Improvements In Glucose Regulation Research Articles

Vertical sleeve gastrectomy increases duodenal Lactobacillus spp. richness associated with the activation of intestinal HIF2α signaling and metabolic benefits

ObjectiveVertical Sleeve Gastrectomy (VSG) is one of the most efficacious treatments for obesity and its comorbidities. Although a range of evidence suggests that alterations of the microbiota in the distal gut following VSG are pivotal to these metabolic improvements, the effect of surgery to alter the microbiota of the proximal intestine and its effect on host physiology remain largely unknown. As the main bacteria in the upper small intestine, Lactobacillus subspecies have been appreciated as important regulators of gut function. These bacteria also regulate intestinal Hypoxia- Inducible Factor 2α (HIF2α) signaling that plays an integral role in gut physiology and iron absorption. In the present study, we sought to determine the impact of VSG on Lactobacillus spp. in the small intestine and potential downstream impacts of Lactobacillus spp. on HIF2α, specifically in the duodenum. MethodsTo determine the effects of VSG on the microbiota and HIF2α signaling in the duodenum, VSG surgeries were performed on diet-induced obese mice. To further probe the relationship between Lactobacillus spp. and HIF2α signaling in the duodenum, we applied a customized high-fat but iron-deficient diet on mice to increase duodenal HIF2α signaling and determined alterations of gut bacteria. To explore the causal role of Lactobacillus spp. in duodenal HIF2α signaling activation, we chronically administered probiotics containing Lactobacillus spp. to high-fat-fed obese mice. Lastly, we studied the effect of lactate, the major metabolite of Lactobacilli, on HIF2α in ex vivo duodenal organoids. ResultsThere were pronounced increases in the abundance of Lactobacillus spp. in samples isolated from duodenal epithelium in VSG-operated mice as compared to sham-operated mice. This was accompanied by an increase in the expression of genes that are targets of HIF2α in the duodenum of VSG-treated mice. Activating HIF2α signaling with a high-fat but iron-deficient diet resulted in weight loss, improvements in glucose regulation, and increased Lactobacillus spp. richness in the duodenum as compared to mice on an iron-replete diet. Chronic administration of probiotics containing Lactobacillus spp. not only increased HIF2α signaling in the duodenum such as occurs after VSG but also resulted in reduced weight gain and improved glucose tolerance in high-fat-fed mice. Furthermore, lactate was able to activate HIF2α in ex vivo duodenal organoids. ConclusionsThese results support a model whereby VSG increases duodenal Lactobacillus richness and potentially stimulates intestinal HIF2α signaling via increased lactate production.

1784-P: Liraglutide Treatment Stimulates Alpha Cells to Produce Glucagon-Like Peptide-1 via Expression of Prohormone Convertase 1/3 in Mice and Human

Glucagon-like peptide-1 (GLP-1) regulates islet function by enhancing glucose-stimulated insulin secretion (GSIS). We previously found that the beta cell GLP-1 receptor (GLP-1R) contributes to improvements in glucose regulation and islet function in mice that have undergone bariatric surgery, specifically, vertical sleeve gastrectomy (VSG). Further investigation revealed that VSG increases alpha cell GLP-1 production by turning on the expression of prohormone convertase 1/3 (PC1/3, gene: Pcsk1) in a beta cell GLP-1R-dependent fashion. These findings lead us to hypothesize that beta cell GLP-1R signaling increases alpha cell GLP-1 production to augment GSIS in a paracrine positive feedback loop. In the current study, we tested whether the effects of VSG can be recapitulated by pharmacologic stimulation of the GLP-1R, using a GLP-1 analog, liraglutide. We found that liraglutide treatment increases alpha cell GLP-1 expression in a beta cell GLP-1R dependent fashion (GLP-1 area per islet (µm2): Vehicle WT = 132 ± 3, Vehicle KO = 73 ± 2, Liraglutide WT = 241 ± 15, Liraglutide KO = 67 ± 1; P<0.05 Liraglutide WT vs. all groups). We then used an innovative single-cell RNA-sequencing platform, DART-seq, to determine the translational relevance of this new model of islet function. We validated application of DART-seq in human islets, and using this technology we observed that liraglutide induces a 1.5 log-fold increase in Pcsk1 mRNA expression compared with saline treated controls in a subset of alpha cells (P<0.05 saline vs. liraglutide). Additionally, our DART-seq data suggests that liraglutide-induced increase in alpha cell PC1/3 expression may be part of a broader induction of alpha-cell transdifferentiation to beta cells. Thus, our study demonstrates that the effect of beta cell GLP-1R signaling to increase alpha-cell GLP-1 expression can be stimulated by pharmacological activation of the GLP-1R and has translational relevance in humans. Disclosure M. Saikia: None. M.M. Holter: None. D. Garibay: None. A. Garcia-Ocana: None. C.G. Danko: None. B. Cummings: None.

