Medium‐chain fatty acids ameliorate insulin resistance caused by high‐fat diets in rats

Background High dietary intake of saturated fat impairs insulin sensitivity and lipid metabolism. The influence of fatty acid chain length, however, is not yet fully understood, but evidence exists for different effects of saturated long‐chain (LC) versus saturated medium‐chain (MC) fatty acids (FA). Methods To investigate the effects of the FA chain length, male Wistar rats were fed high‐fat diets containing triacylglycerols composed of either MC‐ or LCFA for 4 weeks; rats fed maintenance diet served as a control. The animals underwent euglycemic hyperinsulinemic clamping or oral metabolic tolerance testing respectively; enzyme activities of mitochondrial (EC2.3.1.21 carnitine palmitoyl transferase) and peroxisomal (EC1.3.3.6 acyl‐CoA oxidase) FA oxidation were measured in liver and muscle. Results LCFA consumption resulted in higher fasted serum insulin and glucose concentrations compared to controls, while MCFA‐fed animals did not differ from controls. Insulin sensitivity was reduced by 30% in the LCFA group while the MCFA group did not differ from controls. Feeding MCFA resulted in the controls' lowered fasted and post‐prandial triacylglycerol concentration compared to LCFA, while triacylglycerol concentrations in muscle were higher in both high‐fat groups compared to controls. No diet‐induced changes were found in acyl‐CoA oxidase (ACO) activity (liver and muscle), while LCFA feeding significantly raised carnitine palmitoyltransferase activity. Conclusions The chain length of saturated fatty acids in isocaloric diets affects insulin sensitivity, lipid metabolism and mitochondrial fatty acid oxidation without influencing body weight. While dietary LCFA clearly impair insulin sensitivity and lipid metabolism, MCFA seem to protect from lipotoxicity and subsequent insulin resistance without caloric restriction. Copyright © 2009 John Wiley & Sons, Ltd.     

Diabetes resolution and hyperinsulinaemia after metabolic Roux‐en‐Y gastric bypass

The global prevalence of type 2 diabetes mellitus and impaired glucose metabolism continues to rise in conjunction with the pandemic of obesity. The metabolic Roux‐en‐Y gastric bypass operation offers the successful resolution of diabetes in addition to sustained weight loss and excellent long‐term outcomes in morbidly obese individuals. The procedure consists of the physiological BRAVE effects: (i) Bile flow alteration; (ii) Reduction of gastric size; (iii) Anatomical gut rearrangement and altered flow of nutrients; (iv) Vagal manipulation and (v) Enteric gut hormone modulation. This operation provides anti‐diabetic effects through decreasing insulin resistance and increasing the efficiency of insulin secretion. These metabolic outcomes are achieved through weight‐independent and weight‐dependent mechanisms. These include the foregut, midgut and hindgut mechanisms, decreased inflammation, fat, adipokine and bile metabolism, metabolic modulation, shifts in gut microbial composition and intestinal gluconeogenesis. In a small minority of patients, gastric bypass results in hyperinsulinaemic hypoglycaemia that may lead to nesidioblastosis (pancreatic beta‐cell hypertrophy with islet hyperplasia). Elucidating the precise metabolic mechanisms of diabetes resolution and hyperinsulinaemia after surgery can lead to improved operations and disease‐specific procedures including ‘diabetes surgery’. It can also improve our understanding of diabetes pathogenesis that may provide novel strategies for the management of metabolic syndrome and impaired glucose metabolism.     

Comparison of the effect of Roux‐en‐Y gastric bypass and sleeve gastrectomy on remission of type 2 diabetes: A systematic review and meta‐analysis of randomized controlled trials

Bariatric surgery is an effective treatment option for patients with type 2 diabetes mellitus (T2DM) and obesity. This study aims to compare the effects of Roux‐en‐Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on remission of T2DM. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for studies published between database inception and 21 November 2019. A meta‐analysis, using a random effects model, was performed to calculate relative risk (RR) of T2DM remission between the groups in randomized controlled trials (RCTs). Of 2650 records identified, 12 records from 10 different RCTs were finally included. The studies comprised 705 patients with follow‐up from 1 to 5 years. The remission rate of T2DM at 1 year was higher among those undergoing RYGB (156/276, 57%) compared with those undergoing SG (128/275, 47%), RR (95% CI) 1.20 (1.00‐1.45), P = .047, I² = 24.9%, moderate‐quality evidence. Among studies with 2‐ to 5‐year follow‐up, there was no difference in remission rates between the RYGB (132/263, 50%) and SG (121/266, 46%) groups, RR 1.06 (0.94‐1.20), P = .34, I² = 0.0%, low‐quality evidence. RYGB resulted in a higher rate of T2DM remission compared with SG after 1 year. The T2DM remission rates did not differ in studies with 2‐ to 5‐year follow‐up.     

