Metabolic Effects Of Duodenojejunal Bypass Surgery In A Rat Model Of Type 1 Diabetes

Background Metabolic surgery has beneficial metabolic effects, including remission of type 2 diabetes. We hypothesized that duodenojejunal bypass (DJB) surgery can protect against development of type 1 diabetes (T1D) by enhancing regulation of cellular and molecular pathways that control glucose homeostasis. Methods BBDP/Wor rats, which are prone to develop spontaneous autoimmune T1D, underwent loop DJB (n = 15) or sham (n = 15) surgery at a median age of 41 days, before development of diabetes. At T1D diagnosis, a subcutaneous insulin pellet was implanted, oral glucose tolerance test was performed 21 days later, and tissues were collected 25 days after onset of T1D. Pancreas and liver tissues were assessed by histology and RT-qPCR. Fecal microbiota composition was analyzed by 16S V4 sequencing. Results Postoperatively, DJB rats weighed less than sham rats (287.8 vs 329.9 g,P = 0.04). In both groups, 14 of 15 rats developed T1D, at similar age of onset (87 days in DJB vs 81 days in sham,P = 0.17). There was no difference in oral glucose tolerance, fasting and stimulated plasma insulin and c-peptide levels, and immunohistochemical analysis of insulin-positive cells in the pancreas. DJB rats needed 1.3 +/- 0.4 insulin implants vs 1.9 +/- 0.5 in sham rats (P = 0.002). Fasting and glucose stimulated glucagon-like peptide 1 (GLP-1) secretion was elevated after DJB surgery. DJB rats had reduced markers of metabolic stress in liver. After DJB, the fecal microbiome changed significantly, including increases inAkkermansiaandRuminococcus, while the changes were minimal in sham rats. Conclusion DJB does not protect against autoimmune T1D in BBDP/Wor rats, but reduces the need for exogenous insulin and facilitates other metabolic benefits including weight loss, increased GLP-1 secretion, reduced hepatic stress, and altered gut microbiome

Fat induces glucose metabolism in nontransformed liver cells and promotes liver tumorigenesis

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC

Interrogation of the perturbed gut microbiota in gouty arthritis patients through in silico metabolic modeling

Recent studies have shown perturbed gut microbiota associated with gouty arthritis, a metabolic disease characterized by an imbalance between uric acid production and excretion. To mechanistically investigate altered microbiota metabolism associated with gout disease, 16S rRNA gene amplicon sequence data from stool samples of gout patients and healthy controls were computationally analyzed through bacterial community metabolic models. Patient-specific community models constructed with the metagenomics modeling pipeline, mgPipe, were used to perform k-means clustering of samples according to their metabolic capabilities. The clustering analysis generated statistically significant partitioning of samples into a Bacteroides-dominated, high gout cluster and a Faecalibacterium-elevated, low gout cluster. The high gout cluster was predicted to allow elevated synthesis of the amino acids D-alanine and L-alanine and byproducts of branched-chain amino acid catabolism, while the low gout cluster allowed higher production of butyrate, the sulfur-containing amino acids L-cysteine and L-methionine, and the L-cysteine catabolic product H2S. By expanding the capabilities of mgPipe to provide taxa-level resolution of metabolite exchange rates, acetate, D-lactate and succinate exchanged from Bacteroides to Faecalibacterium were predicted to enhance butyrate production in the low gout cluster. Model predictions suggested that sulfur-containing amino acid metabolism generally and H2S more specifically could be novel gout disease markers

Changes in bone macro- and microstructure in diabetic obese mice revealed by high resolution microfocus X-ray computed tomography.

High resolution microfocus X-ray computed tomography (HR-microCT) was employed to characterize the structural alterations of the cortical and trabecular bone in a mouse model of obesity-driven type 2 diabetes (T2DM). C57Bl/6J mice were randomly assigned for 14 weeks to either a control diet-fed (CTRL) or a high fat diet (HFD)-fed group developing obesity, hyperglycaemia and insulin resistance. The HFD group showed an increased trabecular thickness and a decreased trabecular number compared to CTRL animals. Midshaft tibia intracortical porosity was assessed at two spatial image resolutions. At 2 mum scale, no change was observed in the intracortical structure. At 1 mum scale, a decrease in the cortical vascular porosity of the HFD bone was evidenced. The study of a group of 8 week old animals corresponding to animals at the start of the diet challenge revealed that the decreased vascular porosity was T2DM-dependant and not related to the ageing process. Our results offer an unprecedented ultra-characterization of the T2DM compromised skeletal micro-architecture and highlight an unrevealed T2DM-related decrease in the cortical vascular porosity, potentially affecting the bone health and fragility. Additionally, it provides some insights into the technical challenge facing the assessment of the rodent bone structure using HR-microCT imaging

Cereulide food toxin, beta cell function and diabetes: Facts and hypotheses.