Biomarkers of Colorectal Cancer Risk Decrease 6\xa0months After Roux-en-Y Gastric Bypass Surgery

PurposeThe impact of weight loss on obesity-related colorectal cancer (CRC) risk is not well defined. Previous studies have suggested that Roux-en-Y gastric bypass (RYGB) surgery may have an unexpected adverse impact on CRC risk. This study aimed to investigate the impact of RYGB on biomarkers of CRC risk.Materials and methodsRectal mucosal biopsies and blood were obtained from patients undergoing RYGB (n = 22) and non-obese control participants (n = 20) at baseline and at a median of 6.5 months after surgery. Markers of systemic inflammation and glucose homeostasis were measured. Expression of pro-inflammatory genes and proto-oncogenes in the rectal mucosa was quantified using qPCR. Crypt cell proliferation state of the rectal mucosa was assessed by counting mitotic figures in whole micro-dissected crypts.ResultsAt 6.5 months post-surgery, participants had lost 29 kg body mass and showed improvements in markers of glucose homeostasis and in systemic inflammation. Expression of pro-inflammatory genes in the rectal mucosa did not increase and COX-1 expression fell significantly (P = 0.019). The mean number of mitoses per crypt decreased from 6.5 to 4.3 (P = 0.028) after RYGB.ConclusionRYGB in obese adults led to lower rectal crypt cell proliferation, reduced systemic and mucosal markers of inflammation and improvements in glucose regulation. These consistent findings of reduced markers of tumourigenic potential suggest that surgically induced weight loss may lower CRC risk.

Association between exercise-induced change in body composition and change in cardiometabolic risk factors in postmenopausal South Asian women.

The South Asian population suffers from a high prevalence of type 2 diabetes and cardiovascular disease (CVD). A unique obesity phenotype of elevated visceral adipose tissue (VAT) is associated with CVD risk among South Asians. Exercise-induced reduction in VAT and body fat is an effective mechanism to improve cardiometabolic risk factors but this has not been shown in South Asians. Whether exercise-induced changes in measurements such as waist circumference (WC) are independently related to changes in cardiometabolic risk factors in South Asians is unknown. Multi-slice computed tomography scanning was used to assess VAT, cardiometabolic risk factors through a fasting blood sample, and body fat using dual-energy X-ray absorptiometry. Forty- nine postmenopausal South Asian women who participated in two 12-week aerobic exercise programs were included. Bivariate correlations were used to assess associations between change in cardiometabolic risk factors and change in body composition. Regression analyses were conducted with change in glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) as dependent variables and change in body composition as independent variables of interest. There were significant associations between changes in fasting insulin, glucose, and HOMA-IR with change in VAT. The association between change in VAT and these cardiometabolic risk factors was independent of change in other body composition variables of interest. South Asian women should be encouraged to engage in aerobic activity to reduce their risk of type 2 diabetes and CVD, and physicians should be aware of improvements in glucose regulation with exercise training not observed through reductions in WC.

Effects of Exercise Training on Regulation of Skeletal Muscle Glucose Metabolism in Elderly Men.

