Effect of fasting on short-term visual plasticity in adult humans.

Brain plasticity and function is impaired in conditions of metabolic dysregulation, such as obesity. Less is known on whether brain function is also affected by transient and physiological metabolic changes, such as the alternation between fasting and fed state. Here we asked whether these changes affect the transient shift of ocular dominance that follows short-term monocular deprivation, a form of homeostatic plasticity. We further asked whether variations in three of the main metabolic and hormonal pathways affected in obesity (glucose metabolism, leptin signalling and fatty acid metabolism) correlate with plasticity changes. We measured the effects of 2 h monocular deprivation in three conditions: post-absorptive state (fasting), after ingestion of a standardised meal and during infusion of glucagon-like peptide-1 (GLP-1), an incretin physiologically released upon meal ingestion that plays a key role in glucose metabolism. We found that short-term plasticity was less manifest in fasting than in fed state, whereas GLP-1 infusion did not elicit reliable changes compared to fasting. Although we confirmed a positive association between plasticity and supraphysiological GLP-1 levels, achieved by GLP-1 infusion, we found that none of the parameters linked to glucose metabolism could predict the plasticity reduction in the fasting versus fed state. Instead, this was selectively associated with the increase in plasma beta-hydroxybutyrate (B-OH) levels during fasting, which suggests a link between neural function and energy substrates alternative to glucose. These results reveal a previously unexplored link between homeostatic brain plasticity and the physiological changes associated with the daily fast-fed cycle.

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.

SIRT1 rs7896005 polymorphism affects major vascular outcomes, not all-cause mortality, in Caucasians with type 2 diabetes: A 13-year observational study.

AIMS: SIRT1 exerts effects on ageing and lifespan, as well cardiovascular (CV) disease risk. SIRT1 gene is very polymorph with a few tagging single nucleotide polymorphisms (SNPs) so far identified. Some SNPs, including rs7896005, were associated with type 2 diabetes (T2DM). We aimed to ascertain whether this SNP may be associated with CV disease at baseline as well with these same outcomes and all-cause mortality over a 13-year follow-up. MATERIALS AND METHODS: Genotypes of SIRT1 gene were determined using TaqMan SNP assay. RESULTS: Out of 905 T2DM, 9.1% had the AA genotype, 43.2% the AG, and 47.7% the GG. Hardy-Weinberg Equilibrium was met (minor allele frequency 0.306; p = 0.8899). At baseline, there was no difference across genotypes for sex, age, diabetes duration, CV risk factors, treatments, and microangiopathy. Major CV outcomes, myocardial infarction (MI), any coronary heart disease (CHD), and peripheral artery disease (PAD) were more frequent in GG than in AA/AG (p from 0.013 to 0.027), with no association with cerebrovascular events. By fully adjusted regression, GG remained independently related to major CV outcomes, MI, CHD, and PAD. Over follow-up, we recorded 258 major CV events (28.5%; AA/AG 25.2%, GG 32.2%; p = 0.014) with an adjusted hazard ratio (HR) of GG versus AA/AG of 1.296 (95% CI 1.007-1.668, p = 0.044); 169 coronary events (18.7%; AA/AG 15.4%, GG 22.2%; p = 0.006) with HR 1.522 (1.113-2.080, p = 0.008); 79 (8.7%) hospitalisation for heart failure (AA/AG 7.0%, GG 10.6%; p = 0.045) and HR 1.457 (0.919-2.309, p = 0.109); 36 PAD (4.0%; AA/AG 2.3%, GG 5.8%; p = 0.007) with HR 2.225 (1.057-4.684, p = 0.035). No association was found with cerebrovascular events, end stage renal disease, and all-cause mortality. CONCLUSIONS: The rs7896005 SNP of SIRT1 might play a role in cardiovascular disease, mainly CHD risk in T2DM. Results call for larger association studies as well as studies to ascertain mechanisms by which this variant confers increased risk.

Evidence for two distinct phenotypes of chronic kidney disease in individuals with type 1 diabetes mellitus.

