AIM:Patients with type 2 diabetes (T2D) often develop metabolic inflexibility and reduced exercise capacity. We examined whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) modify substrate oxidation during exercise. METHODS:As a pre-specified exploratory analysis, aimed at understanding the relevance of circulating lipid substrate availability in the effect of empagliflozin on cardiopulmonary function, we measured fasting plasma β-hydroxybutyrate (β(OH)B) and free fatty acids in 44 patients with T2D undergoing cardiopulmonary exercise tests (CPETs) before and after 6 months of randomised therapy with empagliflozin (n = 22) or sitagliptin (n = 22). We used indirect calorimetry to estimate the rates of fat (FATox) and glucose oxidation (CHOox) and identified maximal fat oxidation (MFO) and the exercise intensity at which MFO occurs (FATmax). RESULTS:After treatment, during low-to-moderate intensity exercise (40% V ̇ O2max), FATox increased (+32 [5/65]%, p = 0.02) and CHOox decreased (-30 [-45/-1]%, p = 0.04), in the empagliflozin group only. Also, MFO (empa +0.66 [0/1.31] vs. sita -0.59 [-1.49/0.31] mg/min/kg fat-free mass, p = 0.0249) and FATmax (empa +5 [2/8] vs. sita 0 [-4/3] % V ̇ O2max, p = 0.0433) increased in the empagliflozin group. Plasma β(OH)B concentrations increased with empagliflozin (+51 [21/81] μmol/L, p = 0.012) and correlated both with MFO and with FATmax (p < 0.05). In the whole population, the improvements in FATox correlated with changes in cardiopulmonary fitness ( V ̇ O2 at peak exercise) (p < 0.01). CONCLUSIONS:Empagliflozin treatment is associated with enhanced FATox during low-to-moderate intensity exercise with unchanged substrate oxidation at rest and at high-intensity exercise. This effect, if confirmed, has the potential to produce an improvement of exercise capacity in patients with T2D. TRIAL REGISTRATION:EudraCT Code: 2016-002225-10.