The aim was to investigate the molecular mechanisms behind exercise training-induced improvements in glucose regulation in aged subjects. Twelve elderly male subjects completed 8 weeks of exercise training. Before and after the training period, the subjects completed an oral glucose tolerance test (OGTT) and a muscle biopsy was obtained from the vastus lateralis before and 45 minutes into the OGTT. Blood samples were collected before and up to 120 minutes after glucose intake. Exercise training increased Hexokinase II, GLUT4, Akt2, glycogen synthase (GS), pyruvate dehydrogenase (PDH)-E1α, PDK2 protein, and glycogen content in skeletal muscle. Furthermore, in response to glucose, GS activity was increased and the dephosphorylation of GS site 2 + 2a and 3a was enhanced after the training intervention. The glucose-mediated insulin stimulation of TBC1D4 Thr(642) phosphorylation was increased after exercise training. In the trained state, the PDHa activity was reduced following glucose intake and without changes in phosphorylation level of PDH-E1α. The present results suggest that exercise training improves glucose regulation in elderly subjects by enhancing the capacity and acute regulation of glucose uptake and by enhancing intracellular glucose removal to glycogen synthesis rather than glucose oxidation.

Glucose regulation and cognitive function after bariatric surgery

Introduction: Obesity is associated with cognitive impairment, and bariatric surgery has been shown to improve cognitive functioning. Rapid improvements in glycemic control are common after bariatric surgery and likely contribute to these cognitive gains. We examined whether improvements in glucose regulation are associated with better cognitive function following bariatric surgery. Method: A total of 85 adult bariatric surgery patients underwent computerized cognitive testing and fasting blood draw for glucose, insulin, and glycated hemoglobin (HbA1c) at baseline and 12 months postoperatively. Results: Significant improvements in both cognitive function and glycemic control were observed among patients. After controlling for baseline factors, 12-month homeostatic model assessment of insulin resistance HOMA-IR predicted 12-month digits backward (β = –.253, p < .05), switching of attention–A (β = .156, p < .05), and switching of attention–B (β = –.181, p < .05). Specifically, as HOMA-IR decreased over time, working memory, psychomotor speed, and cognitive flexibility improved. Decreases in HbA1c were not associated with postoperative cognitive improvements. After controlling for baseline cognitive test performance, changes in body mass index (BMI) were also not associated with 12-month cognitive function. Conclusions: Small effects of improved glycemic control on improved aspects of attention and executive function were observed following bariatric surgery among severely obese individuals. Future research is needed to identify the underlying mechanisms for the neurocognitive benefits of these procedures.

Differences in post‐exercise inflammatory and glucose regulatory response between sedentary indigenous australian and caucasian men completing a single bout of cycling

This study compared the acute inflammatory and glucose responses following aerobic exercise in sedentary Indigenous Australian and Caucasian men, matched for fitness and body composition. Sedentary Indigenous (n = 10) and Caucasian (n = 9) Australian men who were free from chronic disease volunteered to participate. Following baseline testing, participants completed a 40 min cycling bout at ∼80% maximal heart rate. Fasting venous blood was collected pre, 0, 30, 60, and 240 min post-exercise for analysis of glucose, insulin, cortisol, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-1 receptor agonist (ra), and C-reactive protein (CRP). Resting TNF-α and glucose concentrations were significantly higher in the Indigenous group (P < 0.05). IL-6 and IL-1ra were elevated for longer in Caucasian (P < 0.05), compared with the Indigenous group (P > 0.05). The post-exercise (0 min) increase in cortisol and glucose for the Caucasians was higher (P < 0.05) than the attenuated responses within the Indigenous group (P > 0.05). Despite being matched for fitness and body composition the Indigenous men had elevated resting TNF-α and glucose compared with the Caucasian men, which may have contributed to the suppressed post-exercise anti-inflammatory response of the Indigenous men; however, glucose normalized between groups post-exercise. As such, it is recommended for acute moderate-intensity exercise to be completed daily for long-term improvements in glucose regulation, irrespective of ancestry. Of note, results suggest it to be even more pertinent for exercise to be encouraged for Indigenous Australian men due to their elevated resting glucose levels at a younger age, when compared to the respective Caucasian group.