Brown rice‐specific γ‐oryzanol as a promising prophylactic avenue to protect against diabetes mellitus and obesity in humans

Chronic overconsumption of animal fats causes a variety of health problems, including diabetes mellitus and obesity. Underlying molecular mechanisms encompass leptin resistance, a decrease in rewarding effects of physical activities, xanthine oxidase‐induced oxidative stress in vasculature and peripheral tissue, impaired activation of incretin signaling, deviation in food preference, and dysbiosis of gut microbiota. Based on our clinical observation that daily intake of brown rice effectively ameliorates bodyweight gain, impaired glucose tolerance/insulin resistance and dependence on fatty foods in obese, prediabetes men, a line of research on brown rice (rice bran)‐derived γ‐oryzanol in mice experiments, cultured cells and human clinical trials is underway in our laboratory. Our works in mice showed that γ‐oryzanol, an ester mixture of ferulic acid and several kinds of phytosterols, acts as a molecular chaperone, thereby attenuating the strong preference for animal fats through suppression of endoplasmic reticulum stress in the hypothalamus. In pancreatic islets from both high‐fat diet‐induced and streptozotocin‐induced diabetic mice, γ‐oryzanol ameliorates endoplasmic reticulum stress and protects β‐cells against apoptosis. Noticeably, γ‐oryzanol also acts as a potent inhibitor against deoxyribonucleic acid methyltransferases in the brain reward system (striatum) in mice, thereby attenuating, at least partly, the preference for a high‐fat diet through the epigenetic modulation of striatal dopamine D2 receptor. Because dopamine D2 receptor signaling in the brain reward system is considerably attenuated in obese humans and rodents, γ‐oryzanol might represent a unique property to ameliorate both hedonic and metabolic dysregulation of feeding behavior, highlighting a promising prophylactic avenue to protect against metabolic derangement.     

JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, ameliorates impaired glucose and lipid metabolism in Zucker diabetic fatty rats

Aim: Microsomal triglyceride transfer protein (MTP) takes part in the mobilization of triglyceride‐rich lipoproteins from enterocytes and hepatocytes. We investigated the effects of JTT‐130, a novel intestine‐specific MTP inhibitor, on impaired glucose and lipid metabolism in Zucker diabetic fatty (ZDF) rats. Methods: Male ZDF rats were fed a regular powdered diet with or without JTT‐130 as a food admixture (0.01–0.02%) for 6 weeks. Food intake, body weight, blood biochemical parameters, fecal lipid contents, hepatic lipid contents, tissue mRNA levels and glucose utilization in adipose tissues were assessed. An intraperitoneal glucose tolerance test (IPGTT) and histological analysis of the pancreas were performed. Results: JTT‐130 treatment decreased food intake, glycated hemoglobin, plasma levels of glucose, triglycerides and total cholesterol, hepatic levels of triglycerides and cholesterol and hepatic mRNA levels of glucose‐6‐phosphatase, phosphoenolpyruvate carboxykinase and fructose‐1,6‐bisphosphatase. JTT‐130 treatment increased fecal levels of free fatty acids and cholesterol, plasma levels of glucagon‐like peptide‐1 and peptide YY, mRNA levels of glucose transporter 4 (GLUT4) and lipoprotein lipase in adipose tissues and GLUT4 in muscle and glucose utilization in adipose tissues. Plasma insulin decreased after 2 weeks and increased after 4 weeks of JTT‐130 treatment. Plasma glucose in the JTT‐130‐treated rats was lower with higher plasma insulin than in the control rats during the IPGTT. The islets of the JTT‐130‐treated rats were larger and contained more insulin than those of the control rats. Conclusions: JTT‐130 ameliorates impaired glucose and lipid metabolism in the ZDF rats thereby suggesting that JTT‐130 could be useful for prevention and treatment of type 2 diabetes.     

