Brain effect of bariatric surgery in people with obesity.

BACKGROUND/OBJECTIVES: The link between obesity and brain function is a fascinating but still an enigmatic topic. We evaluated the effect of Roux-en-Y gastric bypass (RYGB) on peripheral glucose metabolism, insulin sensitivity, brain glucose utilization and cognitive abilities in people with obesity. SUBJECTS/METHODS: Thirteen subjects with obesity (F/M 11/2; age 44.4 ± 9.8 years; BMI 46.1 ± 4.9 kg/m2) underwent 75-g OGTT during a [18F]FDG dynamic brain PET/CT study at baseline and 6 months after RYGB. At the same timepoints, cognitive performance was tested with Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Trail making test (TMT) and Token test (TT). Glucose, insulin, C-peptide, GLP-1, GIP, and VIP levels were measured during OGTT. Leptin and BDNF levels were measured before glucose ingestion. RESULTS: RYGB resulted in significant weight loss (from 46.1 ± 4.9 to 35.3 ± 5.0 kg/m2; p < 0.01 vs baseline). Insulin sensitivity improved (disposition index: from 1.1 ± 0.2 to 2.9 ± 1.1; p = 0.02) and cerebral glucose metabolic rate (CMRg) declined in various brain areas (all p ≤ 0.01). MMSE and MoCA score significantly improved (p = 0.001 and p = 0.002, respectively). TMT and TT scores showed a slight improvement. A positive correlation was found between CMRg change and HOMA-IR change in the caudate nucleus (ρ = 0.65, p = 0.01). Fasting leptin decreased (from 80.4 ± 13.0 to 16.1 ± 2.4 ng/dl; p = 0.001) and correlated with CMRg change in the hippocampus (ρ = 0.50; p = 0.008). CMRg change was correlated with cognitive scores changes on the TMT and TT (all p = 0.04 or less). CONCLUSIONS: Bariatric surgery improves CMRg directly related to a better cognitive testing result. This study highlights the potential pleiotropic effects of bariatric surgery. TRIAL REGISTRY NUMBER: NCT03414333.

Bariatric surgery restores visual cortical plasticity in nondiabetic subjects with obesity.

BACKGROUND/OBJECTIVES: Obesity leads to changes in synaptic plasticity. We aimed at investigating the impact of bariatric surgery (RYGB) on visual neural plasticity (NP) and its relationship with the main gut peptides, leptin, and brain-derived neurotrophic factor (BDNF). SUBJECTS/METHODS: NP was assessed testing binocular rivalry before and after 2 h of monocular deprivation (index of visual brain plasticity) in 15 subjects with obesity (age 42.3 ± 9.8 years; BMI 46.1 ± 4.9 kg/m2) before and after RYGB. Gut peptides, leptin, and BDNF were obtained at baseline and 6 months after surgery in 13 subjects. RESULTS: A significant reduction in BMI (p < 0.001 vs. baseline) and a significant increase of disposition index (DI, p = 0.02 vs baseline) were observed after RYGB. Total and active GLP-1 release in response to glucose ingestion significantly increased after RYGB, while no changes occurred in VIP, GIP, and BDNF levels. Fasting leptin concentration was lower after RYGB (p = 0.001 vs. baseline). Following RYGB, NP was progressively restored (p < 0.002). NP was correlated with DI and fasting glucose at baseline (r = 0.75, p = 0.01; r = -0.7, p = 0.02; respectively), but not with BMI. A positive correlation between post-pre-RYGB changes in AUCactive GLP-1 and NP was observed (r = 0.70, p < 0.01). Leptin was inversely correlated with NP 6 months after surgery (r = -0.63, p = 0.02). No correlation was observed between GIP, VIP, BDNF, and NP. CONCLUSIONS: Visual plasticity is altered in subjects with obesity, and it can be restored after RYGB. The improvement may be mediated by amelioration of insulin sensitivity, increased GLP-1 levels, and reduced leptin levels.

De-intensification of basal-bolus insulin regimen after initiation of a GLP-1 RA improves glycaemic control and promotes weight loss in subjects with type 2 diabetes.

