Significant Improvement In Glucose Tolerance Research Articles

FRI107 Ketogenic Diet Prevents Development Of Atherosclerotic Plaques In Apolipoprotein E Knockout Mice

Abstract Disclosure: V. Marzolla: None. A. Armani: None. C. Mammi: None. S. Gorini: None. E. Camajani: None. M. Caprio: None. Higher aldosterone (aldo) levels are associated with increased risk of cardiovascular ischemic events and mortality. It has been demonstrated that aldo accelerates the development of atherosclerosis in apolipoprotein E knockout mice (ApoE KO). Ketogenic diet (KD) positively impacts several cardiovascular risk factors, yet its effect on atherosclerosis is elusive. We hypothesize that KD protects from development of atherosclerotic plaques in ApoE KO mice, a murine model of atherosclerosis. Eight-week-old male ApoE KO mice were fed a KD (90,5% Kcal from fat, 0.4% Kcal from carbohydrate, 9.1% Kcal from protein) or a moderate high fat die (HFD) (42% Kcal from fat, 42.7% Kcal from carbohydrate, 15.2% Kcal from protein) and treated with aldosterone (aldo, 6 μg/mouse per day) or vehicle through osmotic mini-pumps. Cholesterol content was comparable in KD and HFD. After 4 weeks of treatment, in all experimental groups, intraperitoneal glucose tolerance test was performed, and peripheral blood samples were collected. We analysed cryosections of embedded aortic root to quantify the atherosclerotic plaque size, lipid and collagen content. We assessed vascular inflammation in speciments of thoracic aorta by analysing pro-inflammatory (ICAM-1, VCAM-1, IL-6, TNF-α, MCP-1) and anti-inflammatory (Arg-1, RETNLA, CCL5) genes. In ApoE KO mice treated with aldo, KD determined a significant improvement in glucose tolerance, compared to mice fed a HFD, without any significant effect on body weight. Beta-hydroxybutyrate levels were always significantly higher in KD-mice than in AD-mice, confirming nutritional ketosis in KD-mice. Analysis of aortic root showed that aldo treatment determined a significant increase in atherosclerotic plaque size and lipid content in HFD-mice. Such effects were significantly reduced in KD-mice, suggesting a favorable impact of ketosis in preventing atherosclerosis development. Plaque fibrosis did not differ among treatment groups. Finally, we observed a significant reduction in vascular inflammatory markers in KD-mice, when compared to HFD-mice. In particular, KD determined a significant reduction in gene expression of pro-inflammatory markers (ICAM-1, VCAM-1, IL-6, TNF-α, MCP-1) with the concomitant up-regulation of anti-inflammatory markers (Arg-1, RETNLA, CCL5), compared to HFD. The study suggests KD as a potential non-pharmacological approach to prevent the development of atherosclerotic disease in subjects with high cardiovascular risk. Presentation: Friday, June 16, 2023

Construction and application of artificial lipoproteins using adiposomes

Lipoproteins are complex particles comprised of a neutral lipid core wrapped with a phospholipid monolayer membrane and apolipoproteins on the membrane, which is closely associated with metabolic diseases. To facilitate the elucidation of its formation and dynamics, as well as its applications, we developed an in vitro system in which adiposomes, consisting of a hydrophobic core encircled by a monolayer-phospholipid membrane, were engineered into artificial lipoproteins (ALPs) by recruiting one or more kinds of apolipoproteins, for example, apolipoprotein (Apo) A-I, ApoE, ApoA-IV, and ApoB. In vitro and in vivo studies demonstrated the stability and biological activity of ALPs derived from adiposomes, which resembles native lipoproteins. Of note, adiposomes bearing ApoE were internalized via clathrin-mediated endocytosis following LDLR binding and were delivered to lysosomes. On the other hand, adiposomes bearing ApoA-IV mimicked the existing form of endogenous ApoA-IV and exhibited significant improvement in glucose tolerance in mice. In addition, the construction process was simple, precise, reproducible, as well as easy to adjust for mass production. With this experimental system, different apolipoproteins can be recruited to build ALPs for some biological goals and potential applications in biomedicine.

Botulinum Injection Into the Proximal Intestinal Wall of Diet-Induced Obese Mice Leads to Weight Loss and Improves Glucose and Fat Tolerance.

