No abstract

Risk of neurodegenerative disorders, cognitive dysfunction and impaired neuroplasticity (NP) is increased in obesity. We evaluated the effect of metabolic surgery (RYGB) on insulin sensitivity, brain glucose utilization, cognitive function and NP. Thirteen obese subjects (BMI 46±4.9 kg/m2; HbA1c 40.1±5.9 mmol/mol; age 42.4±9.8 years) with no history of psychiatric illness and psychoactive drug use and major brain disorders were recruited. Subjects underwent a 75 gr OGTT during a 60 min FDG dynamic brain PET study, standardized neurocognitive tests and NP by psychophysical technique at baseline and 6-months after RYGB. Plasma glucose, insulin, GLP-1, GIP, VIP, BDNF and leptin were measured during OGTT. After RYGB, BMI declined (45.7±1.6 to 34.3±1.6 kg/m2; p<0.001) and insulin sensitivity improved (HOMA-IR 4.7±0.9 to 1.6±0.4; P=0.006). Cerebral glucose metabolic rate (CMRg; by voxel-wise paired analysis) declined in several brain regions (p=0.005, kE>50). Token and Trail Making Test score change correlated with CMRg change in orbitofrontal (r=0.6, r=-0.81), parietal (r=0.64, r=-0.77), temporal (r=0.6, r=-0.78) and visual cortex (r=0.64, r=-0.75), hippocampus (r=0.6, r=-0.71) and caudate/putamen (r=0.64, r=-0.80; all p=0.03 or less), respectively. After RYGB, NP increased (0.01± 0.03 to 0.11±0.04; p=0.008) and correlated with CMRg change in orbitofrontal cortex (r=0.59; p=0.03) and hippocampus (r=0.58; p=0.03). CMRg of several cortical and subcortical areas correlated with HOMA-IR (p<0.001) but not with BMI. GLP-1/GIP levels increased (P<0.002) with no correlation with CMRg, VIP or BDNF levels. Fasting leptin decreased (73.8±45.5 to 14.3±5.9 pmol/l; p<0.008) and correlated with CMRg change in hippocampus (r=0.6; r=0.03). These results show that metabolic surgery modulates CMRg in brain areas involved in cognitive function and neuroplasticity, suggesting reduction of brain glucose utilization decrease may contribute to brain neuroprotection. Disclosure G. Daniele: None. A. Dardano: None. D. Volterrani: None. A. Ciccarone: None. L. Giusti: None. G. Aghakhanyan: None. G. Ceccarini: None. F. Santini: None. C. Moretto: None. P. Binda: None. C. Lunghi: None. M. Morrone: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited.

Background and Aim: Obesity and diabetes are associated to increased risk of cognitive impairment, neurodegenerative disorders, neuroinflammation and synaptic plasticity abnormalities. The aim of the study was to evaluate the effect of obesity and bariatric surgery on neural plasticity (NP). Methods: We recruited 20 normal weight subjects (NS; age 26±10 years, BMI 21.7±2.6 kg/m2) and 31 obese subjects (OB; 40±11 years; BMI: 41.6±6.7 kg/m2) in whom NP in the visual cortex was measured as change in ocular dominance after 120 min of monocular deprivation obtained by ocular patch. To explore the effect of body weight reduction on NP, 14 OB (BMI=45.7±1.6 kg/m2) underwent metabolic surgery (RYGB) and NP was measured 6 months after surgery. Hormonal and metabolic parameters were obtained before and after administration of 75g glucose (OGTT). Results: At baseline NP was lower in OB than in NS (0.04±0.vs. 0.12±0.05, p<0.0001). NP was inversely correlated with body weight (r= -0.55; p<0.001). Six-months after RYGB, BMI was markedly reduced (34.3±1.6 kg/m2; p<0.001 vs. baseline) and glucose metabolism improved (HOMA-IR from 4.7±0.9 to 1.6±0.4; P=0.0and Disposition Index from 0.07±0.02 to 0.81±0.30 mUI × ml-1/ mg × dl-1× 1/ mUI × ml-1; p< 0.05). Post-OGTT GLP-1 levels increased (AUCOGTTfrom 5457±715 to 11215±1067 pmol/l×120min; P<0.002). NP showed a 10-fold increase (0.01± 0.03 to 0.10±0.04; p=0.008) indicating restoration of visual plasticity. The NP increase was correlated to increase in active GLP-1 (r=0.86; p<0.007) and BMI reduction (r=0.10; p=0.07). Conclusion: NP is markedly altered in OB, and it is restored to normal after RYGB. The relationship between NP increase and circulating GLP-1 levels suggests a potential role of this hormone in the NP restoration in humans. Disclosure G. Daniele: None. A. Dardano: None. C. Lunghi: None. P. Binda: None. A. Ciccarone: None. F. Santini: None. G. Ceccarini: None. L. Giusti: None. R. Bellini: None. M. Seghieri: None. S. Del Guerra: None. C. Moretto: None. M. Morrone: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.