Effect of adiposity on insulin action after acute and chronic resistance exercise in non-diabetic women

Obesity may attenuate metabolic health improvements following lifestyle interventions. However, the effect of adiposity on insulin action following resistance exercise in young non-diabetic women is unknown. The purpose of this study was to test the hypothesis that adiposity attenuates improvements in insulin sensitivity and glucose-stimulated insulin secretion (INS0-60/GLC0-60) after both acute resistance exercise (ARE) and progressive training (PRT). Twenty-six young non-diabetic women (21.2±0.7years) were randomly assigned to control (C; n=7; BF 40.1±2.1%) or exercise groups: normal body fat (NBF; n=8; BF 29.9±2.3%) and high body fat (HBF; n=12; BF 48.2±1.4%). Acute whole-body exercises were performed at 60% of 1-RM for three sets of 8-12 repetitions, and PRT was performed 3days/week for 7weeks. A 75 g OGTT was conducted before and after ARE and PRT to estimate insulin sensitivity (Matsuda index) and INS0-60/GLC0-60. Insulin area under the curve (AUC) was calculated using the trapezoidal model. ARE had no statistical effect on insulin action across groups. Strength and fat-free mass (via DXA) increased after PRT in both NBF and HBF (p<0.05), but only HBF women decreased BF (p<0.01). HBF women were less insulin sensitive at baseline compared to NBF women (p<0.05). Insulin sensitivity increased 95% and INS0-60/GLC0-60 decreased 32% following PRT in NBF, but not HBF or C (p<0.05). After training, enhanced insulin sensitivity was inversely related to decreased INS0-60/GLC0-60 (r=-0.71, p<0.001), fasting insulin (r=-0.71, p<0.001), and insulin AUC (r=-0.85, p<0.001). Seven weeks of PRT increases insulin sensitivity and reduces glucose-stimulated insulin secretion in NBF, but not HBF women. Obesity attenuates exercise-induced improvements in glucose regulation in young non-diabetic women.

The Pre-diabetes Risk Education and Physical Activity Recommendation and Encouragement (PREPARE) programme study: are improvements in glucose regulation sustained at 2 years?

To determine whether improvements in glucose regulation following the PREPARE structured education programme were sustained at 24 months. Ninety-eight overweight or obese individuals with impaired glucose tolerance were randomized to receive: (1) advice leaflet, (2) 3-h structured education programme aimed at promoting physical activity, (iii) 3-h structured education with personalized pedometer use. The primary outcome was change in 2-h post-challenge plasma glucose. Seventy-three (74%) individuals were included for analysis at 24 months; age 65 ± 8 years, BMI 29.3 ± 4.8 kg/m(2), South Asian ethnicity 21%. A statistically significant reduction in 2-h glucose of -1.6 mmol/l (-0.4 to -2.7) was seen in the education-with-pedometer group compared with the control group. There is no significant difference in the education-only group. Improvements in glucose regulation following a pragmatic group-based structured education with pedometer use were sustained at 24 months.

The role of the gut hormone GLP-1 in the metabolic improvements caused by ileal transposition