Botulinum neurotoxin (available commercially as BOTOX) has been used successfully for treatment of several neuromuscular disorders, including blepharospasm, dystonia, spasticity, and cerebral palsy in children. Our data demonstrate that injection of Botox into the proximal intestinal wall of diet-induced obese (DIO) mice induces weight loss and reduces food intake. This was associated with amelioration of hyperglycemia, hyperlipidemia, and significant improvement of glucose tolerance without alteration of energy expenditure. We also observed accelerated gastrointestinal transit and significant reductions in glucose and lipid absorption, which may account, at least in part, for the observed weight loss and robust metabolic benefits, although possible systemic effects occurring as a consequence of central and/or peripheral signaling cannot be ignored. The observed metabolic benefits were found to be largely independent of weight loss, as demonstrated by pair-feeding experiments. Effects lasted ∼8 weeks, for as long as the half-life of Botox as reported in prior rodent studies. These results have valuable clinical implications. If the observed effects are translatable in humans, this approach could lay the foundation for therapeutic approaches geared toward robust and sustained weight loss, mimicking some of the benefits of bariatric operations without its cost and complications.

Antioxidant and Antidiabetic Potentials of a Standardized Polyherbal Mixture Used in Traditional Medicine

Polyherbal preparations have gained much attention as a potential source for discovering new drug therapeutics for the treatment of diabetes mellitus. The present investigation aims to determine in vitro and in vivo antidiabetic activity and the antioxidant potential of hexane, ethyl acetate and methanol extracts of a polyherbal mixture prepared from equal amounts of garlic cloves (Allium sativum L.), curry leaves (Murraya koenigii L. Sprengel), black pepper seeds (Piper nigrum L.) and rath goraka fruits (Garcinia quaesita Pierre). The standardization and in vitro antioxidant activity and antidiabetic activities were determined using standard methods. The in vivo acute antihyperglycemic activity of the hexane, ethyl acetate and methanol extracts was determined using an oral glucose tolerance test in streptozotocin-induced diabetic Wistar rats. Highest significant in vitro antioxidant capacity in terms of DPPH free radical scavenging (24.71 ± 0.01 ppm, p = 0.02) and reducing antioxidant power of ferric ion (23.29 ± 0.78 mol/dm3, p = 0.01) and in vitro antidiabetic properties in terms of α-amylase (25.74 ± 0.60 ppm, p = 0.01) and α-glucosidase (22.37 ± 0.06 ppm, p = 0.02) inhibition activities were observed in the hexane extract when compared with the respective standard compounds, ascorbic for antioxidant (DPPH 6.78 ± 0.03 ppm; FRAP 25.02 ± 0.21 mol/dm3) and acarbose for antidiabetic activity (α-amylase 5.68 ± 0.35 ppm; α-glucosidase 17.11 ± 0.62 ppm). In the glucose tolerance test, a significant improvement of glucose tolerance was found in the hexane (17.38%) and ethyl acetate (15.81%) extracts-treated groups at the therapeutic dose against the diabetic control group (p < 0.05). The results obtained from the present evaluation showed that the hexane and ethyl acetate extracts of the polyherbal mixture could be considered as a potential source for developing antidiabetic agents targeting the management of diabetes mellitus.

Brief lifestyle interventions for prediabetes in primary care: a service evaluation

BackgroundThe increasing number of cases of prediabetes in the UK is concerning, particularly in Wales where there is no standard programme of support. The aim of the current service evaluation was to examine the effectiveness of brief lifestyle interventions on glucose tolerance in people at risk of developing type 2 diabetes.MethodsIn this pragmatic service evaluation clinical data on people deemed at risk of developing type 2 diabetes were evaluated from two GP clusters. Patients (n = 1207) received a single 15 to 30-min, face-to-face, consultation with a health care practitioner. Interventions were assessed by changes in HbA1c and distribution across the HbA1c ranges 12 months following intervention. Statistical significance of reversion to normoglycaemia and development of diabetes were assessed through comparison with expected rates without intervention.ResultsBetween baseline and 12-month follow-up HbA1c fell from 43.85 ± 1.57 mmol/mol (6.16 ± 0.14%) to 41.63 ± 3.84 mmol/mol (5.96 ± 0.35%), a decrease of 2.22 mmol/mol (0.20%) (95% CI 2.01 (0.18%), 2.42 (0.22%); p < 0.0001). The proportion of people with normal glucose tolerance at 12 months (0.50 95%CI 0.47, 0.52) was significantly larger than the lower (0.06 (p < 0.0001) and the upper (0.19 (p < 0.0001)) estimates based on no intervention.ConclusionResults indicate significant improvement in glucose tolerance across GP clusters. The brief intervention has the potential to offer a robust and effective option to support people at risk of developing type 2 diabetes. Further research in the form of a randomised trial is needed to confirm this and identify those likely to benefit most from this intervention.