Aim: To examine the mechanisms responsible for the increase in glucose and ketone production caused by SGLT2 inhibition with empagliflozin in T2DM patients. Research Design and Methods: 12 T2DM subjects (Age = 53; BMI = 31.7; HbA1c = 7.4%) participated in two studies performed in random order. At 0700h following an overnight fast subjects received an 8-hour infusion of 6,6D2-glucose to measure endogenous (hepatic) glucose production. At 0900 h an infusion of 3H-norepinephrine was started. At 1000h subjects ingested 25 mg of empagliflozin (n=8) or matching placebo (n=4) and were followed for 5 hours (1500 h) . Within 1 week subjects returned for a repeat study with pancreatic clamp to maintain plasma insulin and glucagon concentrations constant at the basal level. As per study one, subjects ingested empagliflozin 25 mg or placebo prior to the pancreatic clamp. Results: When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (-34 mg/dl) and insulin (-52%) concentrations and increases in plasma glucagon (+19%) , FFA (+29%) and β-hydroxybutyrate (β-HB) (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate increased significantly in subjects receiving empagliflozin (+67%) compared to placebo under both fasting and pancreatic clamp conditions. No difference in plasma norepinephrine concentration was observed in either study. Conclusion: The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is explained by the increase in total-body NE turnover. Disclosure S. Abdelgani: None. J. M. Adams: None. G. Daniele: n/a. F. Almulla: None. R. A. Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker’s Bureau; AstraZeneca. M. Abdul-ghani: None. M. Abu-farha: None. S. Del prato: Advisory Panel; Applied Therapeutics, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Consultant; Menarini Group, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker’s Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi, Stock/Shareholder; Novo Nordisk A/S. Funding National Institute of Health, Boehringer Ingelheim provided empagliflozin and placebo

Background: The glucosuria induced by sodium-glucose cotransporter-2 inhibitors (SGLT2i) stimulates endogenous (hepatic) glucose production (EGP) blunting the decline in HbA1c. We hypothesized that, in response to glucosuria, a renal signal is generated and stimulated EGP. Aim: To examine the effect of acute administration of dapagliflozin (DAPA) in nondiabetic, renal transplant subjects on SGLT2i-induced stimulation of EGP. Methods: 20 subjects [10 with intact native kidneys (IK) and 10 with bilateral nephrectomy (NK)] underwent measurement of EGP ([6,6-2H2]-glucose) before and for 6 hours after administration of DAPA or placebo (PLC) on 2 separate days. Results: DAPA induced greater glucosuria in subjects with IK versus NK (8.6±1.1 vs. 5.5±0.5 grams/6-hrs; p=0.02). During 6-hour, plasma glucose decreased slightly and similarly in both groups, with no difference compared to PLC. Following PLC, there was a progressive time-related decline in EGP that was similar in both groups. Following DAPA, EGP declined in both groups but the decrement in EGP was 56% greater in the NK. During DAPA, urinary glucose excretion was correlated with EGP (r = 0.34, p<0.05). Plasma insulin, C-peptide, glucagon, pre-hepatic insulin/glucagon ratio, lactate, alanine and pyruvate concentrations were similar in PLC and DAPA. β-hydroxybutyrate increased with DAPA in the IK, while a small increase was observed only at 360 min in the NK. Plasma epinephrine did not change after DAPA and PLC in both groups. Following DAPA, plasma norepinephrine increased slightly in the IK and decreased in the NK. Conclusions: In NK subjects the hepatic compensatory response to acute SGLT2i-induced glucosuria was attenuated compared to diabetic subjects with IK, suggesting a SGLT2i-mediated stimulation of hepatic glucose production via efferent renal nerves in an attempt to compensate for the urinary glucose loss, i.e., a renal-hepatic axis. Disclosure G. Daniele: None. C. Solis-Herrera: Consultant; Self; Lexicon Pharmaceuticals, Inc. A. Dardano: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. A. Tura: None. L. Giusti: None. J.J. Kurumthodathu: None. A.A.G. Brocchi: None. B. Campi: None. A. Saba: None. A. Bianchi: None. C. Tregnaghi: None. M. Egidi: None. M. Abdul-Ghani: None. R.A. DeFronzo: None. S. DelPrato: None.