Introduction: Intestinal metabolism and microbiota profiles are impaired in obesity and insulin resistance. Moreover, dysbiotic gut microbiota has been suggested to promote systemic low-grade inflammation and insulin resistance through the release of endotoxins particularly lipopolysaccharides. We have previously shown that exercise training improves intestinal metabolism in healthy men. To understand whether changes in intestinal metabolism interact with gut microbiota and its release of inflammatory markers, we studied the effects of sprint interval (SIT) and moderate-intensity continuous training (MICT) on intestinal metabolism and microbiota in subjects with insulin resistance. Methods: Twenty-six, sedentary subjects (prediabetic, n = 9; type 2 diabetes, n = 17; age, 49 [SD, 4] yr; body mass index, 30.5 [SD, 3]) were randomized into SIT or MICT. Intestinal insulin-stimulated glucose uptake (GU) and fatty acid uptake (FAU) from circulation were measured using positron emission tomography. Gut microbiota composition was analyzed by 16S rRNA gene sequencing and serum inflammatory markers with multiplex assays and enzyme-linked immunoassay kit. Results: V˙O_2peak improved only after SIT (P = 0.01). Both training modes reduced systematic and intestinal inflammatory markers (tumor necrosis factor-α, lipopolysaccharide binding protein) (time P < 0.05). Training modified microbiota profile by increasing Bacteroidetes phylum (time P = 0.03) and decreasing Firmicutes/Bacteroidetes ratio (time P = 0.04). Moreover, there was a decrease in Clostridium genus (time P = 0.04) and Blautia (time P = 0.051). Only MICT decreased jejunal FAU (P = 0.02). Training had no significant effect on intestinal GU. Colonic GU associated positively with Bacteroidetes and inversely with Firmicutes phylum, ratio Firmicutes/Bacteroidetes and Blautia genus. Conclusions: Intestinal substrate uptake associates with gut microbiota composition and whole-body insulin sensitivity. Exercise training improves gut microbiota profiles and reduces endotoxemia.

OBJECTIVE The aim of this study was to investigate tissue-specific effects of dapagliflozin on insulin sensitivity and liver and body fat in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This randomized, double-blind, parallel group, placebo-controlled study recruited 32 patients with type 2 diabetes. Enrolled patients were to have HbA_1c 6.5–10.5% (48–91 mmol/mol) and ≥3 months of stable treatment with metformin, dipeptidyl peptidase 4 inhibitor, or their combination. Patients were randomized 1:1 to receive 10 mg dapagliflozin or placebo daily for 8 weeks. Before and after the intervention, tissue insulin sensitivity was measured using [¹⁸F]-fluorodeoxyglucose and positron emission tomography (PET) during hyperinsulinemic-euglycemic clamp. Liver proton density fat fraction (PDFF) and adipose tissue volumes were assessed using MRI, and blood biomarkers were analyzed. RESULTS After 8 weeks, glycemic control was improved by dapagliflozin (placebo-corrected change in HbA_1c −0.39%, P < 0.01), but whole-body glucose uptake was not increased (P = 0.90). Tissue-specific insulin-stimulated glucose uptake did not change in skeletal muscle, liver, myocardium, or white and brown adipose tissue, and endogenous glucose production remained unaffected. However, there were significant placebo-corrected decreases in liver PDFF (−3.74%, P < 0.01), liver volume (−0.10 L, P < 0.05), visceral adipose tissue volume (−0.35 L, P < 0.01), interleukin-6 (−1.87 pg/mL, P < 0.05), and N-terminal prohormone of brain natriuretic peptide (−96 ng/L, P = 0.03). CONCLUSIONS In this study, 8 weeks of treatment with dapagliflozin reduced liver PDFF and the volume of visceral adipose tissue in obese patients with type 2 diabetes. Although glycemic control was improved, no effect on tissue-level insulin sensitivity was observed.