Isoform-Specific Role of GSK-3 in High Fat Diet Induced Obesity and Glucose Intolerance.

Obesity-associated metabolic disorders are rising to pandemic proportions; hence, there is an urgent need to identify underlying molecular mechanisms. Glycogen synthase kinase-3 (GSK-3) signaling is highly implicated in metabolic diseases. Furthermore, GSK-3 expression and activity are increased in Type 2 diabetes patients. However, the isoform-specific role of GSK-3 in obesity and glucose intolerance is unclear. Pharmacological GSK-3 inhibitors are not isoform-specific, and tissue-specific genetic models are of limited value to predict the clinical outcome of systemic inhibiion. To overcome these limitations, we created novel mouse models of ROSA26CreERT2-driven, tamoxifen-inducible conditional deletion of GSK-3 that allowed us to delete the gene globally in an isoform-specific and temporal manner. Isoform-specific GSK-3 KOs and littermate controls were subjected to a 16-week high-fat diet (HFD) protocol. On an HFD, GSK-3α KO mice had a significantly lower body weight and modest improvement in glucose tolerance compared to their littermate controls. In contrast, GSK-3β-deletion-mediated improved glucose tolerance was evident much earlier in the timeline and extended up to 12 weeks post-HFD. However, this protective effect weakened after chronic HFD (16 weeks) when GSK-3β KO mice had a significantly higher body weight compared to controls. Importantly, GSK-3β KO mice on a control diet maintained significant improvement in glucose tolerance even after 16 weeks. In summary, our novel mouse models allowed us to delineate the isoform-specific role of GSK-3 in obesity and glucose tolerance. From a translational perspective, our findings underscore the importance of maintaining a healthy weight in patients receiving lithium therapy, which is thought to work by GSK-3 inhibition mechanisms.

Effect of parthenolide, an NLRP3 inflammasome inhibitor, on insulin resistance in high-fat diet-obese mice.

The activation of Nod-like receptor proteins (NLRP3) containing the pyrin domain inflammasome is a hallmark of the pathogenesis of metabolic disorders. Inhibition of the NLRP3 inflammasome by phytoconstituents has been attempted as a strategy to mitigate these disorders. Therefore, the present study aimed to evaluate the efficacy of an NLRP3 inflammasome inhibitor, parthenolide (PN; 5mg/kg i.p.) against inflammation and insulin resistance in high-fat diet (HFD) - obese mice. Treatment with PN and pioglitazone (PIO; 30mg/kg p.o.) attenuated lipopolysaccharide (LPS; 1 ng/ml) - induced elevation of tumor necrosis factor-α and interleukin-1β in mouse peritoneal macrophages in a dose-dependent manner. Sixty days of PN and PIO treatment marginally reduced obesity-induced insulin resistance in HFD-obese mice. PN treatment also decreased blood glucose from 14th to 60th day, supporting the hypothesis of simultaneous attenuation of inflammation and insulin resistance in obese mice. Thus, PN treatment was also evident with significant improvement in glucose tolerance and peripheral insulin resistance validated through the respective tolerance tests. Therefore, the present study suggests that PN, an NLRP3 inflammasome inhibitor, could be a possible therapeutic agent for attenuating obesity-induced insulin resistance.

Four weeks of electrical stimulation improves glucose tolerance in a sedentary overweight or obese Hispanic population.

Introduction/purposeMost US adults (54%) do not meet the minimum exercise recommendations by the American College of Sports Medicine. Neuromuscular electrical stimulation (NMES) is a novel alternate strategy to induce muscle contraction. However, the effectiveness of NMES to improve insulin sensitivity and energy expenditure is unclear. The purpose of this study was to investigate the effects of 4 weeks of NMES on glucose tolerance in a sedentary overweight or obese population.MethodsParticipants (n = 10; age: 36.8 ± 3.8 years; BMI = 32 ± 1.3 kg/m2) were randomized into either control or NMES group. All participants received bilateral quadriceps stimulation (12 sessions; 30 min/session; three times/week at 50 Hz and 300 µs pulse width) altering pulse amplitude to either provide low-intensity sensory level (control; tingling sensation) or at high-intensity neuromuscular level (NMES; maximum tolerable levels with visible muscle contraction). Glucose tolerance was assessed by a 3-h oral glucose tolerance test (OGTT), and substrate utilization was measured by indirect calorimetry and body composition via dual X-ray absorptiometry at baseline and after 4 weeks of NMES intervention.ResultsControl and NMES groups had comparable fasting blood glucose, glucose tolerance, substrate utilization, and muscle mass at baseline. Four weeks of NMES resulted in a significant improvement in glucose tolerance measured by OGTT, whereas no change was observed in the control group. There was no change in substrate utilization and muscle mass in both control and NMES groups.ConclusionNMES is a novel and effective strategy to improve glucose tolerance in an at-risk overweight or obese sedentary population.

