Neglected cardiometabolic risk factors and subclinical target organ damage in post-menopausal women with normal glucose tolerance.

BACKGROUND: Menopausal transition is a crucial step in the women's cardiovascular health, and the risk stratification in apparently health post-menopausal females has been rarely assessed. Heart ultrasonography, unusually performed in such subjects, would be able to detect initial signs of organ damage. We described the cardiovascular risk profile of non-diabetic post-menopausal women, evaluating how easily computed, biochemistry-derived scores were related to ultrasonographic measures of target organ damage. METHODS: We analyzed the characteristics of a cohort of two-hundred and seventy-three women consecutively referring to a prevention program of Azienda Ospedaliero-Universitaria Pisana (years 2017-2022) who underwent clinical evaluation, complete routine biochemical analyses with proxies of insulin resistance, heart and carotid ultrasonography. The cohort was further divided into four groups according to presence of isolated hypercholesterolemia (HC, 37%), isolated hypertension (HT, 5%), both HC/HT (38%), or none of them. RESULTS: In HC and HC/HT, LDL cholesterol was sharply above the recommended values (149 [134-171] mg/dL and 141 [123-159] mg/dL, respectively). E/e' ratio and left atrium size were augmented in HT women and further worsened in HT/HC, with an independent effect of hypertension (E/e' ß=0.055, P=0.013, left atrium volume ß=0.059, P=0.003). Presence of carotid plaques was independently linked to hypertension (ß=0.474, P=0.003). In HC and HC/HT, the Triglycerides-Glucose Index, a surrogate of insulin resistance, was higher than in the other classes (P=0.0013), and it was associated with E/A in HC and HT/HC, with a significative interaction (P=0.0004) with hypertension. Past hormone replacement therapy did not influence clinical, biochemical or echocardiographic parameters. CONCLUSIONS: Postmenopausal women display a high cardiovascular risk burden; a simple clinical and biochemistry screening would be advisable to identify and treat those more at risk. Cardiac ultrasonographic parameters were worse in hypertensive, hypercholesterolemic and insulin-resistant subjects, who may also deserve a deep and early instrumental characterization, especially when these conditions are associated.

Cardioprotective effects of glucagon-like peptide 1 receptor agonists in heart failure: Myth or truth?

Therapy with glucagon-like peptide 1 (GLP1) receptor agonists has raised great interest for its beneficial cardiovascular effects in preventing atherosclerosis and heart failure-related outcomes. However, while evidence about atherosclerosis consistently suggests a cardioprotective potential with class effect, controversies remain on its impact on heart failure. GLP1 receptor agonists appear to prevent hospitalization for new-onset heart failure and reduce symptoms in heart failure with preserved ejection fraction (as demonstrated by the recent STEP-HFpEF Trial). Still, GLP1 agonism has resulted in neutral or even harmful effects in patients with established heart failure with reduced ejection fraction (the LIVE trial). GLP1 receptor agonists benefit the cardiovascular system indirectly through their marked metabolic effects (improved weight management, glycemic control, blood pressure, systemic and tissue inflammation), while direct effects on the heart have been questioned. Nonetheless, weight loss alone achieved through GLP1 receptor agonists has failed in improving left ventricular functions. Tirzepatide is a dual agonist of GLP1 and glucose-dependent insulinotropic polypeptide, representing an innovative treatment option in diabetes with a major impact on weight loss and promising cardiovascular benefits. Whether this class of therapies is going to change the history of heart failure is an ongoing debate.

Effects of hypertriglyceridemia with or without NEFA elevation on ß-cell function and insulin clearance and sensitivity.

AIMS: Hypertriglyceridemia is a risk factor for developing type 2 diabetes (T2D) and might contribute to its pathogenesis either directly or through elevation of non-esterified fatty acids (NEFAs). This study aimed at comparing the glucometabolic effects of acute hypertriglyceridemia alone or combined with NEFA elevation in non-diabetic subjects. METHODS: Twenty-two healthy lean volunteers underwent two 5-h 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 3h of infusion. Insulin sensitivity, insulin secretion rate (ISR), model-derived ß-cell function, and insulin clearance were measured after 2h 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 (i.e. ß-cell glucose sensitivity) and increased ß-cell potentiation, whereas I+H had neutral effects on these ß-cell functions. CONCLUSION: In healthy non-obese subjects, mild acute hypertriglyceridemia directly reduces glucose tolerance, insulin sensitivity and clearance, and has selective and opposite effects on ß-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.