Adaptive changes in pancreas post Roux‐en‐Y gastric bypass induced weight loss

Background

Obesity has been shown to trigger adaptive increases in pancreas parenchymal and fat volume. Consecutively, pancreatic steatosis may lead to beta‐cell dysfunction. However, it is not known whether the pancreatic tissue components decrease with weight loss and pancreatic steatosis is reversible following Roux‐en‐Y gastric bypass (RYGB). Therefore, the objective of the study was to investigate the effects of RYGB‐induced weight loss on pancreatic volume and glucose homeostasis.

Methods

Eleven patients were recruited in the Obesity Centre of the University Medical Centre Hamburg‐Eppendorf. Before and 6 months after RYGB, total GLP‐1 levels were measured during oral glucose tolerance test. To assess changes in visceral adipose tissue and pancreatic volume, MRI was performed. Measures of glucose homeostasis and insulin indices were assessed. Fractional beta‐cell area was estimated by correlation with the C‐peptide‐to‐glucose ratio; beta‐cell mass was calculated by the product of beta‐cell area and pancreas parenchymal weight.

Results

Pancreas volume decreased from 83.8 (75.7‐92.0) to 70.5 (58.8‐82.3) cm³ (mean [95% CI], P = .001). The decrease in total volume was associated with a significant decrease in fat volume. Fasting insulin and C‐peptide were lower post RYGB. HOMA‐IR levels decreased, whereas insulin sensitivity increased (P = .03). This was consistent with a reduction in the estimated beta‐cell area and mass.

Conclusions

Following RYGB, pancreatic volume and steatosis adaptively decreased to “normal” levels with accompanying improvement in glucose homeostasis. Moreover, obesity‐driven beta‐cell expansion seems to be reversible; however, future studies must define a method to more accurately estimate functional beta‐cell mass to increase our understanding of glucose homeostasis after RYGB.     

The role of obestatin in roux‐en‐Y gastric bypass‐induced remission of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a complex and multifactorial disease that is generally characterized by insulin resistance and loss of β‐cell function that develops in adulthood. To date, more than 6% of the world's population is affected by T2DM. The main treatments of T2DM are dietary and lifestyle changes. However, only dependent on behaviour modification and oral hypoglycemics, many patients are unable to maintain glycemic control. Emerging evidence indicates that up to 80% of patients with T2DM undergoing Roux‐en‐Y gastric bypass (RYGB) experience complete remission of their T2DM and the majority of remissions occur almost immediately following the operation. Obestatin is a 23‐amino‐acid peptide, which is not only thought to suppress food intake and decrease gastric emptying but also found to exert survival effects in pancreatic β cells, increase glucose‐stimulated insulin secretion, and reduce insulin resistance and inflammation. In addition, some researchers demonstrated that obestatin is a nutritional marker reflecting body adiposity and insulin resistance. Although results from previous studies were conflicting, the peripheral blood concentrations of obestatin were changed after RYGB. Therefore, regulation of obestatin level may be another mechanism for RYGB‐induced remission of T2DM. In this article, we review briefly the effect of RYGB on T2DM in humans and offer an overview of the published data on the effects of RYGB on obestatin level in patients with T2DM. Furthermore, the possible roles of obestatin in the remission of T2DM following RYGB are also reviewed. Copyright © 2015 John Wiley & Sons, Ltd.     