AIMS/HYPOTHESIS:Sodium-glucose cotransporter 2 (SGLT2) inhibitors provide cardiovascular and renal protection in type 2 diabetes and chronic kidney disease (CKD). Although both excess and restricted sodium intake are linked to adverse outcomes, the interaction of sodium intake with SGLT2 inhibitors has not been explored. This study aimed to examine how dietary sodium intake affects cardiorenal outcomes and whether canagliflozin modifies these effects. METHODS:A post hoc analysis of the CREDENCE trial (median follow-up 2.6 years) was conducted in individuals with type 2 diabetes and CKD randomised to canagliflozin 100 mg or placebo. Using a validated formula, we estimated daily sodium intake from urine in 2573 participants, divided into low-normal sodium (LNS; n=1286) and high sodium (HS; n=1287) groups. Outcomes included the following: cardiovascular death or hospitalisation for heart failure; heart failure alone; a composite renal outcome; and all-cause death. Cox models were adjusted for confounders. Sodium intake was additionally analysed as a continuous variable to assess non-linearity. RESULTS:In the placebo group, LNS intake increased the risk of heart failure/cardiovascular death vs HS (adjusted HR [adjHR] 1.56 [95% CI 1.10, 2.23]). Canagliflozin significantly reduced this risk in the LNS group (adjHR 0.48 [95% CI 0.33, 0.70]) but not in the HS group (adjHR 1.05 [95% CI 0.73, 1.53]). Similar patterns were seen for heart failure alone. Sodium intake had no effect on renal outcomes, while canagliflozin reduced renal risk in both the LNS group and the HS group. Neither sodium intake nor canagliflozin influenced all-cause mortality. Continuous modelling revealed a near-linear rise in heart failure/cardiovascular death risk as sodium intake decreased in placebo recipients, while this gradient was flattened with canagliflozin. CONCLUSIONS/INTERPRETATION:In individuals with type 2 diabetes and CKD, LNS intake increases the risk of heart failure and cardiovascular death, while renal outcomes are unaffected by sodium intake. Canagliflozin mitigates the increased cardiovascular risk in individuals with LNS intake, while offering renal protection irrespective of dietary sodium. TRIAL REGISTRATION:Clinicaltrial.gov NCT02065791.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) lower blood pressure (BP) and provide cardiovascular protection. In animal models, SGLT2i blunt sodium-induced BP elevation, but this effect remains unexplored in humans. We investigated whether SGLT2i reduce the salt sensitivity of BP in patients with type 2 diabetes (T2D) and explored the underlying mechanisms. In an open-label, non-randomized study, 26 patients with T2D (14 on treatment with SGLT2i, 12 controls) completed two sequential 7-day dietary phases consisting of a very-low-sodium background diet with the addition of either high sodium (HS, + 4,800 mg/day) or low sodium (LS, + 1,200 mg/day). Changes in twenty-four hour ambulatory BP monitoring (24-hour ABPM), postprandial natriuresis and diuresis, plasma renin and aldosterone concentrations, glycosuria, and hydration were assessed. The median change in systolic BP between HS and LS diets was greater in controls (median [IQR] Δ24-h SBP: +5.6 [2.0, 20.3] mmHg, p = 0.005), than in the SGLT2i group (Δ24-h SBP: -1.2 [-3.6, 4.2] mmHg, p = 0.594; p = 0.007 between groups). Diastolic BP changes showed similar patterns (Δ24-h DBP: +4.6 [1.3, 9.8] mmHg vs. -1.2 [-3.1, 1.4] mmHg; p = 0.002 between groups). SGLT2i-treated participants showed enhanced postprandial natriuresis during both HS (median [IQR]: 55.0 [28.3, 126.6] µEq/min vs. -0.7 [-148.6, 109.0] µEq/min; p = 0.049) and the LS diet (18.4 [1.3, 42.2] µEq/min vs. -14.5 [-30.2, 15.7] µEq/min; p = 0.046), and postprandial diuresis during the HS diet (median [IQR]: 0.52 [0.10, 1.18] ml/min vs. -0.21 [-0.58, 0.45] ml/min p = 0.041). In response to the LS diet, renin and aldosterone levels increased markedly in controls but not in SGLT2i-treated patients. Hydration and glycosuria were unchanged and unrelated to natriuretic responses. In T2D, treatment with SGLT2 inhibitors is associated with a reduced BP response to high sodium intake, accompanied by enhanced postprandial sodium and water excretion, along with attenuated neurohormonal activation. These findings identify physiological associations that may contribute to the BP-lowering and cardiovascular protective effects of SGLT2 inhibition. NCT06007157 (registered on 18/08/2023).

Hepatic glucose flux plays a crucial role in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), promoting de novo lipogenesis, inflammation and fibrosis. This study aimed to evaluate the kinetics of oral glucose absorption and one of its key modulators, gastric emptying, in individuals with early-stage MASLD vs matched control individuals. We quantified glucose metabolic fluxes during a 75 g OGTT using stable isotopes in individuals with MASLD without fibrosis and in healthy control individuals. In a separate cohort, we measured the gastric emptying rate using the 13C-acetate breath test during an OGTT and estimated hepatic steatosis risk. Compared with the control group, in the MASLD group the rate of appearance of oral ingested glucose (RaO) normalised to body weight was 34