BackgroundBariatric surgery alters the gastrointestinal hormonal milieu leading to improved glucose homeostasis, though the mechanism leading to these changes is poorly understood. Ileal transposition (IT) is a procedure that is neither restrictive nor malabsorptive but nevertheless produces profound improvements in glucose regulation. Ileal transposition involves a short segment of distal ileum being transposed to the proximal jejunum in an isoperistaltic direction, thereby avoiding any gastric resection or intestinal bypass. MethodsDiet-induced obese rats underwent either ileal transposition (IT) or Sham procedures. The Sham operated rats were pair-fed to the IT surgical group to control for the effects of reduced food intake. Body composition data were recorded at specific time points, and glucose tolerance tests were performed at 5 and 6 wk, both in the presence and absence of Exendin 9-39, a known glucose-like peptide 1 (GLP-1) receptor antagonist. A subset of naïve rats were also maintained for comparison. ResultsIT and Sham operated rats had no differences in food intake and body weight, however, IT rats had a significant decrease in their body fat composition (P < 0.05). No difference existed in glucose tolerance when exposed to an intraperitoneal glucose load, however, IT rats showed markedly improved glucose tolerance when submitted to an oral glucose tolerance test (P < 0.001). Blocking GLP-1 receptors reversed these important improvements in rats with IT surgery. ConclusionsThe present work recapitulates what is seen in rodents and humans that IT improves glucose tolerance and body composition. The present data provide compelling evidence that these improvements are a product of increased GLP-1 secretion that results from placing the key GLP-1 secreting cells closer to chyme coming from the stomach. Such data support the notion that rather than restriction or malabsorption, the underling molecular mechanisms that mediate the potent improvements produced by bariatric procedures involve increased activation of GLP-1 signaling.

The Role Of The Gut Hormone GLP-1 In The Metabolic Improvements Caused By Ileal Transposition

Introduction: Bariatric surgery alters the gastrointestinal hormonal milieu leading to improved glucose homeostasis, though the mechanism leading to these changes is poorly understood. Ileal transposition (IT) is a procedure that is neither restrictive nor malabsorptive but nevertheless produces profound improvements in glucose regulation. Ileal transposition involves a short segment of distal ileum being transposed to the proximal jejunum in an isoperistaltic direction thereby avoiding any gastric resection or intenstinal bypass.

Lifestyle, glucose regulation and the cognitive effects of glucose load in middle-aged adults

Interventions aimed at improving glucose regulatory mechanisms have been suggested as a possible source of cognitive enhancement in the elderly. In particular, previous research has identified episodic memory as a target for facilitation after either moderate increases in glycaemia (after a glucose drink) or after improvements in glucose regulation. The present study aimed to extend this research by examining the joint effects of glucose ingestion and glucose regulation on cognition. In addition, risk factors associated with the development of poor glucose regulation in middle-aged adults were considered. In a repeated measures design, thirty-three middle-aged adults (aged 35-55 years) performed a battery of memory and non-memory tasks after either 25 g or 50 g glucose or a sweetness matched placebo drink. To assess the impact of individual differences in glucose regulation, blood glucose measurements were taken on four occasions during testing. A lifestyle and diet questionnaire was also administered. Consistent with previous research, episodic memory ability benefited from glucose ingestion when task demands were high. Blood glucose concentration was also found to predict performance across a number of cognitive domains. Interestingly, the risk factors associated with poor glucose regulation were linked to dietary impacts traditionally associated with poor health, e.g. the consumption of high-sugar sweets and drinks. The research replicates earlier work suggesting that task demands are critical to the glucose facilitation effect. Importantly, the data demonstrate clear associations between elevated glycaemia and relatively poor cognitive performance, which may be partly due to the effect of dietary and lifestyle factors.

The effects of glucose ingestion and glucose regulation on memory performance in older adults with mild cognitive impairment

Previous research investigating the impact of glucose ingestion and/or improvements in glucose regulation has found selective cognitive facilitation on episodic memory tasks in successful ageing and dementia. The present study aimed to extend this research to mild cognitive impairment (MCI). In a repeated-measures design, 24 older adults with and 24 older adults without MCI performed a battery of memory and attention tasks after 25 g of glucose or a sweetness matched placebo. In addition, to assess the impact of individual differences in glucose regulation, blood glucose measurements were taken throughout the testing session. Consistent with previous research, cognitive facilitation was observed for episodic memory tasks only in both successful ageing and MCI. Older adults with MCI had a similar glucose regulatory response as controls but their fasting levels were elevated. Notably, higher levels of blood glucose were associated with impaired memory performance in both the glucose and placebo conditions. Importantly, both blood glucose and memory performance indices were significant predictors of MCI status. The utility of glucose supplementation and the use of glucose regulation as a biological marker are discussed in relation to these data.