DIO小鼠袖状胃切除术与改良Roux-en-Y胃旁路术模型建立

目的建立饮食诱导的肥胖型（DIO）小鼠袖状胃切除术（SG）与改良Roux-en-Y胃旁路术（RYGB）模型,为代谢外科治疗肥胖伴2型糖尿病（T2DM）机制研究提供动物模型。 方法选取体质量（BMI）、周龄等均无明显差异的13周育龄雄性DIO小鼠,小鼠平均体质量（33.69±2.25）g,平均空腹血糖（11.66±1.52）mmol/L。显微镜下成功建立小鼠SG组（n=7）、改良RYGB组（n=10）和对照组（n=6）模型。术前及术后第l、2、4、7、14天进行小鼠体重和空腹血糖测量。 结果SG组小鼠存活率为85.71%（6/7）,改良RYGB组存活率为60.00%（6/10）。术后SG组和改良RYGB组小鼠体重进行性下降,而对照组小鼠体重变化不明显。术后第4、7、14天,SG组和改良RYGB组体重水平较对照组显著下降（P<0.05）。两种手术组小鼠术后不同观察时间段空腹血糖水平较对照组有明显的差异性（P<0.05）。 结论本研究成功建立DIO小鼠显微镜下袖状胃切除术与改良Roux-en-Y胃旁路术模型。通过DIO小鼠建立改良Roux-en-Y胃旁路术和袖状胃切除术小鼠模型是有效和可行的。此模型为代谢外科治疗肥胖伴T2DM机制的研究提供一个更为合理的动物模型。     

Enhanced amylin-mediated body weight loss in estradiol-deficient diet-induced obese rats

In rodents, ovariectomy (OVX) elicits weight gain and diminished responsiveness to homeostatic signals. Here we characterized the response of obese OVX rats to peripheral amylin. Rats received sham surgery (SHAM), OVX, or OVX with hormonal replacement (17β-estradiol, 2 μg per 4 d; OVX+E) and were infused with vehicle or amylin (50 μg/kg · d) for 28 d. Amylin reduced body weight (5.1 ± 1.1%) and food intake (10.9 ± 3.4%) in SHAM rats but was twice as efficacious in OVX rats in reducing weight (11.2 ± 1.9%) and food intake (23.0 ± 2.0%). There were no differences between amylin-treated SHAM and OVX+E rats. OVX decreased metabolic rate (～24%) and increased respiratory exchange ratio relative to SHAM. Amylin partially normalized metabolic rate (13% increase) in OVX rats and decreased respiratory exchange ratio in OVX and SHAM rats. Regarding central mechanisms, amylin infusion corrected the OVX-induced decrease in hippocampal neurogenesis and increased immobility in the forced swim test. Additionally, amylin increased neurogenesis (～2-fold) within the area postrema of OVX rats. To assess the contribution of endogenous leptin to amylin-mediated weight loss in OVX rats, amylin was administered to SHAM or OVX Zucker diabetic fatty rats. In SHAM rats, amylin infusion reduced food intake but not body weight, whereas in OVX Zucker diabetic fatty rats, food intake, body weight, and insulin were reduced. Overall, amylin induced greater body weight loss in the absence of estradiol via central and peripheral actions that did not require leptin. These findings support the clinical investigation of amylin in low estradiol (e.g. postmenopausal) states.     

Effect of wheat bran derived prebiotic supplementation on gastrointestinal transit,gut microbiota,and metabolic health: a randomized controlled trial in healthy adults with a slow gut transit

ABSTRACT

Acute intake of the wheat bran extract Arabinoxylan-Oligosaccharide (AXOS) modulates the gut microbiota, improves stool characteristics and postprandial glycemia in healthy humans. Yet, little is known on how long-term AXOS intake influences gastrointestinal (GI) functioning, gut microbiota, and metabolic health. In this randomized, placebo-controlled, double-blind study, we evaluated the effects of AXOS intake on GI function and metabolic health in adults with slow GI transit without constipation. Forty-eight normoglycemic adults were included with whole-gut transit time (WGTT) of >35 h receiving either 15 g/day AXOS or placebo (maltodextrin) for 12-wks. The primary outcome was WGTT, and secondary outcomes included stool parameters, gut permeability, short-chain fatty acids (SCFA), microbiota composition, energy expenditure, substrate oxidation, glucose, insulin, lipids, gut hormones, and adipose tissue (AT) function. WGTT was unchanged, but stool consistency softened after AXOS. 12-wks of AXOS intake significantly changed the microbiota by increasing Bifidobacterium and decreasing microbial alpha-diversity. With a good classification accuracy, overall microbiota composition classified responders with decreased WGTT after AXOS. The incretin hormone Glucagon-like protein 1 was reduced after AXOS compared to placebo. Energy expenditure, plasma metabolites, AT parameters, SCFA, and gut permeability were unchanged. In conclusion, intake of wheat bran extract increases fecal Bifidobacterium and softens stool consistency without major effects on energy metabolism in healthy humans with a slow GI transit. We show that overall gut microbiota classified responders with decreased WGTT after AXOS highlighting that GI transit and change thereof were associated with gut microbiota independent of Bifidobacterium. NCT02491125     

Do nutrient–gut–microbiota interactions play a role in human obesity,insulin resistance and type 2 diabetes?