Context Hypertriglyceridemia is a risk factor for developing type 2 diabetes (T2D) and might contribute to its pathogenesis either directly or through elevation of nonesterified fatty acids (NEFAs). Objective This study aimed at comparing the glucometabolic effects of acute hypertriglyceridemia alone or combined with NEFA elevation in subjects without diabetes. Methods Twenty-two healthy lean volunteers underwent 5-hour intravenous infusions of either saline or Intralipid, without (n = 12) or with heparin (I + H; n = 10) to activate the release of NEFAs. Oral glucose tolerance tests (OGTTs) were performed during the last 3 hours of infusion. Insulin sensitivity, insulin secretion rate (ISR), model-derived β-cell function, and insulin clearance were measured after 2 hours of lipid infusion and during the OGTTs. Results In fasting conditions, both lipid infusions increased plasma insulin and ISR and reduced insulin clearance without affecting plasma glucose and insulin sensitivity. These effects on insulin and ISR were more pronounced for I + H than Intralipid alone. During the OGTT, the lipid infusions markedly impaired glucose tolerance, increased plasma insulin and ISR, and decreased insulin sensitivity and clearance, without significant group differences. Intralipid alone inhibited glucose-stimulated insulin secretion (ie, β-cell glucose sensitivity) and increased β-cell potentiation, whereas I + H had neutral effects on these β-cell functions. Conclusion In healthy nonobese subjects, mild acute hypertriglyceridemia directly reduces glucose tolerance and insulin sensitivity and clearance, and has selective and opposite effects on β-cell function that are neutralized by NEFAs. These findings provide new insight into plausible biological signals that generate and sustain insulin resistance and chronic hyperinsulinemia in the development of T2D.

Introduction: post-bariatric hypoglycemia (PBH) is considered a chronic complication after gastric bypass (RYGB) impacting roughly 30 % of patients. Current treatments often focus on nutritional interventions to reduce the frequency of episodes. This prospective study evaluated the effectiveness of Lisosan G (LG), a fermented wheat-based supplement added to the diet, in mitigating PBH episodes and elucidating its mechanism of action on the gut-pancreas axis. Methods: twenty subjects with PBH, who had undergone RYGB between 2015 and 2018, were enrolled. Subjects underwent clinical examination, blood test, and a 3-hour oral glucose load test (OGTT). Then, they were monitored for 2-weeks on a free diet with continuous glucose monitoring (CGM), which was extended for another 2-weeks after introduction of LG supplementation (5 g, twice daily) on the same diet. Finally, subjects repeated OGTT and blood test. PBH was defined as interstitial glucose <= 54 mg/dl. Results: after treatment, a marked reduction in PBH time was observed (75[23-113] vs 16 [0-33], minutes, p < 0.001). During OGTT, there was an increase in glucose nadir (44 +/- 11 vs 56 +/- 10, mg/dl, p = 0.038), and a significantly decrease in total GLP-1 AUC (7.6 +/- 4.1 vs 6.5 +/- 3.8, nmol/L*min, p = 0.043), in potentiation factor ratio (p = 0.037) and in total insulin AUC (57 +/- 12 vs 49 +/- 9, nmol/L*min, p = 0.043). Conclusion: LG effectively reduces PBH frequency and duration, probably by attenuating GLP-1 concentrations and leading to a decrease in the second phase of insulin secretion in response to glucose. These findings underscore the promise of LG as a novel adjunct therapy for PBH, particularly when added to the diet, and emphasize the need for further exploration into its microbiota-modulating and anti-inflammatory effects.

