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Aims: Sodium-glucose cotransporter-2 inhibitors induce less weight loss than expected. This may be explained by sodium-glucose cotransporter-2 inhibitor-induced alterations in central reward- and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists reduce appetite and body weight because of direct and indirect effects on the brain. We investigated the separate and combined effects of dapagliflozin and exenatide on the brain in response to the anticipation and consumption of food in people with obesity and type 2 diabetes., Materials and Methods: As part of a larger study, this was a 16 week, double-blind, randomized, placebo-controlled trial. Subjects with obesity and type 2 diabetes were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice-daily 10 μg with dapagliflozin-matched placebo, dapagliflozin plus exenatide, or double placebo. Using functional magnetic resonance imaging, the effects of treatments on brain responses to the anticipation of food and food receipt were assessed after 10 days and 16 weeks., Results: After 10 days, dapagliflozin increased activation in right amygdala and right caudate nucleus in response to the anticipation of food, and tended to decrease activation in right amygdala in response to actual food receipt. After 16 weeks, no changes in brain activation were observed with dapagliflozin. Dapagliflozin plus exenatide reduced activation in right caudate nucleus and amygdala to the anticipation of food, and decreased activation in the right amygdala in response to food receipt after 16 weeks., Conclusions: The dapagliflozin-induced changes in brain activation may contribute to the discrepancy between observed and expected weight loss with dapagliflozin. Exenatide blunted the dapagliflozin-induced changes in brain activation, which may contribute to the additional weight loss with combined treatment., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To evaluate the effects of separate and combined use of the sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin and the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide on measures of kidney function., Methods: In this prespecified secondary analysis of the DECREASE trial, we enrolled 66 obese patients with type 2 diabetes in a 16-week randomized double-blind placebo-controlled clinical trial to investigate the effects of dapagliflozin and exenatide twice daily, alone or in combination, versus placebo on 24-hour urinary albumin:creatinine ratio (UACR), creatinine and cystatin C-estimated glomerular filtration rate (GFR) and kidney injury molecule-1:creatinine ratio (KIM-1:Cr)., Results: At week 16, the mean UACR change from baseline was -39.6% (95% confidence interval [CI] -58.6, -11.9; P = 0.001) in the combined exenatide-dapagliflozin group, -18.1% (95% CI -43.1, 18.0; P = 0.278) in the dapagliflozin group, -15.6% (95% CI -41.4, 21.6; P = 0.357) in the exenatide group and - 11.0% (95% CI -39.8, 31.5; P = 0.552) in the placebo group. Compared to placebo, UACR difference at week 16 in the exenatide-dapagliflozin group was -32.2% (95% CI -60.7, 16.9; P = 0.159). Effects were similar in 37 participants who were using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at baseline. Compared to placebo, in the exenatide-dapagliflozin group, an acute dip in estimated GFR was observed with creatinine-estimated GFR (-4.0 mL/min/1.73 m 2 [95% CI -9.3, 1.2]; P = 0.129) and cystatin C-estimated GFR (-10.4 mL/min/1.73 m 2 [95% CI -14.9, -5.8]; P < 0.001). The mean KIM-1:Cr difference in the combined treatment arm versus placebo was -43.8% (95% CI -73.5, 18.9; P = 0.129)., Conclusion: This prespecified secondary analysis suggests that combined therapy with exenatide and dapagliflozin may have synergistic effects on markers of kidney function compared to either therapy alone or placebo in obese patients with type 2 diabetes., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To assess the effects of Roux-en-Y gastric bypass surgery (RYGB)-related changes in glucagon-like peptide-1 (GLP-1) on cerebral resting-state functioning in obese women., Materials and Methods: In nine obese females aged 40-54 years in the fasted state, we studied the effects of RYGB and GLP-1 on five a priori selected networks implicated in food- and reward-related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks)., Results: Before surgery, GLP-1 receptor blockade (using exendin9-39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP-1 receptor blockade had a larger effect on connectivity in this region than GLP-1 receptor blockade before RYGB (all P FWE  < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB., Conclusions: These findings suggest GLP-1 involvement in resting-state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP-1-induced changes in resting-state connectivity in RYGB-mediated weight loss and appetite control., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: Cognitive impairments in type 1 diabetes may result from hyperglycemia-associated cerebral microangiopathy. We aimed to identify cerebral microangiopathy and skin microvascular dysfunction-as a surrogate marker for generalized microvascular function-as predictors of cognitive performance over time., Methods: In this prospective cohort study, 25 type 1 diabetes patients with proliferative retinopathy and 25 matched healthy controls underwent neurocognitive testing at baseline and after follow-up (3.8 ± 0.8 years). At baseline, 1.5-T cerebral magnetic resonance imaging was used to detect WML and cerebral microbleeds. Skin capillary perfusion was assessed by means of capillary microscopy., Results: In type 1 diabetes patients, but not in healthy controls, the presence of WML (ß = -0.419; P = 0.037) as well as lower skin capillary perfusion (baseline: ß = 0.753; P < 0.001; peak hyperemia: ß = 0.743; P = 0.001; venous occlusion: ß = 0.675; P = 0.003; capillary recruitment: ß = 0.549; P = 0.022) at baseline was associated with lower cognitive performance over time, independent of age, sex, HbA1c, and severe hypoglycemia. The relationship between WML and lower cognitive performance was significantly reduced after adjusting for capillary perfusion., Conclusions: These data fit the hypothesis that cerebral microangiopathy is a manifestation of generalized microvascular dysfunction, leading to lower cognitive performance., (© 2019 The Authors. Microcirculation Published by John Wiley & Sons Ltd.)

Aim: To test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward., Methods: As part of a larger study, we determined the effects of GLP-1 receptor activation on brain responses to anticipation and receipt of chocolate milk versus a tasteless solution, using functional MRI (fMRI). Obese subjects with type 2 diabetes, and obese and lean subjects with normoglycaemia (n = 48) underwent three fMRI sessions at separate visits with intravenous infusion of the GLP-1 receptor agonist exenatide, exenatide with prior GLP-1 receptor blockade by exendin-9-39 or placebo, during somatostatin pituitary-pancreatic clamps., Results: Body mass index negatively correlated with brain responses to receipt of chocolate milk and positively correlated with anticipation of receipt of chocolate milk in brain areas regulating reward, appetite and motivation. Exenatide increased brain responses to receipt of chocolate milk and decreased anticipation of receipt of chocolate milk compared with placebo, paralleled by reductions in food intake. Exendin-9-39 largely prevented these effects., Conclusions: Our findings show that GLP-1 receptor activation decreases anticipatory food reward, which may reduce cravings for food and increases consummatory food reward, which may prevent overeating., (© 2015 John Wiley & Sons Ltd.)