Isomaltulose Enhances GLP-1 and PYY Secretion to a Mixed Meal in People With or Without Type 2 Diabetes as Compared to Saccharose.

SCOPE: Secretion of the gut hormones glucagon-like peptide (GLP-1) and peptide YY (PYY) are induced by nutrients reaching the lower small intestine which regulate insulin and glucagon release, inhibit appetite, and may improve ß-cell regeneration. The aim is to test the effect of a slowly digested isomaltulose (ISO) compared to the rapidly digested saccharose (SAC) as a snack given 1 h before a standardized mixed meal test (MMT) on GLP-1, PYY, glucose-dependent insulinotropic peptide (GIP), and metabolic responses in participants with or without type 2 diabetes (T2DM). METHODS AND RESULTS: Fifteen healthy volunteers and 15 patients with T2DM consumed either 50 g ISO or SAC 1 h preload of MMT on nonconsecutive days. Clinical parameters and incretin hormones are measured throughout the whole course of MMT. Administration of 50 g ISO as compared to SAC induced a significant increase in GLP-1, GIP, and PYY responses over 2 h after intake of a typical lunch in healthy controls. Patients with T2DM showed reduced overall responses of GLP-1 and delayed insulin release compared to controls while ISO significantly enhanced the GIP and almost tripled the PYY response compared to SAC. CONCLUSION: A snack containing ISO markedly enhances the release of the metabolically advantageous gut hormones PYY and GLP-1 and enhances GIP release in response to a subsequent complex meal.

Prevalence and risk factors of glomerular hyperfiltration in adults with type 2 diabetes: A population-based study.

AIMS: Glomerular hyperfiltration characterises the earliest stage of diabetic nephropathy and predicts adverse kidney and cardiovascular outcomes. We aimed to assess the prevalence and risk factors of glomerular hyperfiltration in a population-based contemporary cohort of individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: The prevalence of unequivocal glomerular hyperfiltration (defined by an estimated glomerular filtration rate >120 mL/min/1.73 m2 ) and its associated risk factors were identified in a cohort of 202,068 adult patients with T2D receiving specialist care in 2021-2022, whose center-aggregated data were automatically extracted from electronic medical records of 75 diabetes clinics in Italy. RESULTS: Glomerular hyperfiltration was identified in 1262 (0.6%) participants. The prevalence of glomerular hyperfiltration varied widely across centers (0%-3.4%) and correlated with mean center age, HbA1c , body mass index (BMI), and low-density lipoprotein cholesterol. Patients in centers with high glomerular hyperfiltration prevalence (>0.8%) were more often men and had lower age and BMI, but more frequent albuminuria and worse glucose, lipid, and blood pressure control, compared with low-normal prevalence centers. CONCLUSIONS: Unequivocal glomerular hyperfiltration can be identified in up to 3.4% of patients receiving up-to-date specialist diabetes care. Glomerular hyperfiltration prevalence varies across centers and substantially increases with suboptimal control of metabolic risk factors, which would require improved management to mitigate the negative health consequences of this pathological condition.

Overall survival, disease-free survival and quality of life in patients affected by HPV mediated p16+ oropharyngeal squamous cell carcinoma treated with upfront trans-oral robotic surgery vs radiotherapy or chemoradiotherapy.

PURPOSE: Treatment de-intensification for p16 + oropharyngeal squamous cell carcinoma (OPSCC) is an area of active research to reduce the side effects and improve patients' quality of life (QoL). In this paper we evaluated the Overall Survival (OS), the Disease-Free Survival (DFS) and the QoL of patients affected by p16 + OPSCC according to their prognostic stage group (PSG) and different treatments. METHODS: Patients were selected retrospectively through our Electronic Tumor Board Database according to prespecified inclusion criteria. Basic data of eligible patients were recorded and analyzed. Then, OS and DFS were evaluated according to the PSG and the treatments performed. Patients alive completed three questionnaires: the QoL Questionnaire Core 30 (QLQ-C30), the QoL Questionnaire Head & Neck 43 (QLQ-HN43) and the MD Anderson Dysphagia Inventory (MDADI) questionnaire. RESULTS: Sixty-one patients were included in this study. Eight patients died from the disease and the remaining 53 patients completed the 3 questionnaires. Fifteen (25%) patients were treated with upfront surgery, 6 (10%) patients with definitive radiotherapy and 40 (65%) patients with concomitant chemoradiotherapy. Comparing the DFS and the OS of PSG I patients by the different treatments performed, no statistically significant difference was identified. Patients treated with upfront surgery showed better outcomes in some aspects of their QoL. CONCLUSION: For p16 + OPSCC PSG I patients, upfront surgery can be considered a valid alternative to radiotherapy or chemoradiotherapy while maintaining a comparable DFS and OS and giving patients better results in terms of specific aspects of their QoL.