Berberine Ameliorates Hepatic Insulin Resistance by Regulating microRNA-146b/SIRT1 Pathway.

ObjectiveHepatic insulin resistance is a major initiating factor for type 2 diabetes mellitus. In previous study, Gegen Qinlian Decoction containing berberine could enhance hepatic insulin sensitivity by SIRT1-dependent deacetylation of FOXO1. However, it is not clear whether berberine also can improve hepatic insulin sensitivity by SIRT1/FOXO1 pathway. This study aimed to evaluate the efficacy of berberine for improving hepatic insulin resistance and the possible molecular mechanisms involved.MethodsIn vitro, HepG2 cells were induced with palmitic acid, and glycogen synthesis was examined. In vivo, a high-fat diet (HFD)-fed mouse model was established, and metabolic parameters were assessed. The expressions of miR-146b and sirtuin 1 (SIRT1) in liver were also examined. The relationship between miR-146b and SIRT1 was examined by the dual-luciferase reporter gene assay.ResultsSerum biochemical parameters, such as glucose and HOMA-IR index, were increased in HFD mice; miR-146b and SIRT1 were abnormally expressed in HFD mice and palmitic acid-treated HepG2 cells. Interestingly, berberine reduced body weight and caused a significant improvement in glucose tolerance and HOMA-IR index without altering food intake in mice. Overexpression of miR-146b abolished the protective effect of berberine on palmitic acid-induced impaired glycogen synthesis in HepG2 cells. Luciferase assay showed that miR-146b directly targeted SIRT1.ConclusionThe present findings suggest that berberine could attenuate hepatic insulin resistance through the miR-146b/SIRT1 pathway, which may represent a potential therapeutic target for the prevention and treatment of metabolic diseases, particularly diabetes.

CD4+ T cells regulate glucose homeostasis independent of adipose tissue dysfunction in mice.

Obesity is frequently associated with a chronic low-grade inflammation in the adipose tissue (AT) and impaired glucose homeostasis. Adipose tissue macrophages (ATMs) have been shown to accumulate in the inflamed AT either by means of recruitment from the blood or local proliferation. ATM proliferation and activation can be stimulated by TH2 cytokines, such as IL-4 and IL-13, suggesting involvement of CD4-positive T cells in ATM proliferation and activation. Furthermore, several studies have associated T cells to alterations in glucose metabolism. Therefore, we sought to examine a direct impact of CD4-positive T cells on ATM activation, ATM proliferation and glucose homeostasis using an in vivo depletion model. Surprisingly, CD4 depletion did not affect ATM activation, ATM proliferation, or insulin sensitivity. However, CD4 depletion led to a significant improvement of glucose tolerance. In line with this, we found moderate disturbances in pancreatic endocrine function following CD4 depletion. Hence, our data suggest that the effect on glucose metabolism observed after CD4 depletion might be mediated by organs other than AT and independent of AT inflammation.

ARCGHR Neurons Regulate Muscle Glucose Uptake.

The growth hormone receptor (GHR) is expressed in brain regions that are known to participate in the regulation of energy homeostasis and glucose metabolism. We generated a novel transgenic mouse line (GHRcre) to characterize GHR-expressing neurons specifically in the arcuate nucleus of the hypothalamus (ARC). Here, we demonstrate that ARCGHR+ neurons are co-localized with agouti-related peptide (AgRP), growth hormone releasing hormone (GHRH), and somatostatin neurons, which are activated by GH stimulation. Using the designer receptors exclusively activated by designer drugs (DREADD) technique to control the ARCGHR+ neuronal activity, we demonstrate that the activation of ARCGHR+ neurons elevates a respiratory exchange ratio (RER) under both fed and fasted conditions. However, while the activation of ARCGHR+ promotes feeding, under fasting conditions, the activation of ARCGHR+ neurons promotes glucose over fat utilization in the body. This effect was accompanied by significant improvements in glucose tolerance, and was specific to GHR+ versus GHRH+ neurons. The activation of ARCGHR+ neurons increased glucose turnover and whole-body glycolysis, as revealed by hyperinsulinemic-euglycemic clamp studies. Remarkably, the increased insulin sensitivity upon the activation of ARCGHR+ neurons was tissue-specific, as the insulin-stimulated glucose uptake was specifically elevated in the skeletal muscle, in parallel with the increased expression of muscle glycolytic genes. Overall, our results identify the GHR-expressing neuronal population in the ARC as a major regulator of glycolysis and muscle insulin sensitivity in vivo.