&lt;p&gt;The incidence of both type 1 and type 2 diabetes is increasing and although environmental pollutants are believed to be potential culprits, the extent to which they can be held responsible remains uncertain. Some bacterial strains of the Bacillus cereus produce a toxin, cereulide, which is frequently found in starchy meals and which is difficult to eradicate from the food chain as it is highly resistant to heat, acidity and proteolysis. While cereulide is well known to cause acute emetic toxicity when ingested at high doses, several in vitro studies have shown that also extremely low doses of cereulide can be toxic, with beta cells being particularly sensitive. Mechanistically, such low doses impair the mitochondrial activity of the beta cells thereby leading to hampered insulin secretion and cell death, both key traits in the pathophysiology of diabetes. In vivo studies of chronic or repeated low dose exposure to cereulide are currently lacking, but should be performed to further clarify the true relevance of cereulide as a potential environmental contributor to the ongoing diabetes epidemic.&lt;/p&gt;</p

Effects of gastric bypass surgery on expression of glucose transporters and fibrotic biomarkers in kidney of diabetic fatty rats

BACKGROUND: Diabetic nephropathy is the leading cause of chronic kidney disease. Observational studies suggest Roux-en-Y gastric bypass (RYGB) reduces progression of diabetic nephropathy. OBJECTIVES: To unravel the mechanisms by which RYGB is beneficial and protective for diabetic nephropathy. SETTING: Academic laboratories. METHODS: Forty-eight Zucker diabetic fatty rats were randomized to RYGB, sham surgery (SHAM), or pair-fed (PF) groups. An oral glucose tolerance test was performed at 25 days post intervention and kidneys were harvested at 30 days. Primary outcome measures included expression of key genes and proteins in the glucose transport, oxidative stress, inflammation, and fibrosis pathways. RESULTS: Thirty days post intervention, RYGB rats weighed 349 ± 8 g, which was lower than SHAM (436 ± 14 g, P < .001), but not PF (374 ± 18 g) rats. RYGB rats had lower fasting glucose than PF animals and improved homeostatic model assessment of insulin resistance compared with PF and SHAM groups. These enhanced metabolic outcomes were accompanied by reduced sodium-glucose co-transporter 1 (Sglt1) gene expression (-23% versus PF, P = .01) in the kidney of RYGB rats. Expression of Sglt2, Glut1, or Glut2 mRNA, or oxidative stress and inflammation markers did not differ significantly. However, RYGB surgery induced a 19% lower expression of transforming growth factor (Tgfβ) mRNA (P = .004) compared with SHAM treated animals. Notably, adenosine monophosphate-activated protein kinase phosphorylation was increased (P = .04) in kidneys of the RYGB surgery animals. CONCLUSIONS: Improvement of hyperglycemia after RYGB may reduce the glucose load on the kidney leading to a downregulation of specific glucose transporters. RYGB surgery may also attenuate kidney fibrosis through the adenosine monophosphate-activated protein kinase/TGFβ pathway.status: publishe

Does Colectomy Improve Type 2 Diabetes?

Gastrectomy and gastric bypass improve type 2 diabetes (T2DM), potentially through alterations in intestinal hormones and the microbiome. The aim of this study was to analyze whether colorectal resections result in improvement of T2DM. A total of 171 patients with T2DM who underwent colectomy for benign diseases were studied with a median postoperative follow-up of 3 years (interquartile range [IQR] 1-5). The median BMI and glycated hemoglobin (HbA1c) at baseline and post-colectomy were 30.3 kg/m2 (IQR 26.6-34.6) versus 30.4 kg/m2 (IQR 26.2-35) (p = 0.1), and 6.7% (IQR 6.2-7.5) versus 6.5% (IQR 6.5-7.1) (p = 0.5), respectively. The proportion of patients taking diabetes medications at baseline versus post-colectomy did not differ significantly. Changes in BMI, HbA1c, and status of diabetes medications were not statistically different between the subtypes of colorectal resection. Our experience suggests that colectomy for benign colorectal diseases is not associated with long-term changes in body weight or glycemic control.status: publishe