AIMS/HYPOTHESIS: In a retrospective, observational, cross-sectional, single-centre study, we assessed the prevalence and correlates of different CKD phenotypes (with and without albuminuria) in a large cohort of patients of white ethnicity with type 1 diabetes. METHODS: From 2001 to 2009, 408 men and 369 women with type 1 diabetes (age 40.2 ± 11.7 years, diabetes duration 19.4 ± 12.2 years, HbA1c 7.83 ± 1.17% [62.0 ± 12.9 mmol/mol]) were recruited consecutively. Albumin-to-creatinine ratio (ACR) and eGFR (Modification of Diet in Renal Disease) were obtained for all individuals, together with CKD stage. Diabetic retinopathy and peripheral polyneuropathy were detected in 41.5% and 8.1%, respectively, and cardiovascular disease (CVD) occurred in 8.5%. Adjudications of CKD phenotype were made by blinded investigators. RESULTS: Normo- (ACR <3.4), micro- (ACR 3.4-34) or macroalbuminuria (ACR ≥34 mg/mmol) were present in 91.6%, 6.4% and 1.9% of individuals, respectively. eGFR categories 1 (≥90 ml min-1 [1.73 m]-2), 2 (60-89 ml min-1 [1.73 m]-2) and 3 (<60 ml min-1 [1.73 m]-2) were present in 57.3%, 39.0% and 3.7%, respectively. The majority of participants had no CKD (89.4%), while stages 1-2 and ≥3 CKD were detected in 6.8% and 3.7%, respectively. The albuminuric (Alb+) and non-albuminuric (Alb-) phenotypes were present in 12 (41.4%) and 17 (58.6%) individuals with stage ≥3 CKD, respectively. Individuals with an ACR <3.4 mg/mmol were subdivided into those with normal albuminuria (<1.1 mg/mmol; 77.2%) and mildly increased albuminuria (1.1-3.4 mg/mmol; 14.4%), and individuals with stage 2 CKD were subdivided into those with eGFR 75-89 ml min-1 [1.73 m]-2 and 60-74 ml min-1 [1.73 m]-2. ACR <3.4 mg/mmol (88.7%) and even <1.1 mg/mmol (70.4%) were common in individuals with eGFR 60-74 ml min-1 [1.73 m]-2. The prevalence of ACR <1.1 mg/mmol was lower but still significant (34.5%) in those with stage ≥3 CKD. In logistic regression analysis, stages 1-2 and ≥3 CKD were independently associated with age, HbA1c, γ-glutamyltransferase, fibrinogen, hypertension, but not with sex, BMI, smoking, HDL-cholesterol or triacylglycerol. Inclusion of advanced retinopathy removed HbA1c from the model. The CKD Alb+ phenotype correlated with diabetes duration, HbA1c, HDL-cholesterol, fibrinogen and hypertension, while the CKD Alb- phenotype was associated with age and hypertension, but not with diabetes duration, HbA1c and fibrinogen. CONCLUSIONS/INTERPRETATION: The Alb- CKD phenotype is present in a significant proportion of individuals with type 1 diabetes supporting the hypothesis of two distinct pathways (Alb+ and Alb-) of progression towards advanced kidney disease in type 1 diabetes. These are probably distinct pathways as suggested by different sets of covariates associated with the two CKD phenotypes.

ß-Cell Function, Incretin Effect, and Glucose Kinetics in Response to a Mixed Meal in Patients With Type 2 Diabetes Treated With Dapagliflozin Plus Saxagliptin.