AIMS: To evaluate the impact of adding a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in people with type 2 diabetes (T2D) in basal-bolus (BB) insulin regimen, on insulin requirement, HbA1c, weight loss up to 24 months. METHODS: Data on subjects with T2D on BB who initiated a GLP-1 RA have been retrospectively collected. HbA1c, body weight, and insulin dose were recorded at baseline, 6, 12, and 24 months after initiation of GLP-1 RA therapy. A linear mixed model for repeated measures was used to evaluate the changes in HbA1c, body weight, and insulin requirement over time. RESULTS: We included 156 subjects (63.5% males; age 62 ± 11 years, HbA1c 70 ± 22.0 mmol/mol; 8.6 ± 4.2%). Compared to baseline, HbA1c and body weight were significantly lower at 6 months after introducing a GLP-1RA and remained stable up to 24 months (all p < 0.0001 vs. baseline). At 24 months, 81% of subjects discontinued prandial insulin, while 38.6% discontinued basal insulin as well. Insulin requirement at baseline (aOR 0.144; 95% CI, 0.046-0.456; P = 0.001) was the only significant predictor of prandial insulin discontinuation. CONCLUSIONS: Replacing prandial insulin with GLP-1 RA is a valuable strategy to simplify the BB insulin regimen while improving glycaemic control and promoting weight loss in subjects with T2D.

Impact of COVID-19 lockdown on glucose control of elderly people with type 2 diabetes in Italy.

AIMS: to evaluate the effect of home confinement related to COVID-19 lockdown on metabolic control in subjects with T2DM in Italy. METHODS: we evaluated the metabolic profile of 304 individuals with T2DM (65% males; age 69 ± 9 years; diabetes duration 16 ± 10 years) attending our Diabetes Unit early at the end of lockdown period (June 8 to July 7, 2020) and compared it with the latest one recorded before lockdown. RESULTS: There was no significant difference in fasting plasma glucose (8.6 ± 2.1 vs 8.8 ± 2.5 mmol/L; P = 0.353) and HbA1c (7.1 ± 0.9 vs 7.1 ± 0.9%; P = 0.600) before and after lockdown. Worsening of glycaemic control (i.e., ΔHbA1c ≥ 0.5%) occurred more frequently in older patients (32.2% in > 80 years vs 21.3% in 61-80 years vs 9.3% in < 60 years; P = 0.05) and in insulin users (28.8 vs 16.5%; P = 0.012). On multivariable analysis, age > 80 years (OR 4.62; 95%CI: 1.22-16.07) and insulin therapy (OR 1.96; 95%CI: 1.10-3.50) remained independently associated to worsening in glycaemic control. CONCLUSIONS: Home confinement related to COVID-19 lockdown did not exert a negative effect on glycaemic control in patients with T2DM. However, age and insulin therapy can identify patients at greatest risk of deterioration of glycaemic control.

Plasma N-Acetylaspartate Is Related to Age, Obesity, and Glucose Metabolism: Effects of Antidiabetic Treatment and Bariatric Surgery.

Background: N-acetylaspartate (NAA) is synthesized only by neurons and is involved in neuronal metabolism and axonal myelination. NAA is the strongest signal on brain magnetic resonance spectroscopy, and its concentration have been associated with cognitive dysfunction in neurodegenerative diseases, obesity, and type 2 diabetes (T2D). Materials and Methods: We explored the impact of obesity and T2D on circulating NAA as well as the impact of bariatric surgery and antidiabetic treatments. We developed an LC-MS method for the accurate measurements of fasting plasma NAA levels in 505 subjects (156 subjects with normal glucose tolerance, 24 subjects with impaired glucose tolerance, and 325 patients with T2D) to examine the associations of NAA with obesity and dysglycemia. To validate cross-sectional findings, plasma NAA was measured 6 months after Roux-en-Y Gastric Bypass (RYGB) in 55 morbidly obese subjects, and after 1 year of antidiabetic treatment (with dapagliflozin, exenatide, or dapagliflozin plus exenatide) in 192 T2D patients. Results: In the whole population, NAA was associated with age (r = 0.31, p <0.0001) and BMI (r = -0.20, p <0.0001). Independently of age and BMI, NAA was reciprocally related to HbA1c and fasting plasma glucose (partial r = -0.13, both p = 0.01). Surgically-induced weight loss raised NAA (by 18 nmol/L on average, p <0.02). Glucose lowering treatment increased NAA in proportion to the drop in HbA1c (r = 0.31, p <0.0001) regardless of the agent used. Conclusions: Circulating NAA concentrations are modulated by age, obesity, and glycemic control. Whether they may mark for the corresponding metabolic effects on brain function remains to be established by joint measurements of spectroscopic signal and cognitive function.