Abstract SGLT2 inhibitors have been shown to provide pronounced reductions in cardio-renal outcomes, including cardiovascular death, heart failure, and renal failure. The mechanisms underlying these benefits remain uncertain. We hypothesized that the effects could be attributed to the elevated glycosuria induced by these drugs. Urine concentrations of glucose, creatinine, and ketones were measured at baseline and after 1-year treatment with either placebo or canagliflozin 100mg/day in ~2600 individuals from the CREDENCE trial (enrolling patients with type 2 diabetes, chronic kidney disease, and albuminuria). Associations between glycosuria and the primary composite endpoint from CREDENCE and secondary outcomes were assessed using Cox proportional hazards models. Canagliflozin treatment increased fractional urinary glucose excretion from 3±9% at baseline to 30±26% at year 1 (vs 5±19% with placebo, p<0.001). Subjects on canagliflozin and in the top quartile of urine glucose/creatinine ratio at year 1 were significantly protected for the primary endpoint (HR=0.42 [95% C.I.:0.30–0.61]); similar results were seen for hospitalized heart failure (HR=0.45 [0.27–0.73]) and all-cause death (HR=0.56 [0.39–0.80]). These associations persisted on adjustments for multiple conventional risk factors. In patients with T2D and CKD treated with canagliflozin, individuals with the highest amount of glycosuria showed the strongest protection against multiple cardio-renal outcomes. Article Highlights § In cardiovascular outcome trials, SGLT2 inhibitors have been shown to provide marked protection against both cardiovascular morbidity and progression of kidney disease. The mechanisms underlying these effects remain imperfectly understood. § By using urine samples from patients with type 2 diabetes and kidney disease treated with canagliflozin, we asked the question of the relationship of glycosuria – the readout of SGLT2 engagement – with cardio-renal outcomes. § Individuals with the highest amount of glycosuria showed the strongest protection against multiple cardio-renal outcomes. § Glycosuria is mechanistically linked with several effects underlying cardio-renal benefit.

Postprandial hypoglycaemia (PPHG) is a frequent late complication of Roux-en-Y gastric bypass (RYGB) in people without diabetes. We aimed to examine the pathogenetic mechanisms of PPHG and its clinical consequences in people with a history of type 2 diabetes. In this case–control study, 24 participants with type 2 diabetes treated with RYGB (14 women; median [IQR] age 53.5 [13.8] years, BMI 29.3 [6.3] kg/m2, HbA1c 36.0 [6.2] mmol/mol [5.4

Abstract Context Sodium glucose co-transporter-2 inhibitors exert clinically relevant cardiorenal protection. Among several mechanisms, inhibition of sodium-hydrogen exchanger-3 (NHE3) in proximal renal tubules has been proposed in rodents. Demonstration of this mechanism with the associated electrolyte and metabolic changes in humans is lacking. Objective The present proof-of-concept study was designed to explore the involvement of NHE3 in modulating the response to sodium glucose co-transporter-2 inhibitors in humans. Methods Twenty healthy male volunteers received 2 tablets of empagliflozin 25 mg during a standardized hydration scheme; freshly voided urines and blood samples were collected at timed intervals for 8 hours. Protein expression of relevant transporters was examined in exfoliated tubular cells. Results Urine pH levels increased after empagliflozin (from 5.81 ± 0.5 to 6.16 ± 0.6 at 6 hours, P = .008) as did urinary output (from median, 1.7; interquartile range [IQR, 0.6; 2.5] to 2.5 [IQR, 1.7; 3.5] mL/min−1, P = .008) and glucose (from median, 0.03 [IQR, 0.02; 0.04] to 34.8 [IQR, 31.6; 40.2] %, P < .0001), and sodium fractional excretion rates (from median, 0.48 [IQR, 0.34; 0.65] to 0.71 [IQR, 0.55; 0.85] %, P = .0001), whereas plasma glucose and insulin concentrations decreased and plasma and urinary ketones increased. Nonsignificant changes in NHE3, phosphorylated NHE3, and membrane-associated protein 17 protein expression were detected in urinary exfoliated tubular cells. In a time-control study in 6 participants, neither urine pH nor plasma and urinary parameters changed. Conclusions In healthy young volunteers, empagliflozin acutely increases urinary pH while inducing a substrate shift toward lipid utilization and ketogenesis, without significant changes in renal NHE3 protein expression.