The current obesity and type 2 diabetes pandemics have causes beyond changes in eating and exercise habits against a susceptible genetic background. Gut bacteria seem to additionally contribute to the differences in body weight, fat distribution, insulin sensitivity and glucose‐ and lipid‐metabolism. Data, mostly derived from preclinical studies, suggest that gut microbiota play an important role in conditions such as obesity, diabetes, metabolic syndrome and non‐alcoholic fatty liver disease. Regulation of energy uptake from the gut, by digesting otherwise indigestible common polysaccharides in our diet, production or activation of signalling molecules involved in host metabolism, modification of gut permeability, the release of gut hormones and inflammation, are among the mechanisms by which gut microbiota may influence the host cardiometabolic phenotype. Recent evidence suggests that quantitative and qualitative differences in gut microbiota exist between lean and obese, and between diabetic and non‐diabetic individuals. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may favourably affect host metabolism. Large‐scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high‐risk populations, are eagerly awaited.     

Low dietary fiber intake increases Collinsella abundance in the gut microbiota of overweight and obese pregnant women

The gut microbiota contributes to the regulation of glucose metabolism in pregnancy. Abundance of the genus Collinsella is positively correlated with circulating insulin; however, it is unclear what determines Collinsella abundance. This study aims to validate the correlation between Collinsella and insulin and to elucidate if macronutrient intake alters Collinsella abundance and gut microbiota composition.

Gut microbiota profiles were assessed by 16S rRNA sequencing in 57 overweight and 73 obese pregnant women from the SPRING (Study of PRobiotics IN Gestational diabetes) trial at 16 weeks gestation and correlated with metabolic hormone levels and macronutrient intake. Gut microbiota composition in the top and bottom 10% of dietary fiber intake was evaluated through network analysis.

Collinsella abundance correlated positively with circulating insulin (rho = 0.30, p = 0.0006), independent of maternal BMI, but negatively with dietary fiber intake (rho = ?0.20, p = 0.025) in this cohort. Low dietary fiber intake was associated with a gut microbiota favoring lactate fermentation while high fiber intake promotes short-chain fatty acid-producing bacteria.

Low dietary fiber may enable overgrowth of Collinsella and alter the overall fermentation pattern in gut microbiota. This suggests that dietary choices during pregnancy can modify the nutritional ecology of the gut microbiota, with potential deleterious effects on the metabolic and inflammatory health of the host.

Trial registration: ANZCTR 12611001208998, registered 23/11/2011     

Duodenal switch versus Roux‐en‐Y gastric bypass for morbid obesity: systematic review and meta‐analysis of weight results,diabetes resolution and early complications in single‐centre comparisons

Long‐term weight loss after Roux‐en‐Y gastric bypass (RYGB) in super‐obese patients has not been ideal. Biliopancreatic diversion with duodenal switch (DS) is argued to be better; however, additional side effects are feared. The aim of the present study was to determine differences in results after DS and RYGB in publications from single‐centre comparisons. A systematic review of studies containing DS and RYGB performed at the same centre was performed. Outcome data were weight results, resolution of comorbid conditions, perioperative results and complications. Main outcome was difference in weight loss after DS and RYGB. Secondary outcomes were difference in resolution of comorbidities, perioperative results and complications. The final analysis included 16 studies with in total 874 DS and 1,149 RYGB operations. When comparing weight results at the longest follow‐up of each study, DS yielded 6.2 (95% confidence interval 5.0–7.5) body mass index units additional weight loss compared with RYGB, P < 0.001. Operative time and length of stay were significantly longer after DS, as well as the risk for post‐operative leaks, P < 0.05. DS is more effective than RYGB as a weight‐reducing procedure. However, this comes at the price of more early complications and might also yield slightly higher perioperative mortality.     

