Background Coronary computed tomography angiography (CCTA) is the gold standard for non-invasive coronary atherosclerosis evaluation. Purpose To evaluate the performance of advanced atherosclerosis analysis by CCTA in predicting long-term major cardiac events in subjects enrolled in the multicenter CAPIRE study. Materials and methods CAPIRE prospectively enrolled subjects with suspected coronary artery disease (CAD) who underwent advanced plaque assessment by CCTA. Outcome measures were two combined endpoints: acute coronary syndrome (ACS) and major adverse cardiac events MACE (ACS+cardiac death+late non-urgent revascularization). Results The final CAPIRE population comprised 528 subjects (age 60 ± 8 years, 308 men). CCTA showed no CAD in 348 (65.9

Recent studies have identified relationships between diabetes mellitus and short-chain fatty acids, including 2hydroxybutyrate (2-HB) and 2-hydroxyisobutyrate (2-HiB); 2-HB has been associated to the early stages of insulin resistance, while 2-HiB with the risk and progression of complications of Type 1 diabetes. Their metabolism and pathophysiological role in humans are not fully clarified. The possible association between 2-HB and 2-HiB and diabetes mellitus was investigated with a novel mass spectrometry-based assay, capable of discriminating plasma 2-HiB and 2-HB from their HB isomers. Accuracy and precision (RSD%) were always in the range 99-102% and 0.7-3.5%, respectively. The study involved samples from subjects with normal glucose tolerance (NGT) and Type 2 diabetes (T2D), originally included in a multicenter study investigating mechanisms involved in atherothrombosis. NGT subjects exhibited concentrations of 2-HB and 2-HiB of 61 (36) and 3.1 (1.9) mu mol/L, median (interquartile range), respectively, that were significantly lower than those of the T2D patients, whose values were 74 (4.0) and 3.8 (2.9) mu mol/L, respectively. The pattern of association of these molecules with clinical and metabolic variables is partially different: both compounds were directly related to male sex, BMI, HbA1c, and plasma glucose, 2-HiB also with age, systolic blood pressure, and HDL-cholesterol. Furthermore, they correlate with free fatty acids, glycerol, and triglyceride concentrations, but the latter correlation was negative for 2-HB and positive for 2-HiB. Results confirmed the clinical significance of 2-HB and 2-HiB, in differential association with metabolic features of T2D.

OBJECTIVE:Obesity is a major cause of morbidity and mortality worldwide. Tirzepatide is a glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist providing substantial weight reduction and metabolic benefits both in type 2 diabetes and obesity. We hypothesized that tirzepatide can improve morbidity and mortality in adults with obesity or overweight but without diabetes. METHODS:SURMOUNT-MMO is a randomized, double-blind, event-driven trial to investigate the impact on morbidity and mortality with once-weekly tirzepatide compared with placebo in adults living with obesity, without diabetes, and with, or at risk of, cardiovascular disease. The primary endpoint is time to first occurrence of a five-component composite outcome of nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, heart failure events, or death from any cause. RESULTS:The trial will enroll ~15,000 participants aged ≥40 from 664 sites across 27 countries with BMI ≥27.0 kg/m2 and either established cardiovascular disease or multiple cardiovascular risk factors. CONCLUSIONS:SURMOUNT-MMO will provide evidence of the clinical benefits of tirzepatide on multiple outcomes among individuals with overweight or obesity but without diabetes. This is the first outcome trial of an incretin medication that assesses both primary and secondary cardiovascular disease prevention.

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.