Aims/hypothesis Early time-restricted carbohydrate consumption (eTRC) is a novel dietary strategy that involves restricting carbohydrate-rich food intake to the morning and early afternoon to align with circadian variations in glucose tolerance. We examined the efficacy, feasibility and safety of eTRC in individuals with type 2 diabetes under free-living conditions. Methods In this randomised, parallel-arm, open label, controlled trial, participants with type 2 diabetes and overweight/obesity (age 67.2±7.9 years, 47.8% women, BMI 29.4±3.7 kg/m 2 , HbA 1c 49±5 mmol/mol [6.6±0.5%]) were randomised, using computer-generated random numbers, to a 12 week eTRC diet or a Mediterranean-style control diet with matched energy restriction and macronutrient distribution (50% carbohydrate, 30% fat and 20% protein). The primary outcome was the between-group difference in HbA 1c at 12 weeks. Body composition, 14 day flash glucose monitoring and food diary analysis were performed every 4 weeks. Mixed meal tolerance tests with mathematical beta cell function modelling were performed at baseline and after 12 weeks. Results Twelve (85.7%) participants in the eTRC arm and 11 (84.6%) participants in the control arm completed the study, achieving similar reductions in body weight and fat mass. The two groups experienced comparable improvements in HbA 1c (−3 [−6, −0.3] mmol/mol vs −4 [−6, −2] mmol/mol, corresponding to −0.2 [−0.5, 0]% and −0.3 [−0.5, −0.1]%, respectively, p =0.386), fasting plasma glucose, flash glucose monitoring-derived glucose variability and mixed meal tolerance test-derived glucose tolerance, insulin resistance, insulin clearance and plasma glucagon levels, without changes in model-derived beta cell function parameters, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide and non-esterified fatty acid levels. The two diets similarly reduced liver function markers and triglyceride levels, being neutral on other cardiometabolic and safety variables. In exploratory analyses, diet-induced changes in body weight and glucometabolic variables were not related to the timing of carbohydrate intake. Conclusions/interpretation The proposed eTRC diet provides a feasible and effective alternative option for glucose and body weight management in individuals with type 2 diabetes, with no additional metabolic benefits compared with conventional dieting. Trial registration ClinicalTrials.gov NCT05713058 Funding This study was supported by the European Society for Clinical Nutrition and Metabolism (ESPEN) and the Italian Society of Diabetology (SID). Graphical Abstract

Aim To investigate the impact of epicardial adipose tissue (EAT) thickness on cardiopulmonary performance in patients with type 2 diabetes (T2D) and normal heart function. Materials and methods We analysed EAT thickness in subjects with T2D and normal biventricular systo-diastolic functions undergoing a maximal cardiopulmonary exercise test combined with stress echocardiography, speckle tracking and pulmonary function assessment, as well as serum N-terminal pro B-type natriuretic peptide (NT-proBNP). Results In the 72 subjects enrolled, those with EAT thickness above the median (> 5 mm) showed higher body fat mass, smaller indexed left ventricular dimensions and marginally reduced diastolic function variables at rest. Higher EAT thickness was associated with lower peak oxygen uptake (VO2peak 17.1 +/- 3.6 vs. 21.0 +/- 5.7 ml/min/kg, P = .001), reduced systolic reserve (Delta S ' 4.6 +/- 1.6 vs. 5.8 +/- 2.5 m/s, P = .02) and higher natriuretic peptides (NT-proBNP 64 [29-165] vs. 31 [26-139] pg/ml, P = .04), as well as chronotropic insufficiency and impaired heart rate recovery. Ventilatory variables and peripheral oxygen extraction were not different between groups. EAT was independently associated with VO2peak and linearly and negatively correlated with peak heart rate, heart rate recovery, workload, VO2 at the anaerobic threshold and at peak, and cardiac power output, and was directly correlated with natriuretic peptides. Conclusion Higher EAT thickness in T2D is associated with worse cardiopulmonary performance and multiple traits of subclinical cardiac systolic dysfunction.

