Time Course of Metabolic, Neuroendocrine, and Adipose Effects During 2 Years of Follow-up After Gastric Bypass in Patients With Type 2 Diabetes.

CONTEXT: Roux-en-Y gastric bypass surgery (RYGB) markedly improves glycemia in patients with type 2 diabetes (T2D), but underlying mechanisms and changes over time are incompletely understood. OBJECTIVE: Integrated assessment of neuroendocrine and metabolic changes over time in T2D patients undergoing RYGB. DESIGN AND SETTING: Follow-up of single-center randomized study. PATIENTS: Thirteen patients with obesity and T2D compared to 22 healthy subjects. INTERVENTIONS: Blood chemistry, adipose biopsies, and heart rate variability were obtained before and 4, 24, and 104 weeks post-RYGB. RESULTS: After RYGB, glucose-lowering drugs were discontinued and hemoglobin A1c fell from mean 55 to 41 mmol/mol by 104 weeks (P < 0.001). At 4 weeks, morning cortisol (P < 0.05) and adrenocorticotropin (P = 0.09) were reduced by 20%. Parasympathetic nerve activity (heart rate variability derived) increased at 4 weeks (P < 0.05) and peaked at 24 weeks (P < 0.01). C-reactive protein (CRP) and white blood cells were rapidly reduced (P < 0.01). At 104 weeks, basal and insulin-stimulated adipocyte glucose uptake increased by 3-fold vs baseline and expression of genes involved in glucose transport, fatty acid oxidation, and adipogenesis was upregulated (P < 0.01). Adipocyte volume was reduced by 4 weeks and more markedly at 104 weeks, by about 40% vs baseline (P < 0.01). CONCLUSIONS: We propose this order of events: (1) rapid glucose lowering (days); (2) attenuated cortisol axis activity and inflammation and increased parasympathetic tone (weeks); and (3) body fat and weight loss, increased adipose glucose uptake, and whole-body insulin sensitivity (months-years; similar to healthy controls). Thus, neuroendocrine pathways can partly mediate early glycemic improvement after RYGB, and adipose factors may promote long-term insulin sensitivity and normoglycemia.

Effects of Gastric Bypass Surgery on the Brain: Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia.

While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by 18F-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.

Human macrophages stimulate expression of inflammatory mediators in adipocytes; effects of second-generation antipsychotics and glucocorticoids on cellular cross-talk.

OBJECTIVE: Adipose tissue inflammation and distorted macrophage-adipocyte communication are positively associated with metabolic disturbances. Some pharmacological agents, such as second-generation antipsychotics (SGAs) and synthetic glucocorticoid (GC) dexamethasone, tend to induce adverse metabolic side effects and the underlying mechanisms are not fully understood. Our work aimed to study whether SGAs and dexamethasone affect macrophage phenotype and macrophage-adipocyte communication on gene expression level. We selected the model involving THP-1-derived macrophages, polarized into M0, M1, and M2 phenotypes, and primary human mature subcutaneous adipocytes. METHODS: Abdominal subcutaneous adipose tissue needle biopsies were obtained from 6 healthy subjects (4F/2M; age: 22-64 yr; BMI: 21.7-27.6 kg/m2) followed by isolation of mature adipocytes. THP-1-human monocytic cell line was used for the study. THP-1 monocytes were differentiated and polarized into M0 (naïve), M1 (classically activated), and M2 (alternatively activated) macrophages. During and after polarization the macrophages were treated for 24 h without (control) or with therapeutic and supra-therapeutic concentrations of olanzapine (0.2 µM and 2.0 µM), aripiprazole (1.0 µM and 10 µM) and its active metabolite dehydroaripiprazole (0.4 µM and 4.0 µM). Isolated mature human adipocytes were co-incubated with THP-1-derived polarized macrophages pre-treated with SGAs after their polarization. Adipocytes and macrophages were collected before and after co-culture for mRNA expression analysis of genes involved in inflammation. RESULTS: Co-incubation of mature human adipocytes with human macrophages, regardless of polarization, resulted in a marked induction of pro-inflammatory cytokines in adipocytes, including IL1B, IL6, TNFA, and IL10. Remarkably, it did not affect the expression of adipokines and genes involved in the regulation of energy, lipid, and glucose metabolism in adipocytes. Dexamethasone markedly reduced gene expression of pro-inflammatory cytokines in macrophages and prevented macrophage-induced inflammatory response in adipocytes. In contrast, SGAs did not affect macrophage-adipocyte communication and had a minute anti-inflammatory effect in macrophages at supra-therapeutic concentrations. Interestingly, the adipocytes co-incubated with M1 macrophages pre-treated with dexamethasone and SGAs particularly the supra-therapeutic concentration of olanzapine, reduced expression of LPL, LIPE, AKT1, and SLC2A4, suggesting that the expression of metabolic genes in adipocytes was dependent on the presence of pro-inflammatory M1 macrophages. CONCLUSION: Together, these data suggest that macrophages induce expression of pro-inflammatory genes in human subcutaneous adipocytes without affecting the expression of adipokines or genes involved in energy regulation. Furthermore, our findings demonstrated that SGAs and dexamethasone had a mild effect on macrophage-adipocyte communication in M1 macrophage phenotype.

Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism.

OBJECTIVE: Metabolic syndrome is prevalent in up to 50% of schizophrenia patients, which reduces their quality of life and their compliance with the treatment. It is unclear whether metabolic adverse effects of these agents are due to their direct effect on insulin-sensitive tissues or are secondary to increased adiposity. The study aimed to investigate the direct effects of the second-generation antipsychotics olanzapine and aripiprazole on human subcutaneous adipose tissue and isolated adipocyte metabolism. METHODS: Abdominal subcutaneous adipose tissue needle biopsies were taken from 72 healthy subjects (49 F/23 M; age: 19-78 yr; BMI: 20.0-35.6 kg/m2). Isolated adipocytes or adipose tissue were respectively pre-incubated short- (30 min) and long-term (24 h, 72 h) with or without olanzapine (0.004 µM - 20 µM) and aripiprazole (0.002 µM - 100 µM). Pre-incubated adipose tissue was then snap-frozen for mRNA expression analysis of adipokines genes and genes involved in inflammation, adipogenesis, and mitochondrial function. Isolated adipocytes were used to measure basal and insulin-stimulated glucose uptake and lipolysis. RESULTS: Acute treatment with a therapeutic concentration of olanzapine decreases basal lipolysis in isolated adipocytes; this effect was not observed after long-term incubation with the drug. Supra-therapeutic concentration of aripiprazole reduced basal and insulin-stimulated glucose uptake after short- and long-term pre-incubation. Both drugs at supra-therapeutic concentrations downregulated the expression of the pro-inflammatory cytokines IL6 and IL1B genes after 72 h incubation. Similarly, supra-therapeutic concentrations of both drugs and therapeutic concentration of olanzapine, reduced the expression of PPARGC1A, PDK4, and CPT1B genes involved in the regulation of mitochondrial functions. Neither of the antipsychotics affected the expression of the main adipokines LEP and ADIPOQ, genes involved in the regulation of lipid metabolism, LPL and FASN, nor the master adipogenesis regulator, PPARG. CONCLUSION: Therapheutic concentrations of olanzapine and aripiprazole have a moderate direct effect on adipocyte lipid and glucose metabolism, respectively. At supra-therapeutic concentrations, both of the antipsychotics seem to act as anti-inflammatory agents and mildly suppressed genes involved in the regulation of mitochondrial functions, which could potentially contribute to metabolic adverse effects. Alternatively, second-generation antipsychotics could induce metabolic side effects via acting on other insulin-sensitive tissues and central nervous system.

Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery.

OBJECTIVES: The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP). DESIGN: Experimental hyperinsulinemic-hypoglycemic clamp study. METHODS: Twelve post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/L) performed on separate days with concomitant infusions of the GLP-1 analog exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps. RESULTS: No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed. CONCLUSIONS/INTERPRETATION: Short-term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the improvement in symptomatic hypoglycemia post-GBP seen following treatment with GLP-1 receptor agonists may be mediated by mechanism not directly involved in counter-regulation.