Melatonin ameliorates neuropathy in diabetic rats by abating mitochondrial dysfunction and metabolic derangements.

ObjectivesTo investigate the impact of melatonin per se and in combination with gabapentin in a laboratory animal model of experimental diabetes and associated neuropathy in rats. MethodsRats from all the groups except the vehicle control group received a single dose of streptozotocin 45 mg/kg, i.p. and fructose 10% through drinking water for 8 weeks and subsequently administered with melatonin (25 and 50 mg/kg, p.o.) per se or along with gabapentin (100 mg/kg, p.o.) daily for 4 weeks. The impact of the treatments on blood glucose, serum lipid profile, nociceptive pain parameters, motor nerve conduction velocity was captured and analyzed. Further, the effect on histopathology of liver and sciatic nerve and mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC1-α) and Mitochondrial transcription factor A (TFAM) in hepatic tissue were investigated. ResultsRats administered with melatonin per se and in combination with gabapentin revealed significant improvement in glucose tolerance, lipid profile, hyperalgesia, nerve conduction velocity, and histopathological alteration in the liver and sciatic nerve when compared with the positive control group. Rats treated with melatonin expressed increased hepatic gene expression of PGC1-α and TFAM compared to positive control rats. ConclusionMelatonin per se positively modulated altered mitochondrial biogenesis by upregulating hepatic gene expression of PGC1-α and TFAM, which was not noted in the group administered with both melatonin and gabapentin. Thus, indicating an inverse relationship concerning the influence on mitochondrial biogenesis which needs to be explored further. In the current study melatonin in the higher dose shows improvement in the clinical outcomes in the model that inflicting hyperglycemia, glucose intolerance, dyslipidemia, and neuropathy in the rats.

Effect of long-term treatment of Carvacrol on glucose metabolism in Streptozotocin-induced diabetic mice

BackgroundCarvacrol is a food additive with various bioactivities, including reducing the blood glucose level as well as improvement of heart function, in diabetic mice. We explored the antihyperglycemic effect of carvacrol and its effect on the key hepatic enzymes accounting for glucose metabolism.MethodsA streptozotocin (STZ)-induced diabetes-mellitus model in mice was used. Mice were divided randomly into a control group, diabetic group, low dose carvacrol-treated diabetic group (10 mg/kg body weight [BW]), and high dose carvacrol-treated diabetic group (20 mg/kg BW). Carvacrol was injected intraperitoneally (i.p.) in each carvacrol-treated group daily for 4 weeks and 6 weeks, respectively. The level of random plasma glucose, fasting plasma glucose, and plasma insulin was determined at 4 weeks and 6 weeks after carvacrol administration. The plasma level of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and the activity of hepatic key enzymes related to glucose metabolism were determined.ResultsCarvacrol treatment decreased the levels of random plasma glucose and fasting plasma glucose, significantly in a dose-dependent manner. A significant improvement in glucose tolerance and a significant decrease in the plasma level of TG were observed in carvacrol-treated diabetic mice at a dose of 20 mg/kg BW compared with that in vehicle-treated diabetic mice. There was no significant difference in the plasma level of TC and insulin between vehicle-treated diabetic mice and carvacrol-treated diabetic mice. Carvacrol treatment at a dose of 20 mg/kg BW significantly reduced the plasma level of LDH but not AST, ALT, or ALP, compared with that in the vehicle-treated diabetic group. The activity of hexokinase (HK), 6-phosphofructokinase (PFK), and citrate synthetase (CS) was increased by carvacrol treatment in diabetic mice.ConclusionsCarvacrol exerted an anti-hyperglycemic effect in STZ-induced diabetic mice. This was achieved through regulating glucose metabolism by increasing the activity of the hepatic enzymes HK, PFK, and CS.