Learning prevalent patterns of co-morbidities in multichronic patients using population-based healthcare data.

The prevalence of longstanding chronic diseases has increased worldwide, along with the average age of the population. As a result, an increasing number of people is affected by two or more chronic conditions simultaneously, and healthcare systems are facing the challenge of treating multimorbid patients effectively. Current therapeutic strategies are suited to manage each chronic condition separately, without considering the whole clinical condition of the patient. This approach may lead to suboptimal clinical outcomes and system inefficiencies (e.g. redundant diagnostic tests and inadequate drug prescriptions). We develop a novel methodology based on the joint implementation of data reduction and clustering algorithms to identify patterns of chronic diseases that are likely to co-occur in multichronic patients. We analyse data from a large adult population of multichronic patients living in Tuscany (Italy) in 2019 which was stratified by sex and age classes. Results demonstrate that (i) cardio-metabolic, endocrine, and neuro-degenerative diseases represent a stable pattern of multimorbidity, and (ii) disease prevalence and clustering vary across ages and between women and men. Identifying the most common multichronic profiles can help tailor medical protocols to patients' needs and reduce costs. Furthermore, analysing temporal patterns of disease can refine risk predictions for evolutive chronic conditions.

Simple proxies of insulin resistance identify obese metabolic dysfunction-associated fatty liver disease subjects with advanced liver disease.

AIMS: Insulin resistance (IR) plays a pivotal role in the pathogenesis of Metabolic dysfunction-Associated Fatty Liver Disease (MAFLD), which can progress to liver fibrosis. We examined the relationship of different IR scores with markers of MAFLD severity in obese individuals. MATERIALS AND METHODS: In this retrospective observational study, 346 non-diabetic, overweight/obese individuals with newly diagnosed MAFLD (age 50.2 ± 13.3 years, 34% females, BMI 30.8 ± 4.4 kg/m2 ) underwent liver stiffness (LS) and controlled attenuation parameter (CAP) measurements by Fibroscan® to assess liver fibrosis and steatosis. Biochemical data were collected to calculate surrogate markers of IR (Homoeostasis model assessment - insulin resistance index [HOMA-IR], triglyceride-glucose index, triglyceride by HDL ratio), liver fibrosis (Nonalcoholic Fatty Liver Diseases fibrosis score, fibrosis-4 score, Aspartate aminotransferase to platelet ratio index) and steatosis (fatty liver index, hepatic steatosis index). RESULTS: All three IR scores were associated with CAP, while only HOMA-IR positively correlated with LS (r = 0.275, p < 0.0001), independent of age and sex, BMI, transaminases, and fibrosis markers. Insulin-resistant individuals (HOMA-IR >2.5, n = 165) had higher liver enzymes, CAP and LS, with a 4-fold increased risk of severe liver disease (LS >9.7 kPa, OR 4.42[1.95-10.01], p = 0.0002). Among HOMA-IR components, fasting plasma insulin (FPI) was independently associated with LS (r = 0.270, p < 0.0001). ROC AUC for HOMA-IR and FPI to predict severe liver disease were virtually identical (0.748 and 0.758, respectively). CONCLUSIONS: HOMA-IR is independently associated with non-invasive markers of MAFLD severity in overweight/obese individuals. This relationship is largely mediated by hyperinsulinemia, regardless of BMI. Measuring insulin levels in MAFLD individuals might be useful to identify those at risk of liver fibrosis.

Early time-restricted carbohydrate consumption vs conventional dieting in type 2 diabetes: a randomised controlled trial.

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/m2, HbA1c 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 HbA1c 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 HbA1c (-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).

Distinct effects of type 2 diabetes and obesity on cardiopulmonary performance.