Atypical Progeroid Syndrome and Partial Lipodystrophy Due to LMNA Gene p.R349W Mutation.

Atypical progeroid syndrome (APS) comprises heterogeneous disorders characterized by variable degrees of fat loss, metabolic alterations, and comorbidities that affect skeleton, muscles, and/or the heart. We describe 3 patients that were referred to our center for the suspicion of lipodystrophy. They had precocious aging traits such as short stature, mandibular hypoplasia, beaked nose, and partial alopecia manifesting around 10 to 15 years of age recurrently associated with: (1) partial lipodystrophy; (2) proteinuric nephropathy; (3) heart disease (rhythm disorders, valvular abnormalities, and cardiomyopathy); and (4) sensorineural hearing impairment. In all patients, genetic testing revealed a missense heterozygous lamin A/C gene (LMNA) mutation c.1045 C > T (p.Arg349Trp). Ten patients with LMNA p.R349W mutation have been reported so far, all presenting with similar features, which represent the key pathological hallmarks of this subtype of APS. The associated kidney and cardiac complications occurring in the natural history of the disease may reduce life expectancy. Therefore, in these patients a careful and periodic cardiac and kidney function evaluation is required.

Metabolic regulation of GLP-1 and PC1/3 in pancreatic α-cell line.

BACKGROUND AND AIMS: An intra-islet incretin system has been recently suggested to operate through modulation of the expression and activity of proconvertase 1/3 and 2 (PC1/3, PC2) in pancreatic alpha-cell accounting for local release of GLP-1. Little is known, whether this alpha-cell activity can be affected by the metabolic alterations occurring in type 2 diabetes, such as hyperglycemia, hyperlipidemia or hyperglucagonemia. MATERIALS AND METHODS: AlphaTC1/6 cells from a mice pancreatic cell line were incubated in the presence of two glucose (G) concentration (5.5 and 16.7 mM) for 16 h with or without free fatty acid, IL6 or glucagon. GLP-1 secretion was measured by ELISA and expression of PC1/3 and PC2 by RT-PCR and western blot; cell viability was determined by MTT method, Reactive Oxygen Species generation (ROS) by H2DCFDA fluorescence and apoptosis by Annexin staining and Propidium Iodine (PI) fluorescence. RESULTS: Upon 16.7G incubation, GLP-1 secretion (total and active) was significantly increased in parallel with a significant increment in PC1/3 expression, a slight increase in cell viability and ROS generation and by a decrement in PC2 expression with no change in cell apoptosis. When cells were incubated at 5.5mM glucose with FFA, also an increment in GLP-1 secretion and PC1/3 expression was observed together an increment in ROS generation, a decrement in cell viability, and a modest increment in apoptosis. When incubated with 16.7mM glucose with FFA, the increment in GLP-1 secretion was reduced to basal, accompanied by an increment in apoptosis and ROS generation. This was also observed with IL-6, but in this case, no modification in ROS generation or apoptosis was observed when compared to 16.7mM glucose. The presence of glucagon did not modify any of the parameters studied. CONCLUSION: These data suggest that under hyperglycemic, hyperlipidemia or inflammatory conditions, alpha cells can increase expression PC1/3 and activate GLP-1 secretion, which may contribute protecting both alpha and beta-cells from glucose and lipotoxicity, while this effect seems to be lost in the presence of both pathophysiological conditions.

Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts.