Abstract Background The mechanism through which sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent the incidence of heart failure and/or affect cardiac structure and function remains unclear. Methods The EMPA-HEART trial is aimed at verifying whether empagliflozin improves myocardial contractility (left ventricle global longitudinal strain, LV-GLS) and/or cardiopulmonary fitness (peak oxygen uptake, VO2peak) in subjects with type 2 diabetes (T2D) without heart disease. Patients with T2D, normal LV systolic function (2D-Echo EF > 50%), and no heart disease were randomized to either empagliflozin 10 mg or sitagliptin 100 mg for 6 months and underwent repeated cardiopulmonary exercise tests with echocardiography and determination of plasma biomarkers. Results Forty-four patients completed the study, 22 per arm. Despite comparable glycaemic control, modest reductions in body weight (− 1.6; [− 2.7/− 0.5] kg, p = 0.03) and plasma uric acid (− 1.5; [− 2.3/− 0.6], p = 0.002), as well as an increase in haemoglobin (+ 0.7; [+ 0.2/+ 1.1] g/dL, p = 0.0003) were evident with empagliflozin. No difference was detectable in either LV-GLS at 1 month (empagliflozin vs sitagliptin: + 0.44; [− 0.10/+ 0.98]%, p = 0.11) and 6 months of therapy (+ 0.53; [− 0.56/+ 1.62]%), or in VO 2peak (+ 0.43; [− 1.4/+ 2.3] mL/min/kg, p = 0.65). With empagliflozin, the subgroup with baseline LV-GLS below the median experienced a greater increase (time*drug p < 0.05) in LV-GLS at 1 month (+ 1.22; [+ 0.31/+ 2.13]%) and 6 months (+ 2.05; [+ 1.14/+ 2.96]%), while sitagliptin induced a modest improvement in LV-GLS only at 6 months (+ 0.92; [+ 0.21/+ 0.62]%). Conclusions Empagliflozin has neutral impact on both LV-GLS and exercise tolerance in subjects with T2D and normal left ventricular function. However, in patients with subclinical dysfunction (LV-GLS < 16.5%) it produces a rapid and sustained amelioration of LV contractility. Trial registration EUDRACT Code 2016-002225-10

Aims: Hypertriglyceridemia is associated with an increased risk of type 2 diabetes. We aimed to comprehensively examine the effects of hypertriglyceridemia on major glucose homeostatic mechanisms involved in diabetes progression. Methods: In this randomized, cross-over, single-blinded study, two dual-labeled, 3-hour oral glucose tolerance tests were performed during 5-hour intravenous infusions of either 20 % Intralipid or saline in 12 healthy subjects (age 27.9 +/- 2.6 years, 11 men, BMI 22.6 +/- 1.4 kg/m2) to evaluate lipid-induced changes in insulin metabolism and glucose kinetics. Insulin sensitivity, beta cell secretory function, and insulin clearance were assessed by modeling glucose, insulin and C-peptide data. Intestinal glucose absorption, endogenous glucose production, and glucose clearance were assessed from glucose tracers. The effect of triglycerides on beta-cell secretory function was examined in perifusion experiments in murine pseudoislets and human pancreatic islets. Results: Mild acute hypertriglyceridemia impaired oral glucose tolerance (mean glucose: +0.9 [0.3, 1.5] mmol/L, p = 0.008) and whole-body insulin sensitivity (Matsuda index: -1.67 [-0.50, -2.84], p = 0.009). Post-glucose hyperinsulinemia (mean insulin: +99 [17, 182] pmol/L, p = 0.009) resulted from reduced insulin clearance (-0.16 [-0.32, -0.01] L min- 1 m- 2, p = 0.04) and enhanced hyperglycemia-induced total insulin secretion (+11.9 [1.1, 22.8] nmol/m2, p = 0.02), which occurred despite a decline in model-derived beta cell glucose sensitivity (-41 [-74, -7] pmol min-1 m- 2 mmol- 1 L, p = 0.04). The analysis of tracer-derived glucose metabolic fluxes during lipid infusion revealed lower glucose clearance (-96 [-152, -41] mL/kgFFM, p = 0.005), increased 2-hour oral glucose absorption (+380 [42, 718] mu mol/kgFFM, p = 0.04) and suppressed endogenous glucose production (-448 [-573, -123] mu mol/kgFFM, p = 0.005). High-physiologic triglyceride levels increased acute basal insulin secretion in murine pseudoislets (+11 [3, 19] pg/aliquot, p = 0.02) and human pancreatic islets (+286 [59, 512] pg/islet, p = 0.02). Conclusion: Our findings support a critical role for hypertriglyceridemia in the pathogenesis of type 2 diabetes in otherwise healthy individuals and dissect the glucose homeostatic mechanisms involved, encompassing insulin sensitivity, beta cell function and oral glucose absorption.