AIM: Effort intolerance is frequent in patients with overweight/obesity and/or type 2 diabetes (T2D) free from cardiac and respiratory disease. We sought to quantify the independent effects of T2D and body mass index (BMI) on cardiopulmonary capacity and gain insights on the possible pathophysiology by case-control and regression analyses. METHODS: Patients at high/moderate cardiovascular risk, with or without T2D, underwent spirometry and combined echocardiography-cardiopulmonary exercise test as part of their clinical workup. Subjects with evidence of cardiopulmonary disease were excluded. The effects of T2D and obesity were estimated by multivariable models accounting for known/potential confounders and the major pathophysiological determinants of oxygen uptake at peak exercise (VO2peak ) normalized for fat-free mass (FFM). RESULTS: In total, 109 patients with T2D and 97 controls were included in the analysis. The two groups had similar demographic and anthropometric characteristics except for higher BMI in T2D (28.6 ± 4.6 vs. 26.3 ± 4.4 kg/m2 , p = .0003) but comparable FFM. Patients with T2D achieved lower VO2peak than controls (18.5 ± 4.4 vs. 21.7 ± 8.3 ml/min/kg, p = .0006). Subclinical cardiovascular dysfunctions were observed in T2D: concentric left ventricular remodelling, autonomic dysfunction, systolic dysfunction and reduced systolic reserve. After accounting for confounders and major determinants of VO2peakFFM , T2D still displayed reduced VO2peak by 1.0 (-1.7/-0.3) ml/min/kgFFM , p = .0089, while the effect of BMI [-0.2 (-0.3/0.1) ml/min/kgFFM , p = .06 per unit increase], was largely explained by a combination of chronotropic incompetence, reduced peripheral oxygen extraction, impaired systolic reserve and ventilatory (in)efficiency. CONCLUSIONS: T2D is an independent negative determinant of VO2peak whose effect is additive to other pathophysiological determinants of oxygen uptake, including BMI.

Incretin effect determines glucose trajectory and insulin sensitivity in youths with obesity.

In youths with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on ß cell function and insulin sensitivity. Youths with obesity and 2-hour glucose level ≥ 120 mg/dL underwent a 3-hour oral glucose-tolerance test (OGTT) and an isoglycemic i.v. glucose infusion to quantify the incretin effect. After 2 years, 30 of 39 participants had a repeated OGTT and were stratified into 3 tertiles according to the baseline incretin effect. The high-incretin effect group demonstrated a longitudinal increase in ß cell function (disposition index, minimal model [DIMM]), with greater insulin sensitivity at follow-up and stable insulin secretion (φtotal). A lower incretin effect at baseline was associated with higher 1-hour and 2-hour glucose level at follow-up. The high-incretin effect group displayed a greater increase of GLP-17-36 than the moderate- and low-incretin group at baseline, while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin in respect to the high-incretin group. The incretin effect during pubertal transition affected the longitudinal trajectory of ß cell function and weight in youths with obesity.

Alterations in adipose tissue distribution, cell morphology and function mark primary insulin hypersecretion in youths with 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 ß-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 ß-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 ß-cell and adipocyte may help identify individuals at risk for chronic hyperinsulinemia, body weight gain, and glucose intolerance.

Incretins and cardiovascular disease: to the heart of type 2 diabetes?

Major cardiovascular outcome trials and real-life observations have proven that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), regardless of structural GLP-1 homology, exert clinically relevant cardiovascular protection. GLP-1RAs provide cardioprotective benefits through glycaemic and non-glycaemic effects, including improved insulin secretion and action, body-weight loss, blood-pressure lowering and improved lipid profile, as well as via direct effects on the heart and vasculature. These actions are likely combined with anti-inflammatory and antioxidant properties that translate into robust and consistent reductions in atherothrombotic events, particularly in people with type 2 diabetes and established atherosclerotic CVD. GLP-1RAs may also have an impact on obesity and chronic kidney disease, conditions for which cardiovascular risk-reducing options are limited. The available evidence has prompted professional and medical societies to recommend GLP-1RAs for mitigation of the cardiovascular risk in people with type 2 diabetes. This review summarises the clinical evidence for cardiovascular protection with use of GLP-1RAs and the main mechanisms underlying this effect. Moreover, it looks into how the availability of upcoming dual and triple incretin receptor agonists might expand the possibility for cardiovascular protection in people with type 2 diabetes.

Nutrients and Cardiometabolic Health in Type 2 Diabetes.

Paralleling the obesity pandemic, the prevalence and socioeconomic burden of type 2 diabetes are growing worldwide, requiring immediate attention and novel cost-effective preventive and therapeutic strategies [...].

Comparison of Metabolic Response to Colonic Fermentation in Lean Youth vs Youth With Obesity.