Inflammatory change of fatty liver induced by intraportal low‐dose lipopolysaccharide infusion deteriorates pancreatic insulin secretion in fructose‐induced insulin‐resistant rats

Background: This study tested whether subacute inflammatory change of fatty liver induced by portal endotoxaemia is detrimental to pancreatic insulin secretion in fructose‐fed rats (FFRs) with fatty liver. Methods: Rats were randomly assigned into two groups with a regular or fructose‐enriched diet for 8 weeks. Rats, after fructose feeding for 4 weeks, were further divided into three subgroups: on fructose diet alone, on fructose diet combined with intraportal saline or lipopolysaccharide (LPS) infusion (n=8 per group) for the next 4 weeks. In another set of experiments, the liver and pancreatic tissues were obtained for histological examination in these four groups. Pancreatic insulin secretion was evaluated by in vivo hyperglycaemic clamp study. Results: Fasting plasma insulin concentrations and homoeostasis model assessment‐insulin resistance, an insulin resistance score, were significantly increased in FFRs but failed to change in rats with LPS treatment. The 4‐week intraportal LPS infusion significantly increased circulating aspartate transaminase, alanine transaminase and C‐reactive protein levels but did not alter endotoxin levels in FFRs. The increased white blood cell count was also noted in rats after intraportal LPS infusion for 2 and 4 weeks. The attenuated first‐phase and second‐phase insulin responses in FFRs shown in hyperglycaemic clamp were further deteriorated in those with intraportal LPS infusion. Increased histopathological scores of liver and pancreas shown in FFRs were further increased in those combined with portal endotoxaemia. Conclusion: This study demonstrates that the chronic subacute inflammatory change of fatty liver induced by mild portal endotoxaemia could deteriorate insulin secretion in a rodent model of metabolic syndrome and fatty liver.     

Pregnancy-related changes in the maternal gut microbiota are dependent upon the mother's periconceptional diet

Shifts in the maternal gut microbiome have been implicated in metabolic adaptations to pregnancy. We investigated how pregnancy and diet interact to influence the composition of the maternal gut microbiota. Female C57BL/6 mice were fed either a control or a high fat diet for 8 weeks prior to mating. After confirmation of pregnancy, maternal weight gain and food intake were recorded. Fecal pellets were collected at 2 timepoints prior to mating (at the beginning of the experiment, and after 6 weeks of the specified diet) and at 4 timepoints during pregnancy (gestation day 0.5, 5.5, 10.5, and 15.5). The microbial composition and predicted metabolic functionality of the non-pregnant and pregnant gut was determined via sequencing of the variable 3 region of the 16S rRNA gene. Upon conception, differences in gut microbial communities were observed in both control and high fat-fed mice, including an increase in mucin-degrading bacteria. Control versus high fat-fed pregnant mice possessed the most profound changes to their maternal gut microbiota as indicated by statistically significant taxonomic differences. High fat-fed pregnant mice, when compared to control-fed animals, were found to be significantly enriched in microbes involved in metabolic pathways favoring fatty acid, ketone, vitamin, and bile synthesis. We show that pregnancy-induced changes in the female gut microbiota occur immediately at the onset of pregnancy, are vulnerable to modulation by diet, but are not dependent upon increases in maternal weight gain during pregnancy. High fat diet intake before and during pregnancy results in distinctive shifts in the pregnant gut microbiota in a gestational-age dependent manner and these shifts predict significant differences in the abundance of genes that favor lipid metabolism, glycolysis and gluconeogenic metabolic pathways over the course of pregnancy.     