Obesity is characterized by an imbalance in the brain circuits promoting reward seeking and those governing cognitive control. Here we show that the dorsal caudate nucleus and its connections with amygdala, insula and prefrontal cortex contribute to abnormal reward processing in obesity. We measured regional brain glucose uptake in morbidly obese (n = 19) and normal weighted (n = 16) subjects with 2-[18F]fluoro-2-deoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) during euglycemic hyperinsulinemia and with functional magnetic resonance imaging (fMRI) while anticipatory food reward was induced by repeated presentations of appetizing and bland food pictures. First, we found that glucose uptake rate in the dorsal caudate nucleus was higher in obese than in normal-weight subjects. Second, obese subjects showed increased hemodynamic responses in the caudate nucleus while viewing appetizing versus bland foods in fMRI. The caudate also showed elevated task-related functional connectivity with amygdala and insula in the obese versus normal-weight subjects. Finally, obese subjects had smaller responses to appetizing versus bland foods in the dorsolateral and orbitofrontal cortices than did normal-weight subjects, and failure to activate the dorsolateral prefrontal cortex was correlated with high glucose metabolism in the dorsal caudate nucleus. These findings suggest that enhanced sensitivity to external food cues in obesity may involve abnormal stimulus-response learning and incentive motivation subserved by the dorsal caudate nucleus, which in turn may be due to abnormally high input from the amygdala and insula and dysfunctional inhibitory control by the frontal cortical regions. These functional changes in the responsiveness and interconnectivity of the reward circuit could be a critical mechanism to explain overeating in obesity.

Objective: Insulin resistance is reflected by the rates of reduced glucose uptake (GU) into the key insulin-sensitive tissues, skeletal muscle, liver and adipose tissue. It is unclear whether insulin resistance occurs simultaneously in all these tissues or whether insulin resistance is tissue specific.Design and methods: We measured GU in skeletal muscle, adipose tissue and liver and endogenous glucose production (EGP), in a single session using¹⁸F-fluorodeoxyglucose with positron emission tomography (PET) and euglycemic–hyperinsulinemic clamp. The study population consisted of 326 subjects without diabetes from the CMgene study cohort.Results: Skeletal muscle GU less than 33 µmol/kg tissue/min and subcutaneous adipose tissue GU less than 11.5 µmol/kg tissue/min characterized insulin-resistant individuals. Men had considerably worse insulin suppression of EGP compared to women. By using principal component analysis (PCA), BMI inversely and skeletal muscle, adipose tissue and liver GU positively loaded on same principal component explaining one-third of the variation in these measures. The results were largely similar when liver GU was replaced by EGP in PCA. Liver GU and EGP were positively associated with aging.Conclusions: We have provided threshold values, which can be used to identify tissue-specific insulin resistance. In addition, we found that insulin resistance measured by GU was only partially similar across all insulin-sensitive tissues studied, skeletal muscle, adipose tissue and liver and was affected by obesity, aging and gender.

Objective: Little is known about the mechanisms by which obesity influences brain structure. In this study, the obesity‐related changes in brain white and gray matter integrity were examined.Design and Methods: 23 morbidly obese subjects and 22 nonobese volunteers were studied using voxel‐based analysis of diffusion tensor imaging and of T1‐weighted MRI images. Full‐volume statistical parametric mapping analysis was used to compare fractional anisotropy (FA) and mean diffusivity (MD) values as well as gray (GM) and white matter (WM) density between these groups.Results: Obese subjects had lower FA and MD values and lower focal and global GM and WM volumes than control subjects did. The focal structural changes were observed in brain regions governing reward seeking, inhibitory control, and appetite. Regression analysis showed that FA and MD values as well as GM and WM density were negatively associated with body fat percentage. Moreover, the volume of abdominal subcutaneous fat was negatively associated with GM density in most regions.Conclusion: These findings imply that changes in GM and WM in obesity may be due to metabolic factors. Atrophy in regions involved in reward processing and appetite control may further promote abnormal reward seeking and eating behavior.