Importance: Pediatric obesity is a growing health care burden. Understanding how the metabolic phenotype of youth with obesity may modify the effect of intestinal fermentation on human metabolism is key to designing early intervention. Objective: To assess whether adiposity and insulin resistance in youth may be associated with colonic fermentation of dietary fibers and its production of acetate, gut-derived hormone secretion, and adipose tissue lipolysis. Design, Setting, and Participants: Cross-sectional study of youths aged 15 to 22 years with body mass index in the 25th to 75th percentile or higher than the 85th percentile for age and sex throughout the New Haven County community in Connecticut. Recruitment, studies, and data collection occurred from June 2018 to September 2021. Youths were assigned to a lean, obese insulin sensitive (OIS), or obese insulin resistant (OIR) group. Data were analyzed from April 2022 to September 2022. Exposure: Participants consumed 20 g of lactulose during a continuous 10-hour sodium d3-acetate intravenous infusion to measure the rate of appearance of acetate in plasma. Main Outcomes and Measures: Plasma was obtained hourly to measure acetate turnover, peptide tyrosine tyrosine (PYY), ghrelin, active glucagon-like peptide 1 (GLP-1), and free fatty acids (FFA). Results: A total of 44 youths participated in the study (median [IQR] age, 17.5 [16.0-19.3] years; 25 [56.8%] were female; 23 [52.3%] were White). Consequent to lactulose ingestion, there was a reduction of plasma FFA, an improvement of adipose tissue insulin sensitivity index, an increase in colonic acetate synthesis, and an anorexigenic response characterized by an increased plasma concentration of PYY and active GLP-1 and a reduction of ghrelin in the subgroups. Compared with the lean and OIS groups, the OIR group showed a less marked median (IQR) rate of acetate appearance (OIR: 2.00 [-0.86 to 2.69] µmol × kg-1 × min-1; lean: 5.69 [3.04 to 9.77] µmol × kg-1 × min-1; lean vs OIR P = .004; OIS: 2.63 [1.22 to 4.52] µmol × kg-1 × min-1; OIS vs OIR P = .09), a blunted median (IQR) improvement of adipose insulin sensitivity index (OIR: 0.043 [ 0.006 to 0.155]; lean: 0.277 [0.220 to 0.446]; lean vs OIR P = .002; OIS: 0.340 [0.048 to 0.491]; OIS vs OIR P = .08), and a reduced median (IQR) PYY response (OIR: 25.4 [14.8 to 36.4] pg/mL; lean: 51.3 [31.6 to 83.3] pg/mL; lean vs OIR P = .002; OIS: 54.3 [39.3 to 77.2] pg/mL; OIS vs OIR P = .011). Conclusions and Relevance: In this cross-sectional study, lean, OIS, and OIR youth demonstrated different associations between colonic fermentation of indigestible dietary carbohydrates and the metabolic response, with OIR youth showing minimal metabolic modifications as compared with the other 2 groups. Trial Registration: ClinicalTrials.gov Identifier: NCT03454828.

Proatherogenic changes in lipoprotein particles associated with a high triglyceride to high-density lipoprotein cholesterol ratio in youths.

OBJECTIVE: A high triglyceride (TG) to high-density lipoprotein cholesterol (HDL) ratio (TG/HDL) predicts atherosclerosis and cardiovascular events. This study examined whether a proatherogenic distribution of plasma lipoprotein subclasses is associated with a high TG/HDL ratio in youths with obesity. METHODS: Lipoprotein particle concentration and size were measured by proton nuclear magnetic resonance in a multiethnic cohort of 592 adolescents with overweight/obesity (age 13 ± 3 years, 58% females, BMI z score 2.1 ± 0.8) who were phenotyped with a 3-hour oral glucose tolerance test and abdominal magnetic resonance imaging. RESULTS: The highest TG/HDL quartile showed a higher particle concentration of very low-density lipoprotein (VLDL; +178%, p < 0.0001), intermediate-density lipoprotein (+338%, p < 0.0001), and low-density lipoprotein (LDL; +42%, p < 0.0001), compared with the lowest quartile. The prevalence of large VLDL, very small LDL, and small HDL progressively increased across TG/HDL quartiles. The TG/HDL ratio correlated positively with the average particle size of VLDL (r = 0.37, p < 0.0001) and negatively with particle size of both LDL (r = -0.51, p < 0.0001) and HDL (r = -0.69, p < 0.0001). These associations were independent of sex, age, race/ethnicity, body mass, fasting plasma glucose, and insulin sensitivity. CONCLUSIONS: In youths with obesity, an elevated TG/HDL ratio is associated with high concentrations of proatherogenic lipoprotein subclasses. This phenotype may explain the increased cardiovascular risk associated with a high TG/HDL ratio.

