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.

Low HDL cholesterol and the eNOS Glu298Asp polymorphism are associated with inducible myocardial ischemia in patients with suspected stable coronary artery disease.

BACKGROUND: The endothelial nitric oxide synthase (eNOS) gene deficiency is known to cause impaired coronary vasodilating capability in animal models. In the general clinical population, the eNOS gene polymorphisms, able to affect eNOS activity, were associated with cardiometabolic risk features and prevalence of coronary artery disease (CAD). AIM: To investigate the association of eNOS Glu298Asp gene polymorphism, cardiometabolic profile, obstructive CAD and inducible myocardial ischemia in patients with suspected stable CAD. METHODS: A total of 506 patients (314 males; mean age 62 ± 9 years) referred for suspected CAD was enrolled. Among these, 325 patients underwent stress ECG or cardiac imaging to assess the presence of inducible myocardial ischemia and 436 patients underwent non-invasive computerized tomography or invasive coronary angiography to assess the presence of obstructive CAD. Clinical characteristics and blood samples were collected for each patient. RESULTS: In the whole population, 49.6% of patients were homozygous for the Glu298 genotype (Glu/Glu), 40.9% heterozygotes (Glu/Asp) and 9.5% homozygous for the 298Asp genotype (Asp/Asp). Obstructive CAD was documented in 178/436 (40.8%) patients undergoing coronary angiography while myocardial ischemia in 160/325 (49.2%) patients undergoing stress testing. Patients with eNOS Asp genotype (Glu/Asp + Asp/Asp) had no significant differences in clinical risk factors and in circulating markers. Independent predictors of obstructive CAD were age, gender, obesity, and low HDL-C. Independent predictors of myocardial ischemia were gender, obesity, low HDL-C and Asp genotype. In the subpopulation in which both stress tests and coronary angiography were performed, the Asp genotype remained associated with increased myocardial ischemia risk after adjustment for obstructive CAD. CONCLUSION: In this population, low-HDL cholesterol was the only cardiometabolic risk determinant of obstructive CAD. The eNOS Glu298Asp gene polymorphism was significantly associated with inducible myocardial ischemia independently of other risk factors and presence of obstructive CAD.

Remission of type 2 diabetes: position statement of the Italian society of diabetes (SID).

The primary cause of the pandemic scale of type 2 diabetes (T2D) is the excessive and/or abnormal accumulation of adiposity resulting from a chronic positive energy balance. Any form of weight loss dramatically affects the natural history of T2D, favoring prevention, treatment, and even remission in the case of significant weight loss. However, weight regain, which is often accompanied by the recurrence or worsening of obesity complications such as T2D, is an inevitable biological phenomenon that is an integral part of the pathophysiology of obesity. This can occur not only after weight loss, but also during obesity treatment if it is not effective enough to counteract the physiological responses aimed at restoring adiposity to its pre-weight-loss equilibrium state. Over the past few years, many controlled and randomized studies have suggested a superior efficacy of bariatric surgery compared to conventional therapy in terms of weight loss, glycemic control, and rates of T2D remission. Recently, the therapeutic armamentarium in the field of diabetology has been enriched with new antihyperglycemic drugs with considerable efficacy in reducing body weight, which could play a pathogenetic role in the remission of T2D, not through the classical incretin effect, but by improving adipose tissue functions. All these concepts are discussed in this position statement, which aims to deepen the pathogenetic links between obesity and T2D, shift the paradigm from a "simple" interaction between insulin resistance and insulin deficiency, and evaluate the efficacy of different therapeutic interventions to improve T2D management and induce diabetes remission whenever still possible.

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.

Plasma levels of PRO-C3, a type III collagen synthesis marker, are associated with arterial stiffness and increased risk of cardiovascular death.

BACKGROUND AND AIMS: The N-terminal propeptide of type III collagen (PRO-C3) assay measures a pro-peptide released during type III collagen synthesis, an important feature of arterial stiffening and atherogenesis. There is a clinical need for improved non-invasive, cheap and easily accessible methods for evaluating individuals at risk of cardiovascular disease (CVD). In this study, we investigate the potential of using circulating levels of PRO-C3 to mark the degree of vascular stenosis and risk of cardiovascular events. METHODS: Baseline plasma levels of PRO-C3 were measured by ELISA in subjects belonging to the SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort (N = 1354). Associations between PRO-C3 levels with vascular characteristics, namely stiffness and stenosis, and risk of future cardiovascular events were explored. Subjects were followed up after a median of 35 months (interquartile range 34-36 months), with recorded outcomes cardiovascular death and all-cause mortality. RESULTS: We found a correlation between PRO-C3 levels and pulse wave velocity (rho 0.13, p = 0.000009), a measurement of arterial stiffness. Higher PRO-C3 levels were also associated with elevated blood pressure (rho 0.07, p = 0.014), as well as risk of cardiovascular mortality over a three-year follow-up period (OR 1.56, confidence interval 1.008-2.43, p = 0.046). CONCLUSIONS: Elevated circulating PRO-C3 levels are associated with arterial stiffness and future cardiovascular death, in the SUMMIT cohort, suggesting a potential value of PRO-C3 as a novel marker for declining vascular health.