Abstract Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduces liver steatosis and cardiometabolic risk (CMR). Only few data are available on lipid metabolism and no information on the postprandial lipidomic profile. Thus, we investigated how exenatide treatment changes lipid metabolism and composition during fasting and after a meal tolerance test (MTT) in adults with severe obesity without diabetes. Thirty individuals (26F/4M, 30-60 years old, BMI>40 kg/m2, HbA1c=5.76%) were assigned (1:1) to diet with exenatide treatment (EXE, n=15, 10 μg twice-daily) or without treatment as control (CT, n=15) for 3 months. Fasting and postprandial lipidomic profile (by LC/MS-QTOF) and fatty acid metabolism (following a 6-hour MTT/tracer study) and composition (by GC/MS) were evaluated before and after treatment. Both groups had slight weight loss (EXE: -5.5% vs CT: -1.9%, p=0.052). During fasting, exenatide, compared to CT, reduced some ceramides (CER) and lysophosphocholines (LPC) previously associated with CMR, while relatively increasing unsaturated phospholipid species (PC, LPC) with protective effects on CMR, although concentrations of total lipid species were unchanged. During MTT, both groups suppressed lipolysis equally to baseline, but EXE exenatide significantly lowered free fatty acid clearance and postprandial triacyclglycerols (TAG) concentrations, particularly saturated TAGs with 44-54 carbons. Exenatide also reduced some postprandial CERs, PCs, LPCs previously linked to cardiometabolic risk. These changes in lipidomic profile remained statistically significant after adjusting for weight loss. Exenatide improved fasting and postprandial lipidomic profile associated with CMR mainly by reducing saturated postprandial TAGs and CERs, independently of weight loss and diabetes. Highlights · Few data are available on the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on lipid metabolism and no information on the postprandial lipidomic profile. · In non-diabetic adults with severe obesity, 3-month treatment with exenatide improved fasting and postprandial lipidomic profile associated with cardiometabolic risk (CMR) by decreasing saturated species (TAGs, CERs, LPCs) while increasing 7 unsaturated phospholipid species (PC, LPC) with protective effects on CMR compared to control. · Exenatide blunted the rise in postprandial triglycerides especially saturated TAGs. · Postprandial triglycerides reduction was associated to decreased postprandial FFA clearance, with lower saturated FFA incorporation into newly synthesized lipids (TAGs and CERs).

Objective: The aim of this study was to investigate the impact of the sodium-glucose transporter 2 inhibitor dapagliflozin on tissue fatty acid (FA) uptake in skeletal muscle, the brain, small intestine, and subcutaneous and visceral adipose tissue in people with type 2 diabetes by using positron emission tomography (PET). Research Design and Methods: In a 6-week randomized, double-blinded, placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either dapagliflozin 10 mg or placebo daily. Tissue FA uptake was quantified at baseline and at end-of-treatment with PET and the long-chain fatty acid analogue radiotracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA). Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95 % CIs for the difference between groups. Results: 38 patients (dapagliflozin N=21, placebo N=17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin vs placebo (1.0 [0.07, 2.0] µmol.100 g-1.min-1, P=.032), whereas the uptake was not significantly changed in the small intestine, visceral and subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] µmol.100 g-1.min-1, P=.01), an effect observed in both gray and white matter regions. Conclusions: Six weeks of treatment with dapagliflozin increases skeletal muscle and brain fatty acid uptake, partly driven by a rise in FFA availability. This finding is in accordance with previous indirect measurements showing enhanced fatty acid metabolism in response to SGLT2 inhibition, and extends the notion of a shift towards increased fatty acid utilization to muscle and brain.

BACKGROUNDSodium-glucose cotransporter 2 inhibitors slow down progression of chronic kidney disease (CKD). We tested whether the circulating substrate mix is related to CKD progression and cardiovascular outcomes in patients with type 2 diabetes (T2D) and albuminuric CKD in the CREDENCE trial.METHODSWe measured fasting substrates in 2,543 plasma samples at baseline and 1 year after randomization to either 100 mg canagliflozin or placebo and used multivariate Cox models to explore their association with CKD progression, heart failure hospitalization/cardiovascular death (hHF/CVD), and mortality.RESULTSHigher baseline lactate and free fatty acids (FFAs) were independently associated with a lower risk of CKD progression (HR = 0.73 [95% CI: 0.54-0.98] and HR = 0.67 [95% CI: 0.48-0.95], respectively) and hHF/CVD HR = 0.70 [95% CI: 0.50-0.99] and HR = 0.63 [95% CI: 0.42-0.94]). Canagliflozin led to a rise in plasma FFAs, glycerol, β-hydroxybutyrate, and acetoacetate. Changes in substrate between baseline and year 1 predicted an approximately 30% reduction in relative risk of both CKD progression and hHF/CVD independently of treatment. More patients who did not respond to canagliflozin treatment in terms of CKD progression belonged to the bottom lactate and FFA distribution tertiles.CONCLUSIONIn T2D patients with albuminuric CKD, basic energy substrates selectively influenced major long-term endpoints; canagliflozin treatment amplified their effects by chronically raising their circulating levels.