胃旁路术后IRS-1和IRS-2的表达变化对糖尿病大鼠空腹血糖和胰岛素抵抗的影响及作用机制

目的探讨Roux-en-Y胃旁路术（RYGB）后胰岛素受体底物（IRS）-1和IRS-2的表达变化对糖尿病大鼠空腹血糖和胰岛素抵抗的影响及其作用机制。 方法用随机数字表法将30只糖尿病模型的Wistar大鼠分为RYGB组、假手术组和饮食对照组。另选取10只同周龄的正常Wistar大鼠为对照组。RYGB组接受RYGB,假手术组在相同位置处切开胃壁和空肠后行原位缝合,饮食对照组的进食量为RYGB组前1天的进食量,空白对照组自由进食普通饲料。于术前和术后1、2、3、4周检测空腹血糖（FPG）和空腹胰岛素（FIns）水平,并计算胰岛素抵抗指数（HOMA-IR）。其后处死大鼠,取骨骼肌、肝脏和胰腺组织。采用Western blot技术检测各组大鼠骨骼肌和肝脏中IRS-1和IRS-2的表达情况,采用免疫组化方法检测胰腺IRS-2的表达情况。4组数据的比较采用单因素方差分析,组间两两比较采用LSD-t检验;组内两组数据的比较采用配对t检验;4组胰腺组织IRS-2阳性表达率的比较采用χ²检验。 结果术后第4周,RYGB组大鼠的FPG水平较术前明显降低（t=30.617,P<0.05）,低于同期的假手术组和饮食对照组（LSD-t_假手术组=12.112,LSD-t_{饮食对照组}=10.095,P值均<0.05),与空白对照组比较差异无统计学意义（LSD-t=0.347,P>0.05）;RYGB组大鼠的HOMA-IR值也较术前明显下降（t=8.631,P<0.05）,低于同期假手术组和饮食对照组（LSD-t_假手术组=7.713,LSD-t_{饮食对照组}=7.931,P值均<0.05）,与空白对照组比较差异无统计学意义（LSD-t=0.822,P>0.05）。手术4周后,RYGB组大鼠肌肉组织中IRS-1和其磷酸化的p-IRS-1表达水平明显高于假手术组和饮食对照组（P<0.05）;RYGB组大鼠肝脏组织中IRS-2的表达水平明显低于假手术组和饮食对照组（P<0.05）,稍高于空白对照组;RYGB组大鼠胰腺细胞中IRS-2的阳性表达率为76%,明显高于饮食对照组的2%,假手术组的3%和空白对照组的44%（χ²_{饮食对照组}=230.181,χ²_假手术组=222.994,χ²_{空白对照组}=42.667,P值均<0.05）。 结论RYGB能引起相应靶器官内IRS-1和IRS-2的表达变化,这可能是改善2型糖尿病胰岛素抵抗和降低空腹血糖水平的机制之一。     

Gut microbiota in non‐alcoholic fatty liver disease and alcohol‐related liver disease: Current concepts and perspectives

The term, gut–liver axis, is used to highlight the close anatomical and functional relationship between the intestine and the liver. It has been increasingly recognized that the gut–liver axis plays an essential role in the development and progression of liver disease. In particular, in non‐alcoholic fatty liver disease and alcohol‐related liver disease, the two most common causes of chronic liver disease, a dysbiotic gut microbiota can influence intestinal permeability, allowing some pathogens or bacteria‐derived factors from the gut reaching the liver through the enterohepatic circulation contributing to liver injury, steatohepatitis, and fibrosis progression. Pathways involved are multiple, including changes in bile acid metabolism, intestinal ethanol production, generation of short‐chain fatty acids, and other by‐products. Bile acids act through dedicated bile acid receptors, farnesoid X receptor and TGR5, in both the ileum and the liver, influencing lipid metabolism, inflammation, and fibrogenesis. Currently, both non‐alcoholic fatty liver disease and alcohol‐related liver disease lack effective therapies, and therapeutic targeting of gut microbiota and bile acids enterohepatic circulation holds promise. In this review, we summarize current knowledge about the role of gut microbiota in the pathogenesis of non‐alcoholic fatty liver disease and alcohol‐related liver disease, as well as the relevance of microbiota or bile acid‐based approaches in the management of those liver diseases.     

Pregnancy-related changes in the maternal gut microbiota are dependent upon the mother's periconceptional diet