Dominant gut Prevotella copri in gastrectomised non-obese diabetic Goto\u2013Kakizaki rats improves glucose homeostasis through enhanced FXR signalling

Aims/hypothesisDrug and surgical-based therapies in type 2 diabetes are associated with altered gut microbiota architecture. Here we investigated the role of the gut microbiome in improved glucose homeostasis following bariatric surgery.MethodsWe carried out gut microbiome analyses in gastrectomised (by vertical sleeve gastrectomy [VSG]) rats of the Goto–Kakizaki (GK) non-obese model of spontaneously occurring type 2 diabetes, followed by physiological studies in the GK rat.ResultsVSG in the GK rat led to permanent improvement of glucose tolerance associated with minor changes in the gut microbiome, mostly characterised by significant enrichment of caecal Prevotella copri. Gut microbiota enrichment with P. copri in GK rats through permissive antibiotic treatment, inoculation of gut microbiota isolated from gastrectomised GK rats, and direct inoculation of P. copri, resulted in significant improvement of glucose tolerance, independent of changes in body weight. Plasma bile acids were increased in GK rats following inoculation with P. copri and P. copri-enriched microbiota from VSG-treated rats; the inoculated GK rats then showed increased liver glycogen and upregulated expression of Fxr (also known as Nr1h4), Srebf1c, Chrebp (also known as Mlxipl) and Il10 and downregulated expression of Cyp7a1.ConclusionsOur data underline the impact of intestinal P. copri on improved glucose homeostasis through enhanced bile acid metabolism and farnesoid X receptor (FXR) signalling, which may represent a promising opportunity for novel type 2 diabetes therapeutics.

Antidiabetic Effects of Ethanolic Extract of Ficus glomerata (L.) Roots

Background: Ficus glomerata (F. glomerata) Linn. Family Moraceace is a large tree found all over India including outer Himalayan ranges, Punjab, Chota Nagpur, Bihar, Orissa, West Bengal, Rajasthan, Deccan and also as a common plant in South India. It is planted around the home and temples. It is cultivated throughout the year, distributed in evergreen forests and moist localities. Objective: The Ethanolic Extract of roots of F. Glomerata (EEFG) belonging to the family Moraceace, was investigated for its antidiabetic activity using alloxan induced diabetic rats. Methods: Thirty rats were divided into 5 groups having 6 rats in each group. The alloxan was administered to the rats of all groups except normal control group through intraperitoneal route at a concentration of 140mg/kg body weight. A dose of 100mg/kg and 200 mg/kg body weight of EEFG was administered to alloxan induced diabetic rats. The administration of the extract was lasted for 11 days. Effectiveness of the extract on glucose, cholesterol, triglycerides, and high density lipoprotein and protein concentrations was analyzed. Results: Significant (p&lt;0.05) reduction in the levels of glucose, cholesterol, triglyceride of the diabetic rats was observed after treatment with ethanolic extract. After subjecting to oral glucose tolerance test EEFG also showed significant improvement in glucose tolerance. Conclusion: F. glomerata root ethanolic extract showed that it possesses antidiabetic effect and can be found useful for the management of diabetes mellitus.

Autologous transplantation of photoactivated subcutaneous adipose tissue improves glucose homeostasis in high-fat diet-induced obese mice.

Increasing evidence indicates that normal adipose tissue transplantation improves whole-body energy metabolism and glucose homeostasis in a high-fat diet (HFD)-induced obese mouse model. Adipose tissue macrophages are associated with glucose homeostasis and insulin resistance in type 2 diabetes and obesity in humans, offering a potential target for therapeutics. However, whether transplantation of autologous adipose tissue that changes the macrophage phenotype directly contributes to systemic glucose intolerance has not been determined. We specifically developed our device, with more refined wavelengths of light to activate the macrophage phenotype in isolated subcutaneous white adipose tissue (sWAT) from host HFD mice. Autologous transplantation of photoactivated sWAT into HFD mice significantly reverses the M1 macrophage phenotype into M2, reduces the infiltration of macrophages in adipose tissues of HFD mice, and decreases the levels of proinflammatory cytokines. Strikingly, this transplantation reduced blood glucose levels and caused significant improvement in glucose tolerance, which was not shown in sham-operated or nonphotoactivated sWAT-transplanted HFD mice. Moreover, positron emission/computed tomography scans indicated higher glucose uptake in the heart but not in the liver, hindlimb muscles, or abdominal sWAT. These data suggested that the ability of photoactivation to shift Adipose tissue macrophage polarization in HFD mice caused a significant improvement in glucose homeostasis and that autologous transplantation might be a promising therapeutic option for the treatment of diabetes.