The human brain undergoes metabolic adaptations in obesity, but the underlying mechanisms have remained largely unknown. We compared concentrations of often reported brain metabolites measured with magnetic resonance spectroscopy ( 1 H-MRS, 3 T MRI) in the occipital lobe in subjects with obesity and lean controls under different metabolic conditions (fasting, insulin clamp, following weight loss). Brain glucose uptake (BGU) quantified with 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET)) was also performed in a subset of subjects during clamp. In dataset A, 48 participants were studied during fasting with brain 1 H-MRS, while in dataset B 21 participants underwent paired brain 1 H-MRS acquisitions under fasting and clamp conditions. In dataset C 16 subjects underwent brain 18 F-FDG-PET and 1 H-MRS during clamp. In the fasting state, total N-acetylaspartate was lower in subjects with obesity, while brain myo-inositol increased in response to hyperinsulinemia similarly in both lean participants and subjects with obesity. During clamp, BGU correlated positively with brain glutamine/glutamate, total choline, and total creatine levels. Following weight loss, brain creatine levels were increased, whereas increases in other metabolites remained not significant. To conclude, insulin signaling and glucose metabolism are significantly coupled with several of the changes in brain metabolites that occur in obesity.

Excessive insulin secretion independent of insulin resistance, defined as primary hypersecretion, is associated with obesity and an unfavorable metabolic phenotype. We examined the characteristics of the adipose tissue in youths with primary insulin hypersecretion and the longitudinal metabolic alterations influenced by the complex adipo-insular interplay. In a multiethnic cohort of non-diabetic adolescents with obesity, primary insulin hypersecretors had enhanced model-derived β-cell glucose sensitivity and rate sensitivity, but worse glucose tolerance, despite similar demographics, adiposity, and insulin resistance measured by both OGTT and euglycemic-hyperinsulinemic clamp. Hypersecretors had greater intrahepatic and visceral fat depots at abdominal MRI, hypertrophic abdominal subcutaneous adipocytes, higher FFA and leptin serum levels per fat mass, and faster in vivo lipid turnover assessed by a long-term 2H2O labeling protocol. At 2-year follow up, hypersecretors had greater fat accrual and 3-fold higher risk for abnormal glucose tolerance, while individuals with hypertrophic adipocytes or higher leptin levels showed enhanced β-cell glucose sensitivity. Primary insulin hypersecretion is associated with marked alterations in adipose tissue distribution, cellularity, and lipid dynamics, independent of whole-body adiposity and insulin resistance. Pathogenetic insight into the metabolic crosstalk between β-cell and adipocyte may help identify individuals at risk for chronic hyperinsulinemia, body weight gain, and glucose intolerance.

Objective: To explore the associations between mannose, indexes of insulin resistance (IR) and secretion and long-term cardiovascular outcomes.Research Design and Methods: Fasting mannose was assayed in 1403 participants, half of which had a first myocardial infarction (MI), with either normal glucose tolerance (n=1045) or newly detected dysglycaemia (i.e., impaired glucose tolerance or type 2 diabetes; n=358). Regression models were used to explore mannose associations with surrogate indexes of IR/insulin secretion. Multivariate Cox models were used to investigate the independent association between “high” (higher quartile) vs. “low” (lower three quartiles) mannose and major adverse cardiac events (MACE, N=163) during 10-year follow-up.Results: Mannose was independentely associated with IR indexes (all p≤0.001). High vs. low mannose was independentely associated with MACE (hazard ratio: 1.54, 95% confidence interval 1.07-2.20) in the overall population.Conclusions: Mannose might represent a new biomarker able to track early, potentially detrimental glucometabolic alterations, independently of glycaemic state.

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.