Background and aims: The severity of the atherosclerotic burden is hardly quantifiable in subjects at high cardiovascular (CV) risk under intensive pharmacological therapy. Several molecules have been proposed as circulating biomarkers of atherosclerosis, but none has emerged as clinically meaningful. Methods: Circulating proteins involved in inflammation, plaque remodeling, smooth muscle cell migration, apoptosis and endothelial activity were measured by Proximity Extension Assay in the SUMMIT study cohort (n = 1500), including patients with type 2 diabetes (66%) and established CV disease (50%), who underwent ultrasound assessment of carotid atherosclerosis with total plaque area quantification. Results: In patients with evidence of carotid artery atherosclerosis (n = 1174), seven biomarkers were identified as the more closely related to atherosclerosis extension. Compared with a multivariable model including major traditional CV risk factors, the percentage gain of explained variability in total plaque area was the greatest (33%) after inclusion of CD40 receptor (CD40R) ligand, followed by PDGF (30%), CD40R (26%), EGF (22%), CXCL1 (15%), HBEGF and MMP-17 (both 11%). The relationship of total plaque area with CD40R, PDGF was hyperbolic. In the whole study cohort, including subjects without carotid plaques, CD40R was the strongest predictor of the presence and extension of carotid atherosclerosis. Subjects in the third CD40R tertile had a more than two-fold greater atherosclerotic burden compared with lower CD40R tertiles, despite an only marginally higher load of CV risk factors. Conclusions: CD40R stands among an extended set of plausible atherosclerosis-related biomarkers as the most powerful predictor of carotid atherosclerosis burden in a high CV risk cohort.

Nutritional science is gaining increasing attention due to the implicit potential to prevent cardio-metabolic diseases. It is also becoming clear that food-making process might influence the metabolic response to the meal. We have conducted a proof-of-concept study to investigate whether slowly processed pasta might positively impact glucose homeostasis. A total of 14 healthy male volunteers underwent two different mixed-meal tests in a randomized order. One meal was composed of 100 g of normally processed pasta and the other 100 g of slowly processed pasta. Each meal was completed with 10 g of olive oil and 10 g of parmesan cheese. Glucose, insulin, and incretin post-prandial responses were assessed at 15, 30, 60, 90, 120, 150, and 180 min. Glucose tolerance, insulin, and incretin response were unaffected by the two different pasta types. However, a slight difference was evident in the shape of the curve of post-prandial insulin (i.e., mildly delayed with the slowly processed pasta). Despite the common belief of a different impact of normally processed and slowly processed pasta on glucose metabolism, they show a superimposable post-prandial metabolic response after a single meal in male healthy individuals. Further studies are required to confirm these results also in chronic, real-life settings and then to translate them to metabolically impaired individuals.