Shifts in the maternal gut microbiome have been implicated in metabolic adaptations to pregnancy. We investigated how pregnancy and diet interact to influence the composition of the maternal gut microbiota. Female C57BL/6 mice were fed either a control or a high fat diet for 8 weeks prior to mating. After confirmation of pregnancy, maternal weight gain and food intake were recorded. Fecal pellets were collected at 2 timepoints prior to mating (at the beginning of the experiment, and after 6 weeks of the specified diet) and at 4 timepoints during pregnancy (gestation day 0.5, 5.5, 10.5, and 15.5). The microbial composition and predicted metabolic functionality of the non-pregnant and pregnant gut was determined via sequencing of the variable 3 region of the 16S rRNA gene. Upon conception, differences in gut microbial communities were observed in both control and high fat-fed mice, including an increase in mucin-degrading bacteria. Control versus high fat-fed pregnant mice possessed the most profound changes to their maternal gut microbiota as indicated by statistically significant taxonomic differences. High fat-fed pregnant mice, when compared to control-fed animals, were found to be significantly enriched in microbes involved in metabolic pathways favoring fatty acid, ketone, vitamin, and bile synthesis. We show that pregnancy-induced changes in the female gut microbiota occur immediately at the onset of pregnancy, are vulnerable to modulation by diet, but are not dependent upon increases in maternal weight gain during pregnancy. High fat diet intake before and during pregnancy results in distinctive shifts in the pregnant gut microbiota in a gestational-age dependent manner and these shifts predict significant differences in the abundance of genes that favor lipid metabolism, glycolysis and gluconeogenic metabolic pathways over the course of pregnancy.     

Running on mixed fuel‐dual agonistic approach of GLP‐1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non‐human primates

Aim

We performed acute and chronic studies in healthy and diet‐induced obese animals using mouse‐specific or monkey‐specific dual GLP‐1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control and insulin secretion. The selective GLP‐1R agonist liraglutide was used as comparator.

Methods

The mouse‐specific dual agonist and liraglutide were tested in lean wild type, GLP‐1R knockout and diet‐induced obese mice at different doses. A chronic study was performed in DIO mice to investigate the effect on body weight, food consumption and total energy expenditure (TEE) in obese and diabetic monkeys with a focus on body weight and energy intake.

Results

The mouse‐specific dual agonist and liraglutide similarly affected glycaemic control. A higher loss in body weight was measured in dual agonist‐treated obese mice. The dual agonist significantly enhanced plasma glucose excursion in overnight fed GLP‐1R^?/? mice, probably reflecting a potent GCGR agonist activity. It increased TEE and enhanced fat and carbohydrate oxidation, while liraglutide produced no effect on TEE. In obese and diabetic monkeys, treatment with the monkey‐specific dual agonist reduced total energy intake to 60%‐70% of baseline TEI during chronic treatment. A decrease in body weight and significant improvement in glucose tolerance was observed.

Conclusions

In DIO mice and non‐human primates, dual agonists elicited robust glycaemic control, similar to the marketed GLP‐1R agonist, while eliciting greater effects on body weight. Results from DIO mice suggest that the increase in TEE is caused not only by increased fat oxidation but also by an increase in carbohydrate oxidation.     

Taspoglutide,a novel human once‐weekly analogue of glucagon‐like peptide‐1, improves glucose homeostasis and body weight in the Zucker diabetic fatty rat

Aim: Glucagon‐like peptide‐1 (GLP‐1) receptor agonists are a novel class of pharmacotherapy for type 2 diabetes. We investigated the effects of a novel, long‐acting human GLP‐1 analogue, taspoglutide, in the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. Methods: Blood glucose and plasma levels of insulin, peptide YY (PYY), glucose‐dependent insulinotropic polypeptide (GIP) and triglycerides were measured during oral glucose tolerance tests (oGTT) conducted in ZDF rats treated acutely or chronically with a single long‐acting dose of taspoglutide. Pioglitazone was used as a positive control in the chronic study. Postprandial glucose, body weight, glycaemic control and insulin sensitivity were assessed over 21 days in chronically treated animals. Results: Acute treatment with taspoglutide reduced glucose excursion and increased insulin response during oGTT. In chronically treated rats, glucose excursion and levels of GIP, PYY and triglycerides during oGTT on day 21 were significantly reduced. Postprandial glucose levels were significantly lower than vehicle controls by day 15. A significant reduction in body weight gain was noticed by day 8, and continued until the end of the study when body weight was approximately 7% lower in rats treated with taspoglutide compared to vehicle. Glycaemic control (increased levels of 1,5‐anhydroglucitol) and insulin sensitivity (Matsuda index) were improved by taspoglutide treatment. Conclusions: Taspoglutide showed typical effects of native GLP‐1, with improvement in glucose tolerance, postprandial glucose, body weight, glycaemic control and insulin sensitivity.