hepatic fatty acid oxidation genes, and altered microbiota composition. Vascepa has protective effects on diet-induced insulin resistance and glucose intolerance in mice.

Adipocyte CAMK2 deficiency improves obesity-associated glucose intolerance

ObjectiveObesity-related adipose tissue dysfunction has been linked to the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Impaired calcium homeostasis is associated with altered adipose tissue metabolism; however, the molecular mechanisms that link disrupted calcium signaling to metabolic regulation are largely unknown. Here, we investigated the contribution of a calcium-sensing enzyme, calcium/calmodulin-dependent protein kinase II (CAMK2), to adipocyte function, obesity-associated insulin resistance, and glucose intolerance. MethodsTo determine the impact of adipocyte CAMK2 deficiency on metabolic regulation, we generated a conditional knockout mouse model and acutely deleted CAMK2 in mature adipocytes. We further used in vitro differentiated adipocytes to dissect the mechanisms by which CAMK2 regulates adipocyte function. ResultsCAMK2 activity was increased in obese adipose tissue, and depletion of adipocyte CAMK2 in adult mice improved glucose intolerance and insulin resistance without an effect on body weight. Mechanistically, we found that activation of CAMK2 disrupted adipocyte insulin signaling and lowered the amount of insulin receptor. Further, our results revealed that CAMK2 contributed to adipocyte lipolysis, tumor necrosis factor alpha (TNFα)–induced inflammation, and insulin resistance. ConclusionsThese results identify a new link between adipocyte CAMK2 activity, metabolic regulation, and whole-body glucose homeostasis.

Curcumin Improved Glucose Intolerance, Renal Injury, and Nonalcoholic Fatty Liver Disease and Decreased Chromium Loss through Urine in Obese Mice

Obesity-associated hyperglycemia underlies insulin resistance, glucose intolerance, and related metabolic disorders including type 2 diabetes, renal damage, and nonalcoholic fatty liver disease. Turmeric root is commonly used in Asia, and curcumin, one of its pharmacological components, can play a role in preventing and treating certain chronic physiological disorders. Accordingly, this study examined how high-fat diet (HFD)-induced hyperglycemia and hyperlipidemia are reduced by curcumin through changes in fatty liver scores, chromium distribution, and renal injury in mice. Relative to the control group, also fed an HFD, the curcumin group weighed less and had smaller adipocytes; it also had lower daily food efficiency, blood urea nitrogen and creatinine levels, serum alanine aminotransferase and aspartate aminotransferase levels, serum and hepatic triglyceride levels, and hepatic lipid regulation marker expression. The curcumin-treated obese group exhibited significantly lower fasting blood glucose, was less glucose intolerant, had higher Akt phosphorylation and glucose transporter 4 (GLUT4) expression, and had greater serum insulin levels. Moreover, the group showed renal damage with lower TNF-α expression along with more numerous renal antioxidative enzymes that included superoxide dismutase, glutathione peroxidase, and catalase. The liver histology of the curcumin-treated obese mice showed superior lipid infiltration and fewer FASN and PNPLA3 proteins in comparison with the control mice. Curcumin contributed to creating a positive chromium balance by decreasing the amount of chromium lost through urine, leading to the chromium mobilization needed to mitigate hyperglycemia. Thus, the results suggest that curcumin prevents HFD-induced glucose intolerance, kidney injury, and nonalcoholic fatty liver disease.

Electroacupuncture at ST36 Improve the Gastric Motility by Affecting Neurotransmitters in the Enteric Nervous System in Type 2 Diabetic Rats.

Electroacupuncture (EA) can effectively relieve hyperglycemia and gastric emptying disorders in diabetic gastroparesis (DGP). However, the effect of EA on type 2 diabetes mellitus (T2DM) gastroparesis and its mechanism in the enteric nervous system (ENS) are rarely studied. We investigated the therapeutic effect of EA at ST36 and its effect on the main inhibitory and excitatory neurotransmitters in the ENS in DGP rats. Male Sprague-Dawley (SD) rats were fed a high-fat diet for 2 weeks and injected with streptozotocin (STZ) at 35 mg/kg to induce T2DM. T2DM rats were divided into the diabetic mellitus (DM) group and the EA group. The control (CON) group comprised normal rats without any intervention. EA treatment was started 6 weeks after the induction of DM and continued for 5 weeks. The body weight and food intake of the rats were recorded every week. Blood glucose, insulin, glucose tolerance, gastric emptying, and antral motility were measured after treatment. The expression of protein gene product 9.5 (PGP9.5), neuronal nitric oxide synthase (nNOS), and choline acetyltransferase (ChAT) in gastric antrum were quantified by western blotting and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The T2DM gastroparesis model was successfully established. EA treatment reduced the body weight, food intake, and blood glucose; improved glucose intolerance and insulin resistance; increased the gastric emptying rate, the mean antral pressure, and the amplitude of antral motility; and decreased the frequency of antral motility compared with those in the DM group. EA treatment increased the expression level of nNOS, ChAT, and PGP9.5 proteins, and nNOS and ChAT mRNA. The results suggested that EA at ST36 could ameliorate DGP, partly restore the damage to general neurons, and increase nNOS and ChAT in the gastric antrum. EA improved DGP partly via reducing the loss of inhibitory and excitatory neurotransmitters in the ENS.