OBJECTIVE: To explore the complementary effects of a combination of dipeptidyl peptidase 4 and sodium-glucose cotransporter 2 inhibitors added to metformin on hormonal and metabolic responses to meal ingestion. RESEARCH DESIGN AND METHODS: Forty-five patients (age 58 ± 8 years; HbA1c 58 ± 6 mmol/mol; BMI 30.7 ± 3.2 kg/m2) with type 2 diabetes uncontrolled with metformin were evaluated at baseline and 3 and 28 days after 5 mg saxagliptin (SAXA), 10 mg dapagliflozin (DAPA), or 5 mg saxagliptin plus 10 mg dapagliflozin (SAXA+DAPA) using a mixed-meal tolerance test (MMTT) spiked with dual-tracer glucose to assess glucose metabolism, insulin secretion, and sensitivity. RESULTS: At day 3, fasting and mean MMTT glucose levels were lower with SAXA+DAPA (-31.1 ± 1.6 and -91.5 ± 12.4 mg/dL) than with SAXA (-7.1 ± 2.1 and -53 ± 10.5 mg/dL) or DAPA (-17.0 ± 1.1 and -42.6 ± 10.0 mg/dL, respectively; P < 0.001). Insulin secretion rate (SAXA+DAPA +75%; SAXA +11%; DAPA +3%) and insulin sensitivity (+2.2 ± 1.7, +0.4 ± 0.7, and +0.4 ± 0.4 mg ⋅ kg-1⋅ min-1, respectively) improved with SAXA+DAPA (P < 0.007). Mean glucagon-like peptide 1 (GLP-1) was higher with SAXA+DAPA than with SAXA or DAPA. Fasting glucagon increased with DAPA and SAXA+DAPA but not with SAXA. Fasting endogenous glucose production (EGP) increased with SAXA+DAPA and DAPA. During MMTT, EGP suppression was greater (48%) with SAXA+DAPA (vs. SAXA 44%; P = 0.02 or DAPA 34%; P = 0.2). Metabolic clearance rate of glucose (MCRglu) increased more with SAXA+DAPA. At week 4, insulin secretion rate, ß-cell glucose sensitivity, and insulin sensitivity had further increased in the SAXA+DAPA group (P = 0.02), with no additional changes in GLP-1, glucagon, fasting or MMTT EGP, or MCRglu. CONCLUSIONS: SAXA+DAPA provided superior glycemic control compared with DAPA or SAXA, with improved ß-cell function, insulin sensitivity, GLP-1 availability, and glucose clearance.

Albuminuric and non-albuminuric chronic kidney disease in type 1 diabetes: Association with major vascular outcomes risk and all-cause mortality.

AIMS: Albuminuric and non-albuminuric phenotypes of chronic kidney disease (CKD) may have different cardiovascular risk and survival in type 1 diabetes (T1DM). Herein we estimated risk of major vascular outcomes by the EURODIAB PCS score and determined all-cause mortality rate in 774 T1DM according to CKD phenotypes. METHODS: We evaluated the distribution of CKD phenotypes [no CKD, stages 1-2, non-albuminuric stage ≥3 (Alb-CKD), albuminuric stage ≥3 (Alb+CKD)], the EURODIAB risk score for major vascular outcomes [low- (LS), intermediate- (IS), and high- (HS) risk] and all-cause mortality over a follow-up of 8.25 ±â€¯2.34 years. RESULTS: Out of 774 subjects, 692 (89.4%) had no CKD, 53 (6.8%) CKD stages 1-2, 17 (2.2%) Alb-CKD and 12 (1.6%) Alb+CKD; 466 (60.2%) had LS, 205 (26.5%) IS and 103 (13.3%) HS. Distribution of HS was: no CKD, 9.1%; CKD stages 1-2, 34.0%; Alb-CKD, 64.7%; Alb+CKD, 91.7% (P < 0.0001). Mortality increased from no CKD, 3.0%; to stages 1-2, 15.1% (HR 4.504); Alb-CKD, 29.4% (8.573); Alb+CKD, 50.0% (20.683, P < 0.0001). Accounting for age and sex, HRs for mortality compared to no CKD were: CKD stages 1-2, 3.84 (P = 0.001); Alb-CKD, 2.97 (P = 0.046); Alb+CKD, 7.44 (P < 0.0001). Adjusting for sex and the EURODIAB score, HRs for mortality compared to no CKD were: CKD stages 1-2, 2.57 (P = 0.027); Alb-CKD, 2.77 (P = 0.058); Alb+CKD, 4.58 (P = 0.003). CONCLUSIONS: In our T1DM cohort, one fifth of those with CKDs were non-albuminuric. This phenotype was associated with higher risk of major outcomes and similar rate of mortality as compared to CKD stages 1-2. The greatest risk and highest mortality occur in patients with Alb+CKD.