Low-calorie Mediterranean-style or low-carbohydrate dietary regimens are widely used nutritional strategies against obesity and associated metabolic diseases, including type 2 diabetes. The aim of this study was to compare the effectiveness of a balanced Mediterranean diet with a low-carbohydrate diet on weight loss and glucose homeostasis in morbidly obese individuals at high risk to develop diabetes. Insulin secretion, insulin clearance, and different β-cell function components were estimated by modeling plasma glucose, insulin and C-peptide profiles during 75-g oral glucose tolerance tests (OGTTs) performed at baseline and after 4 weeks of each dietary intervention. The average weight loss was 5%, being 58% greater in the low-carbohydrate-group than Mediterranean-group. Fasting plasma glucose and glucose tolerance were not affected by the diets. The two dietary regimens proved similarly effective in improving insulin resistance and fasting hyperinsulinemia, while enhancing endogenous insulin clearance and β-cell glucose sensitivity. In summary, we demonstrated that a low-carbohydrate diet is a successful short-term approach for weight loss in morbidly obese patients and a feasible alternative to the Mediterranean diet for its glucometabolic benefits, including improvements in insulin resistance, insulin clearance and β-cell function. Further studies are needed to compare the long-term efficacy and safety of the two diets.

Chronic hypertriglyceridemia is associated with reduced glucose tolerance. Whether this association is mediated by triglycerides or free fatty acids (FFA) and which mechanisms are involved is unclear. To examine the effect of excess triglycerides alone or combined with FFA, two matched groups of healthy volunteers underwent 5h IV infusions of either saline or Intralipid without (n=12) or with heparin (I+H; n=10), during which 3h oral glucose tolerance tests (OGTT) were performed. Plasma triglycerides reached similar high-physiological levels during both lipid infusions (~2.5 mmol/L) while FFAs were markedly higher during I+H (AUC 249 [130] vs. 77 [20] mmol/L, p=0.0001). At baseline, Intralipid reduced insulin clearance while I+H increased insulin secretion and reduced insulin sensitivity and clearance. Both lipid infusions impaired glucose tolerance. Intralipid inhibited glucose-stimulated insulin secretion (i.e., β-cell glucose sensitivity), stimulated potentiation, and reduced insulin sensitivity and clearance, while I+H induced a greater impairment in insulin sensitivity but enhanced the dynamic component of insulin secretion (i.e., β-cell rate sensitivity). Acute hypertriglyceridemia impairs glucose tolerance in healthy subjects by reducing insulin sensitivity and β-cell glucose sensitivity. A concomitant increase in FFA further reduces insulin sensitivity while enhancing β-cell function.View largeDownload slideView largeDownload slide DisclosureD. Trico: None. B. D. Astiarraga: None. M. Seghieri: None. A. Mengozzi: None. S. Baldi: None. A. Mari: Research Support; Self; Eli Lilly and Company. A. Natali: None.FundingEuropean Foundation for the Study of Diabetes

Postprandial hyperglycemia interferes with vascular reactivity and is a strong predictor of cardiovascular disease. Macronutrient preloads reduce postprandial hyperglycemia in subjects with impaired glucose tolerance (IGT) or type 2 diabetes (T2D), but the effect on endothelial function is unknown. Therefore, we examined whether a protein/lipid preload can attenuate postprandial endothelial dysfunction by lowering plasma glucose responses in subjects with IGT/T2D. Endothelial function was assessed by the reactive hyperemia index (RHI) at fasting, 60 min and 120 min during two 75 g oral glucose tolerance tests (OGTTs) preceded by either water or a macronutrient preload (i.e., egg and parmesan cheese) in 22 volunteers with IGT/T2D. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, free fatty acids, and amino acids were measured through each test. RHI negatively correlated with fasting plasma glucose. During the control OGTT, RHI decreased by 9% and its deterioration was associated with the rise in plasma glucose. The macronutrient preload attenuated the decline in RHI and markedly reduced postprandial glycemia. The beneficial effect of the macronutrient preload on RHI was proportional to the improvement in glucose tolerance and was associated with the increase in plasma GLP-1 and arginine levels. In conclusion, a protein/lipid macronutrient preload attenuates glucose-induced endothelial dysfunction in individuals with IGT/T2D by lowering plasma glucose excursions and by increasing GLP-1 and arginine levels, which are known regulators of the nitric oxide vasodilator system.