Chronic hyperinsulinemia is both a marker and a cause for insulin resistance. This study analyzes the effect of long-term exposure to high insulin levels on the insulin-signaling pathway and glucose transport in cultured human myoblasts. Human myoblasts were grown in the presence of low (107 pmol/L, SkMC-L) or high (1430 pmol/L, SkMC-H) insulin concentrations for 3 weeks. Glucose transport, insulin receptor (IR), and IR substrate 1 (IRS1) phosphorylation, phosphatidylinositol 3'-kinase (PI3K) activity, as well as Akt-Ser473 phosphorylation have been investigated at the end of the incubation period and after a further short-term insulin stimulation. At the end of the incubation period, IR, IRS1, p85/PI3K, Akt, and GLUT4 protein expression levels were similar in both culture conditions. Basal glucose transport was similar in SkMC-L and SkMC-H, but after short-term insulin stimulation significantly increased (P < .01) only in SkMC-L. IR binding was down-regulated in SkMC-H (P < .01), but IR and IRS1 tyrosine phosphorylation and PI3K activity were significantly higher (P < .01) in SkMC-H than SkMC-L. Despite increased PI3K activation, Akt-Ser473 phosphorylation was similar in SkMC-L and SkMC-H. After a short-term insulin stimulation (10 nmol/L insulin for 10 minutes), IR and IRS1 tyrosine phosphorylation, PI3K activation, and Akt-Ser473 phosphorylation significantly increased (P < .01 and P < .05 for Akt) in SkMC-L but not in SkMC-H. Serine phosphorylation of IRS1 was similar in SkMC-L and SkMC-H. Moreover, in the SkMC-H, insulin stimulation was associated with the inhibition of IRS1 tyrosine dephosphorylation (P < .05). In summary, continuous exposure of cultured myoblasts to high insulin levels induces a persistent up-regulation of IR, IRS1, and PI3K activity associated with the demodulation of insulin signaling. Moreover, the impairment of the insulin-signaling steps between PI3K and Akt is concomitant with the desensitization of glucose transport. These alterations may contribute to the derangement insulin-signaling pathway states of hyperinsulinemia such as obesity and type 2 diabetes.

High insulin levels impair intracellular receptor trafficking in human cultured myoblasts.

Chronic hyperinsulinemia is both a marker and a cause for insulin resistance. This study analyzes the effect of long-term exposure to high insulin levels on insulin-insulin receptor metabolism in human myoblasts. Cells were grown in the presence of low (107 pM, SkMC-L) or high (1430 pM, SkMC-H) insulin concentrations. Insulin receptor (IR) phosphorylation, IR internalization, dissociation and recycling, as well as insulin degradation have been investigated. Basal IR phosphorylation was higher in SkMC-H than in SkMC-L (P<0.01) but after acute insulin stimulation (10nM insulin for 10 min), IR phosphorylation increased (P<0.01) in SkMC-L, but not in SkMC-H. Chronic hyperinsulinism significantly decreased insulin-IR complex internalization (P<0.01). Nevertheless the t(1/2) value of receptor internalization was similar in both cells. Intracellular dissociation of insulin-IR complex was slightly but significantly lower in SkMC-H than in SkMC-L. Finally, SkMC-H showed a complete, but significantly delayed recycling of IR to plasma membrane (t(1/2)=20 min versus SkMC-L t(1/2)=7 min). The time course of intracellular degradation measured by HPLC, showed whenever studied, significantly (P<0.01) higher levels of intracellular intact insulin in cells exposed to high insulin concentrations. Nevertheless, the patterns of insulin degradation were over-imposable between SkMC-H and SkMC-L. In summary, continuous exposure of cultured myoblasts to high insulin levels induces subtle derangements of intracellular receptor trafficking and insulin degradation. These alterations may contribute to the insulin resistance of hyperinsulinemic states such as obesity and Type 2 Diabetes.

Obesity modulates the expression of haptoglobin in the white adipose tissue via TNFalpha.

Increase in adipose mass results in obesity and modulation of several factors in white adipose tissue (WAT). Two important examples are tumor necrosis factor alpha (TNFalpha) and leptin, both of which are upregulated in adipose tissue in obesity. In order to isolate genes differentially expressed in the WAT of genetically obese db/db mice compared to their lean littermates, we performed RNA fingerprinting and identified haptoglobin (Hp), which is significantly upregulated in the obese animals. Hp is a glycoprotein induced by a number of cytokines, LPS (Lipopolysaccharide), and more generally by inflammation. A significant upregulation of WAT Hp expression was also evident in several experimental obese models including the yellow agouti (/) A(y), ob/ob and goldthioglucose-treated mice (10-, 8-, and 7-fold, respectively). To identify the potential signals for an increase in Hp expression in obesity, we examined leptin and TNFalpha in vivo. Wild type animals treated with recombinant leptin did not show any alteration in WAT Hp expression compared to controls that were food restricted to the level of intake of the treated animals. On the other hand, Hp expression was induced in mice transgenically expressing TNFalpha in adipose tissue. Finally, a significant downregulation of WAT Hp mRNA was observed in ob/ob mice deficient in TNFalpha function, when compared to the ob/ob controls. These results demonstrate that haptoglobin expression in WAT is increased in obesity in rodents and TNFalpha is an important signal for this regulation.