Background Empagliflozin reduces the risk of cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM) and high cardiovascular risk via mechanisms which have not been fully explained. The mechanisms of such benefit have not been fully understood, and whether empagliflozin can be safely administered as first-line treatment in patients with CVD at the initial stages of glycaemic perturbations remains to be established. We investigated the effects of empagliflozin on insulin resistance, insulin sensitivity and β-cell function indexes in patients with a recent acute coronary event and newly detected dysglycaemia, i.e., impaired glucose tolerance (IGT) or T2DM. Methods Forty-two patients (mean age 67.5 years, 19% females) with a recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected dysglycaemia were randomized to either empagliflozin 25 mg daily (n = 20) or placebo (n = 22). Patients were investigated with stress-perfusion cardiac magnetic resonance imaging before randomization, 7 months after the start of study drug and 3 months following its cessation. Indexes of insulin resistance, sensitivity and β-cell function were calculated based on glucose and insulin values from 2-hour oral glucose tolerance tests (OGTT) and fasting C-peptide. The differences in glucose, insulin, C-peptide, mannose levels and indexes between the two groups were computed by repeated measures ANOVA including an interaction term between the treatment allocation and the time of visit. Results After 7 months, empagliflozin significantly decreased glucose and insulin values during the OGTT, whereas C-peptide, mannose and HbA1c did not differ. Empagliflozin significantly improved insulin sensitivity indexes but did not impact insulin resistance and β-cell function. After cessation of the drug, all indexes returned to initial levels. Insulin sensitivity indexes were inversely correlated with left ventricular mass at baseline. Conclusions Empagliflozin improved insulin sensitivity indexes in patients with a recent coronary event and drug naïve dysglycaemia. These findings support the safe use of empagliflozin as first-line glucose-lowering treatment in patients at very high cardiovascular risk with newly diagnosed dysglycaemia. Trial registration number EudraCT number 2015-004571-73.

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.

Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

To assess the efficacy and safety of sotagliflozin, a dual inhibitor of sodium‐glucose co‐transporters 1 and 2, in adults with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD3).

Following a diagnosis of type 1 diabetes (T1D), persisting C-peptide secretion leads to improved glycemic control and outcomes. Residual β-cell function is often assessed with serial mixed-meal tolerance tests, but these tests do not correlate well with clinical outcomes. Herein, we instead use β-cell glucose sensitivity (βGS) to assess changes in β-cell function, incorporating insulin secretion for a given serum glucose into the assessment of β-cell function. We evaluated changes in βGS in individuals enrolled in the placebo arm of 10 T1D trials performed at diabetes onset. We found that βGS showed a more rapid decline in children, as compared with adolescents and adults. Individuals in the top quartile of βGS baseline distribution had a slower rate in loss of glycemic control time over time. Notably, half of this group were children and adolescents. Finally, to identify predictors of glycemic control throughout follow-up, we ran multivariate Cox models and found that incorporating βGS significantly improved the overall model. Taken together, these data suggest that βGS may be of great utility in predicting those more likely to have a more robust clinical remission and may be of use in design of new-onset diabetes clinical trials and in evaluating response to therapies. Article Highlights We undertook this study to better predict β-cell loss following type 1 diabetes diagnosis. We set out to answer whether β-cell glucose sensitivity (βGS) improves means to evaluate β-cell function postdiagnosis and whether βGS correlates with clinical outcomes. We found that βGS declines faster in children, subjects in the top baseline quartile of βGS exhibit slower β-cell decline (half are children), and incorporating βGS into multivariate Cox models for glycemic improves the model. The implications of our findings are that βGS predicts those likely to have robust clinical remissions and may help with clinical trials design.

Thanks to technical advances in the field of medical imaging, it is now possible to study key features of renal anatomy and physiology, but so far poorly explored due to the inherent difficulties in studying both the metabolism and vasculature of the human kidney. In this narrative review, we provide an overview of recent research findings on renal perfusion, oxygenation, and substrate uptake. Most studies evaluating renal perfusion with positron emission tomography (PET) have been performed in healthy controls, and specific target populations like obese individuals or patients with renovascular disease and chronic kidney disease (CKD) have rarely been assessed. Functional magnetic resonance (fMRI) has also been used to study renal perfusion in CKD patients, and recent studies have addressed the kidney hemodynamic effects of therapeutic agents such as glucagon-like receptor agonists (GLP-1RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2-i) in an attempt to characterise the mechanisms leading to their nephroprotective effects. The few available studies on renal substrate uptake are discussed. In the near future, these imaging modalities will hopefully become widely available with researchers more acquainted with them, gaining insights into the complex renal pathophysiology in acute and chronic diseases.