Empagliflozin and Renal Sodium-Hydrogen Exchange in Healthy Subjects.

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.

Glomerular Hyperfiltration Predicts Kidney Function Decline and Mortality in Type 1 and Type 2 Diabetes: A 21-Year Longitudinal Study.

OBJECTIVE: To evaluate the prognostic value of glomerular hyperfiltration on long-term kidney-related outcomes and mortality in patients with diabetes. RESEARCH DESIGN AND METHODS: We retrospectively analyzed 21-year longitudinal data from 314 patients with long-standing type 1 or type 2 diabetes. Glomerular hyperfiltration was identified based on the age- and sex-specific distribution of measured glomerular filtration rate (mGFR) by 99mTc-DTPA dynamic renal scintigraphy. The primary outcome was a composite of doubling of serum creatinine, end-stage kidney disease (ESKD), or cardiorenal death. The kidney-specific outcome was a composite of doubling of serum creatinine, ESKD, or renal death. RESULTS: Over a median of 21.0 years, the primary composite outcome occurred in 25 (39.7%), 24 (38.1%), and 46 (24.5%) participants with high mGFR (H-mGFR) (n = 63), low mGFR (L-mGFR) (n = 63), or normal mGFR (N-mGFR) (n = 188), respectively. Compared with N-mGFR, the hazard ratio (HR) for the primary composite outcome was 2.09 (95% CI 1.25-3.49) in H-mGFR and 1.81 (1.05-3.16) in L-mGFR. The HR for the kidney-specific composite outcome was 4.95 (2.21-11.09) in H-mGFR and 3.81 (1.70-8.56) in L-mGFR. The HRs for doubling of serum creatinine and cardiorenal death were 4.86 (2.18-10.90) and 2.18 (1.24-3.83) in H-mGFR and 4.04 (1.77-9.20) and 2.26 (1.27-4.01) in L-mGFR, respectively. CONCLUSIONS: Glomerular hyperfiltration, similar to hypofiltration, increases the combined risk of worsening kidney function and mortality from cardiovascular or renal causes in patients with diabetes. These findings encourage the active screening of these patients to optimize risk stratification and treatment of subclinical kidney disease.

Epicardial adipose tissue thickness is associated with reduced peak oxygen consumption and systolic reserve in patients with type 2 diabetes and normal heart function.

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 (ΔS' 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.

Synergistic effect of chronic kidney disease, neuropathy, and retinopathy on all-cause mortality in type 1 and type 2 diabetes: a 21-year longitudinal study.

BACKGROUND: The prognostic value of common and frequently associated diabetic microvascular complications (MVC), namely chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN), peripheral neuropathy (DPN), and retinopathy (DR), is well established. However, the impact of their different combinations on long-term mortality has not been adequately assessed. METHODS: We retrospectively analyzed 21-year longitudinal data from 303 patients with long-standing type 1 (T1D) or type 2 diabetes (T2D), who were thoroughly characterized at baseline for the presence of MVC using 99mTc-DTPA dynamic renal scintigraphy, overnight urine collection, cardiovascular autonomic tests, monofilament testing, and dilated fundus oculi examination. RESULTS: After a 5,244 person-years follow-up, a total of 133 (43.9%) deaths occurred. The presence of CKD and CAN, regardless of other MVC, increased the adjusted all-cause mortality risk by 117% (HR 2.17 [1.45-3.26]) and 54% (HR 1.54 [1.01-2.36]), respectively. Concomitant CKD&CAN at baseline were associated with the highest mortality risk (HR 5.08 [2.52-10.26]), followed by CKD&DR (HR 2.95 [1.63-5.32]), and CAN&DR (HR 2.07 [1.11-3.85]). Compared with patients free from MVC, the mortality risk was only numerically higher in those with any isolated MVC (HR 1.52 [0.87-2.67]), while increased by 203% (HR 3.03 [1.62-5.68]) and 692% (HR 7.92 [2.93-21.37]) in patients with two and three concomitant MVC, respectively. CONCLUSIONS: Our study demonstrates the long-term, synergistic, negative effects of single and concomitant diabetic MVC on all-cause mortality, which should encourage comprehensive screenings for MCV in both T1D and T2D to improve risk stratification and treatment.