Coixol amplifies glucose-stimulated insulin secretion via cAMP mediated signaling pathway

Recently, we reported the role of coixol (6-methoxy-2(3H)-benzoxazolone), an alkaloid from Scoparia dulcis, in glucose-dependent insulin secretion; however, its insulin secretory mechanism(s) remained unknown. Here, we explored the insulinotropic mechanism(s) of coixol in vitro and in vivo. Mice islets were batch incubated, perifused with coixol in the presence of agonists/antagonists, and insulin secretion was measured by ELISA. Intracellular cAMP levels were measured using enzyme immunoassay. K+- and Ca2+-currents were recorded in MIN6 cells using whole-cell patch-clamp technique. The in vivo glucose tolerance and the insulinogenic index were evaluated in diabetic rats treated with coixol at 25 and 50 mg/kg, respectively. Coixol, unlike sulfonylurea, enhanced insulin secretion in batch incubated and perifused islets at high glucose, with no effect at basal glucose concentrations. Coixol showed no pronounced effect on the inward rectifying K+- and Ca2+-currents in whole-cell patch recordings. Moreover, coixol-induced insulin secretion was further amplified in the depolarized islets. Coixol showed an additive effect with forskolin (10 μM)-induced cAMP level, and in insulin secretion; however, no additive effect was observed with isobutylmethylxanthine (IBMX, 100 μM)-induced cAMP level, nor in insulin secretion. The PKA inhibitor H-89 (50 μM), and Epac2 inhibitor MAY0132 (50 μM) significantly inhibited the coixol-induced insulin secretion (P < 0.01). Furthermore, insulin secretory kinetics revealed that coixol potentiates insulin secretion in both early and late phases of insulin secretion. In diabetic animals, coixol showed significant improvement in glucose tolerance and on fasting blood glucose levels. These data suggest that coixol amplifies glucose-stimulated insulin secretion by cAMP-mediated signaling pathways.

Roux-en-Y Gastric Bypass Improves Metabolic Conditions in Association with Increased Serum Bile Acids Level and Hepatic Farnesoid X Receptor Expression in a T2DM Rat Model

Roux-en-Y gastric bypass (RYGB) is an effective surgical treatment for type 2 diabetes mellitus (T2DM). The present study aimed to investigate the effects of RYGB on glucose homeostasis, lipid metabolism, and liver morphological adaption, as well as the changes in bile acids signaling and expression of its target regulatory factors involved in gluconeogenesis, lipogenesis, and fatty acid β oxidation. Twenty adult male T2DM rats induced by high-fat diet and a low dose of streptozotocin were randomly divided into sham and RYGB groups. The parameters of body weight, food intake, glucose tolerance, insulin sensitivity, serum lipid profiles, and bile acids level were assessed to evaluate metabolic changes. Liver sections were stained with hematoxylin-eosin (H&E) and oil red O to assess lipid accumulation. The mRNA and protein expression levels of farnesoid X receptor (FXR), small heterodimer partner (SHP), key regulatory factors of gluconeogenesis, lipogenesis, and fatty acid β oxidation (phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor-α (PPAR-α)) were determined through RT-PCR and Western blotting, respectively. RYGB induced significant improvements in glucose tolerance and insulin sensitivity, along with weight loss and decreased food intake. RYGB also decreased serum TG, FFAs, and increased bile acids levels. The lipid droplets in the liver were significantly decreased after RYGB. The RYGB group exhibited downregulated mRNA and protein expression levels of PEPCK, G6Pase, and SREBP-1c and upregulated expression of FXR, SHP, and PPAR-α in the liver. RYGB ameliorates glucose and lipid metabolism accompanied by weight loss and calorie restriction. The liver exhibited a marked improvement in lipid accumulation after RYGB. The bile acids level, FXR, and its target transcriptional factor SHP expression were elevated. Meanwhile, our study demonstrated that the increased bile acids-FXR signaling, followed by the reduced hepatic gluconeogenesis, lipogenesis, and increased fatty acid β oxidation may contribute to improved metabolic conditions after RYGB.