Mechanisms Mediating Dose-Dependent Effects of Eicosapentaenoic Acid in White Adipose Tissue From High Fat Diet-Induced Obese Mice

ObjectivesObesity is a global epidemic and complex disease associated with an expansion of white adipose tissue (WAT). Obesity is accompanied by chronic low-grade inflammation, characterized by elevated levels of secreted pro-inflammatory cytokines and M1 macrophage infiltration into WAT. Eicosapentaenoic acid (EPA), a long-chain omega-3 polyunsaturated fatty acid, has been reported to have anti-obesity and anti-inflammatory properties. Moreover, we previously showed that EPA dose-dependently improved glucose intolerance, and inflammation in diet-induced obese mice. The objective of this study is to further determine mechanisms underlying these metabolic protective effects of EPA in epididymal WAT (e-WAT). MethodsMale B6 mice were fed a HF diet (45% kcal fat) or a HF diet supplemented with 9, 18, or 36 g/kg of EPA-enriched fish oil (EPA 9, 18 or 36) for 14 weeks. We performed histological assessments in eWAT to determine adipocyte size; and measure macrophage infiltration by immunohistochemistry using galectin-3. RNA was isolated from eWAT for RNA sequencing and gene expression analyses. Data were analyzed using GraphPad Prism software. ResultsEPA36-fed mice had significantly lower body weight and fat percentage, compared to HF (P < 0.05). In addition, EPA18 and 36 significantly decreased weight of e-WAT (P < 0.05) and increased glucose clearance compared to HF (P < 0.05). Moreover, all EPA doses had smaller adipocytes (P < 0.05). Compared to HF, EPA18 and 36 significantly reduced macrophage infiltration in e-7.43 fold, respectively. Consistent with these changes, EPA18 and 36 reduced the mRNA levels of HF-induced inflammatory markers, including arachidonate 5-lipoxygenase (Alox5) and leukotriene B4 receptor (Ltb4r) compared to HF (P < 0.05). RNA Seq analyses revealed that EPA18 attenuated HF-induced inflammation in part by up-regulating cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling pathways and down-regulating triggering receptor expressed on myeloid cells 1 (TREM1) signaling. ConclusionsEPA dose-dependently ameliorated HF-induced obesity and inflammation by reducing adipocyte size and macrophage infiltration and modulating pro- and anti-inflammatory pathways in e-WAT. These effects were achieved at human equivalent doses, that are currently prescribed for reducing triglycerides. Funding SourcesUSDA NIFA NIH.

MO461FGF19 IMPROVES GLUCOSE METABOLISM IN CKD MICE

Abstract Background and Aims Chronic kidney disease (CKD) is associated with high cardiovascular mortality rate, especially because of altered glucose metabolism and insulin resistance. Fibroblast growth factor 19 (FGF19), an intestinal postprandial hormone, has been shown to improve metabolic disturbances and insulin resistance. In CKD, postprandial secretion of FGF19 seems blunted in hemodialyzed patients but the role and regulation of FGF19 in this population is unknown. The aim of our study is to ascertain if FGF19 can improve glucose homeostasis in a mouse model of CKD induced by 5/6 subtotal nephrectomy. Method Four weeks post-surgery, CKD mice or sham mice were treated during 18 days with subcutaneous injections of placebo or human recombinant FGF19 (0.01mg/kg of body weight). The effect on metabolic disturbances was estimated in vivo by glucose tolerance test (GTT, 1g/kg/body weight). Results Fasted hyperglycemia was observed in CKD groups compared to sham mice (151.3 +/- 10.6mg/l and 170.7 +/- 10.9mg/L, p &amp;lt; 0.001 in sham and CKD mice, respectively) and FGF19 tended to improve fasting glycemia in CKD mice (158.9 +/- 18mg/L, p&amp;lt;0.09). The GTT area under the curve (AUC) was significantly decreased in CKD-FGF19 group compared to CKD placebo (P &amp;lt; 0.0001) and control groups (P = 0.0063). Urea blood level was significantly higher in CKD groups (9.6 +/- 1.4 mmol/L and 25.5 +/- 5.6 mmol/L in sham and CKD, respectively) and was not affected by FGF19 treatment (24.8 +/- 5.8 mmol/L, p = 0.91). Conclusion Our results show that FGF19 could contribute to improve glucose intolerance observed in CKD and suggest that this hormone could be a novel therapeutic target for reducing mortality associated with CKD. The comprehension of the molecular and cellular events through which FGF19 exerted its benefits needs however further studies.

Diet Supplementation with Fish-Derived Extracts Suppresses Diabetes and Modulates Intestinal Microbiome in a Murine Model of Diet-Induced Obesity.

Metabolic syndrome-related diseases affect millions of people worldwide. It is well established that changes in nutritional habits and lifestyle can improve or prevent metabolic-related pathologies such as type-2 diabetes and obesity. Previous reports have shown that nutritional supplements have the capacity to limit glucose intolerance and suppress diabetes development. In this study, we investigated the effect of dietary supplementation with fish-derived extracts on obesity and type 2 diabetes and their impact on gut microbial composition. We showed that nutritional supplements containing Fish Complex (FC), Fish Complex combined with Cod Powder (FC + CP), or Cod Powder combined with Collagen (CP + C) improved glucose intolerance, independent of abdominal fat accumulation, in a mouse model of diet-induced obesity and type 2 diabetes. In addition, collagen-containing supplements distinctly modulate the gut microbiome in high-fat induced obesity in mice. Our results suggest that fish-derived supplements suppress diet-induced type 2 diabetes, which may be partly mediated through changes in the gut microbiome. Thus, fish-derived supplements and particularly the ones containing fish collagen have potential beneficial properties as dietary supplements in managing type 2 diabetes and metabolic syndrome via modulation of the gut microbiome.