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.

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.

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.

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.

Effects of sacubitril/valsartan on both metabolic parameters and insulin resistance in prediabetic non-obese patients with heart failure and reduced ejection fraction.

Background: The effects of sacubitril/valsartan (sac/val) on metabolic parameters and insulin resistance (IR) in non-obese/prediabetic patients have not been previously described. Aim: To evaluate the effects of sac/val on glycemic and metabolic parameters, Homeostatic Model Assessment of IR (HOMA-IR), and echocardiographic parameters in prediabetic patients with heart failure with reduced ejection fraction (HFrEF). Methods: Fifty-nine patients with HFrEF (EF < 35%) but without obesity and/or type 2 diabetes mellitus have been enrolled. All the patients at baseline and week 24 underwent complete anthropometrical evaluation and were subjected to an echocardiogram test. IR has been assessed by HOMA-IR. Results: After 24-week of treatment with sac/val, a significant reduction in fasting plasma glucose (109 ± 9 vs 103 ± 8 mg/dl, p < 0.0001), fasting plasma insulin (16 ± 4 vs 10 ± 4 UI/L), and hemoglobin A1c (HbA1c) value (6% ± 0.5% vs 5.3% ± 0.3%, p < 0.0001) was observed. Similarly, we observed a significant improvement in IR (HOMA-IR, 4.4 ± 0.9 vs 2.5 ± 0.6, p < 0.0001). The echocardiogram evaluation showed a significant reduction of the left ventricular end-diastolic volume (168 ± 24 vs 158 ± 22 ml, p < 0.05), a significant reduction of the left ventricular end-systolic volume (111 ± 26 vs 98 ± 22 ml, p < 0.005), and a significant reduction of E/e' ratio. Sac/val use was also associated with an average 5.1% increase in ejection fraction. Conclusions: Our data seem to indicate that sal/val enhances metabolic control and improves insulin resistance also in prediabetic non-obese patients with HFrEF.

Prognostic value of 24-hour ambulatory blood pressure patterns in diabetes: A 21-year longitudinal study.

AIMS: To establish the long-term prognostic value of abnormal circadian blood pressure (BP) patterns in diabetes. MATERIALS AND METHODS: We retrospectively examined a cohort of 349 outpatients with diabetes who were screened for microvascular complications and followed up for 21 years. Dipping, nondipping and reverse-dipping status were defined based on 24-hour ambulatory BP monitoring (ABPM) as ≥10% reduction, <10% reduction, and any increase in average nighttime versus daytime systolic BP (SBP), respectively. RESULTS: After 6251 person-years of follow-up (median [range] follow-up 21.0 [1.1-22.0] years, 52% women, age 57.1 ± 11.9 years, 81.4% type 2 diabetes and 18.6% type 1 diabetes), a total of 136 deaths (39%) occurred. Compared with dippers, the nondippers and reverse dippers showed progressively higher prevalence of chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN) and postural hypotension. Reverse dippers showed a 13.4% (2.5-year) reduction in mean overall survival and a twofold increased risk of all-cause mortality after adjustment for traditional risk factors (hazard ratio 2.2 [95% confidence interval 1.3-3.8]). Each 1% decrease in nighttime versus daytime SBP ratio was independently associated with a 4% reduction in 20-year mortality risk. CONCLUSIONS: In patients with diabetes, reverse dipping is associated with a higher prevalence of CKD and CAN and more than doubled the adjusted risk of all-cause mortality over a 21-year observation.