Chronic allopregnanolone treatment enhances glucose tolerance through parasympathetic activity

It is estimated that one and a half million Americans are diagnosed with diabetes each year. A startling statistic given that diabetes is considered the 7th leading cause of death making diabetes a significant health burden to the United States. It is imperative than that we develop new treatments and regulators of glucose metabolism. The ability of the central nervous system to regulate whole body glucose metabolism is one such treatment avenue. We are particularly interested in the role of the parasympathetic nervous system on glucose homeostasis since stimulation of the vagus nerve alters insulin and glucagon release from the pancreas. Previous work demonstrated that GABAergic signaling to parasympathetic motor neurons is critical to normal parasympathetic function, including the regulation of pancreatic secretions. Recent work from other brain regions identified that allopregnanolone (ALLO) is an endogenous ligand to GABAA receptors and can have positive effects on brain related disorders, such as anxiety, depression, and stroke. There is even evidence that it can improve diabetic neuropathic pain. Therefore, we aimed to determine if ALLO could alter glucose metabolism. We hypothesized that ALLO improves glucose tolerance through improved parasympathetic signaling. In initial experiments, female mice were ovariectomized (OVX), to normalize hormone concentrations, and implanted with subcutaneous silastic capsules (20mm) containing either ALLO (20mg) or vehicle (sesame oil; 0.1% alcohol). After 10 days, mice were administrated an intraperitoneal (i.p.) glucose tolerance test (GTT; 2g/kg) and blood glucose was monitored at intervals of 0, 15, 30, 60, and 120 minutes during the GTT. Mice given ALLO for 10–14 days had a significant improvement in glucose tolerance compared to vehicle (213 ± 12 mg/dL vs 325 ± 37 mg/dL). To determine if the parasympathetic nervous system was involved in the improvement in glucose tolerance after chronic ALLO exposure, a GTT was repeated after a pre‐treatment with atropine methyl nitrate (0.5mg/kg; i.p.). After atropine pre‐treatment mice exposed to ALLO did not demonstrate a significant difference in GTT compared to atropine treated mice exposed to vehicle (351 ± 35 mg/dL vs 362 ± 29 mg/dL), indicating that parasympathetic nervous system function is required for ALLO‐induced improvements in GTT. Follow‐up experiments used interventricular cannula (IVC) administration for ALLO. Again, in OVX females, IVC ALLO improved GTT (265 ± 15 mg/dL vs 346 ± 49 mg/dL), further indicating the important role of the brain in regulating the ability of ALLO to modulate glucose tolerance. On‐going studies will probe the end organ mechanism(s) responsible for this improvement. As well as how ALLO works centrally to modulate vagal motor drive. Interestingly, systematic administration of ALLO to males (20mg) did not demonstrate significant improvements in GTT (423 ± 15 mg/dL vs 410 ± 56 mg/dL). Taken together, these data suggest that ALLO is a novel, modulator of glucose metabolism, particularly in females. By understanding the role of ALLO on vagal drive and glucose homeostasis, we hope to development new therapies to treat diabetes and its complications.Support or Funding InformationAHA 16SDG26590000This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sleeve Gastrectomy with Bypass of Proximal Small Intestine Provides Better Diabetes Control than Sleeve Gastrectomy Alone Under Postoperative High-Fat Diet.

Sleeve gastrectomy (SG) plus procedures have been developed to strengthen the effect of SG on diabetes control. The aim of this study was to compare diabetes control after SG plus bypass of the proximal small intestine with SG alone under adverse conditions for diabetes remission. SG plus duodenojejunal bypass (SG-DJB), SG plus jejunojejunal bypass (SG-JJB), SG alone, and sham surgeries were performed in diabetic rats. A high-fat diet (HFD) was fed postoperatively to induce diabetes recurrence. Body weight, food intake, glucose tolerance, insulin sensitivity, serum hormones, hepatic function, and lipid profiles were measured postoperatively. SG-DJB, SG-JJB, and SG groups exhibited significant improvement in glucose tolerance and insulin sensitivity compared with the sham-operated group at 2weeks postoperatively. Postoperative HFD induced obvious diabetes relapse and re-impaired insulin sensitivity at 16weeks postoperatively. The SG-DJB and SG-JJB groups exhibited superior glucose tolerance and similar insulin sensitivity to SG alone at 16weeks postoperatively. Compared with the SG alone, the SG-DJB and SG-JJB groups exhibited similar food intake, weight loss, fasting ghrelin, glucose-stimulated insulin secretion, and higher glucose-stimulated GLP-1 secretion. SG-DJB and SG-JJB provided better diabetes control than SG alone in rats fed a HFD postoperatively. Further clinical studies are expected to confirm the superiority of SG plus bypass of proximal small intestine.