Impact of sleeve gastrectomy and Roux-en-Y gastric bypass on biopsy-proven non-alcoholic fatty liver disease

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome. Our aim was to study the long-term effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on NAFLD/NASH. METHODS: Between 2008 and 2015, 3813 patients had an intraoperative liver biopsy performed at the time of primary RYGB and SG at a single academic center. Utilizing strict inclusion criteria, 487 patients with biopsy-proven NAFLD who had abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values (≥ 40 IU/L) at baseline were identified. Matching of SG to RYGB patients (1:4) was performed via logistic regression and propensity scores adjusting for clinical and liver histological characteristics. Changes in liver function tests (LFTs) at least 1 year after surgery were compared to baseline values and between the surgical groups. RESULTS: A total of 310 (weighted) patients (SG n = 62, and RYGB n = 248) with a median follow-up time of 4 years (range, 1-10) were included in the analysis. The distribution of covariates was well-balanced after propensity matching. In 84% of patients, LFT values normalized after bariatric surgery at the last follow-up time. The proportions of patients having normalized LFT values did not differ significantly between the SG and RYGB groups (82% vs. 84%, p = 0.66). The AST decreased from (SG: 49.1 ± 21.5 vs. RYGB: 49.3 ± 22.0, p = 0.93) at baseline to (SG: 28.0 ± 16.5 vs. RYGB: 26.5 ± 15.5, p = 0.33) at the last follow-up. Similarly, a significant reduction in ALT values from (SG: 61.7 ± 30.0 vs. RYGB 59.4 ± 24.9, p = 0.75) at baseline to (SG: 27.2 ± 21.5 vs. RYGB: 26.1 ± 19.2, p = 0.52) at the last follow-up was observed. CONCLUSIONS: In patients with biopsy-proven NAFLD/NASH, abnormal LFTs are normalized in most SG and RYGB patients by the end of the first postoperative year and remain normal until the last follow-up. This study also suggests that both bariatric procedures are similarly effective in improving liver function.status: publishe

Pharmacokinetics of Oral Rebaudioside A in Patients with Type 2 Diabetes Mellitus and Its Effects on Glucose Homeostasis: A Placebo-Controlled Crossover Trial

Background and&nbsp;Objectives Rebaudioside A, a steviol glycoside, is deglycosylated by intestinal microflora prior to the absorption of steviol and conjugation to steviol glucuronide. While glucose-lowering properties are observed for rebaudioside A in mice, they have been attributed to the metabolites steviol and steviol glucuronide. We aimed to characterize the pharmacokinetic and pharmacodynamic properties of rebaudioside A and its metabolites in patients with early-onset type 2 diabetes mellitus (T2DM). Methods This randomized, placebo-controlled, open-label, two-way crossover trial was performed in subjects with T2DM on metformin or no therapy at the University Hospitals Leuven, Belgium. Following oral rebaudioside A (3 g), plasma concentrations of rebaudioside A, steviol and steviol glucuronide were determined. The effect on glucose homeostasis was examined by an oral glucose tolerance test (OGTT) performed 19 h following rebaudioside A administration, i.e. the presumed time of maximal steviol and steviol glucuronide concentrations. The primary pharmacodynamic endpoint was the difference in area under the blood glucose concentration–time curve during the first 2 h of the OGTT (AUCGlucose(0–2h)) for rebaudioside A vs.&nbsp;placebo. Results In total, 30 subjects [63.5 (57.8–69.0) years&nbsp;of age, 86.7% male] completed the trial. Rebaudioside A was detected as early as 1 h after administration in nearly all subjects. As expected, steviol and steviol glucuronide reached their maximal concentrations at 19.5 h following rebaudioside A administration. Rebaudioside A did not lower the AUCGlucose(0–2h)&nbsp;compared to placebo (−&nbsp;0.7 (95% CI −&nbsp;22.3; 20.9) h·mg/dL,&nbsp;P&nbsp;= 0.95). Insulin and C-peptide concentrations were also comparable between both conditions (P&nbsp;&gt;&nbsp;0.05). Conclusion Rebaudioside A is readily absorbed after oral administration and metabolized to steviol and steviol glucuronide. However, no effect on glucose nor insulin or C-peptide excursion was observed during the OGTT at the time of maximal metabolite concentrations. Thus, no antidiabetic properties of rebaudioside A could be observed in patients with T2DM after single oral&nbsp;use.</p