Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: Evidence to date

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest therapeutic strategy in the treatment of type 2 diabetes mellitus (T2DM). Using an insulin-independent mechanism (glycosuria), they reduce glucose toxicity and improve insulin sensitivity and \uce\ub2-cell function. The promising results obtained in clinical trials show that SGLT2 significantly improves glycemic control and provides greater cardiovascular protection, combined with a reduction in body weight and blood pressure (BP). This review focuses on ertugliflozin, a new, highly selective, and reversible SGLT2 inhibitor. Clinical trials published to date show that ertugliflozin, both as a monotherapy and as an add-on to oral antidiabetic agents, is safe and effective in reducing glycosylated hemoglobin (HbA1c), body weight, and BP in T2DM patients

Effects of PCSK9 inhibition on glucose metabolism and β-cell function in humans: a pilot study

BackgroundAnti-PCSK9 monoclonal antibodies are effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. PCSK9, however, is also expressed in tissues, including the pancreas, and studies on PCSK9 KO mice have shown impaired insulin secretion. Statin treatment is already known to affect insulin secretion. Our aim was to conduct a pilot study to evaluate the effect of anti-PCSK9 mAb on glucose metabolism and β-cell function in humans.MethodsFifteen non-diabetic subjects, candidates for anti-PCSK9 mAb therapy, were enrolled. All underwent OGTT at baseline and after 6 months of therapy. During OGTT, insulin secretion parameters were derived from C-peptide by deconvolution (β cell glucose sensitivity). Surrogate insulin sensitivity indices were also obtained from OGTT (Matsuda).ResultsGlucose levels during OGTT were unchanged after 6 months of anti-PCSK9 mAb treatment, as well as insulin and C-peptide levels. The Matsuda index remained unchanged, while β-cell glucose sensitivity improved post-therapy (before: 85.3 ± 65.4; after: 118.6 ± 70.9 pmol min-1m-2mM-1; p<0.05). Using linear regression, we found a significant correlation between βCGS changes and BMI (p=0.004). Thus, we compared subjects with values above and below the median (27.6 kg/m2) and found that those with higher BMI had a greater increase in βCGS after therapy (before: 85.37 ± 24.73; after: 118.62 ± 26.83 pmol min-1m-2mM-1; p=0.007). There was also a significant correlation between βCGS change and Matsuda index through linear regression (p=0.04), so we analyzed subjects who had values above and below the median (3.8). This subgroup analysis showed a slight though not significant improvement in βCGS in more insulin resistant patients, (before: 131.4 ± 69.8; after: 170.8 ± 92.7 pmol min-1m-2mM-1; p=0.066).ConclusionsOur pilot study demonstrates that six-month treatment with anti-PCSK9 mAb improves β-cell function, and does not alter glucose tolerance. This improvement is more evident in patients with greater insulin-resistance (low Matsuda) and higher BMI

Effect of Vitamin D Supplementation on Obesity-Induced Insulin Resistance: A Double-Blind, Randomized, Placebo-Controlled Trial

Objective: The aim was to investigate whether vitamin D supplementation, combined with a hypocaloric diet, could have an independent effect on insulin sensitivity in subjects with both overweight and hypovitaminosis D. Changes from baseline in anthropometric parameters, body composition, glucose tolerance, and insulin secretion were considered as secondary outcomes. Methods: Eighteen volunteers who were nondiabetic and vitamin D deficient and had BMI>25 kg/m2 were randomized (1:1) in a double-blind manner to a hypocaloric diet1either oral cholecalciferol at 25,000 IU/wk or placebo for 3 months. Hyperinsulinemic-euglycemic clamp to measure insulin sensitivity was performed at baseline and after intervention. Results: Body weight in both groups decreased significantly (27.5% in the vitamin D group and 210% in the placebo group; P<0.05 for both), with no between-group differences. Serum 25-hydroxyvitamin D levels in the vitamin D group increased considerably (from 36.7613.2 nmol/L to 74.8618.7 nmol/L; P<0.001). Insulin sensitivity in the vitamin D group improved (from 4.662.0 to 6.963.3mgkg21min21; P<0.001), whereas no changes were observed in the placebo group (from 4.961.1 to 5.160.3mgkg21min21; P50.84). Conclusions: Cholecalciferol supplementation, combined with a weight loss program, significantly improves insulin sensitivity in healthy subjects with obesity and might represent a personalized approach for insulin-resistant subjects with obesity

Metabolic syndrome and C reactive protein are associated with a reduced myocardial mechano-energetic efficiency

Context: Metabolic syndrome and elevated high sensitivity C-reactive protein (CRP) levels are associated with risk of cardiovascular diseases (CVD). A reduced myocardial mechano-energetic efficiency (MEE) has been found to be an independent predictor of CVD. Objective: To evaluate the association between metabolic syndrome and hsCRP levels with impaired MEE. Methods: Myocardial MEE was assessed by a validated echocardiography-derived measure in 1975 non-diabetic and prediabetic individuals subdivided into two groups according to the presence of metabolic syndrome. Results: Individuals with metabolic syndrome exhibited increased stroke work and myocardial oxygen consumption estimated by rate pressure product, and a reduced MEE per gram of LV mass (MEEi) as compared to subjects without metabolic syndrome, after adjusting for age, and sex. Myocardial MEEi progressively decreased in parallel with the increase of the number of metabolic syndrome components. In a multivariable regression analysis, both metabolic syndrome and hsCRP contributed to reduced myocardial MEEi independently of sex, total cholesterol, HDL, triglycerides, fasting and 2-h post-load glucose levels. When the study population was divided into 4 groups by the presence or absence of metabolic syndrome and by hsCRP levels above and below 3 mg/L, hsCRP levels ≥3 mg/L were associated with reduced myocardial MEEi both in subjects with metabolic syndrome and in those without the syndrome. Conclusion: Non-diabetic and prediabetic individuals with metabolic syndrome exhibit increased stroke work and myocardial oxygen consumption, and an impaired MEEi, an established predictor of adverse cardiovascular events, and elevated hsCRP levels in combination with metabolic syndrome aggravates the myocardial MEEi impairment

The diagnostic usefulness of the combined COMPASS 31 questionnaire and electrochemical skin conductance for diabetic cardiovascular autonomic neuropathy and diabetic polyneuropathy

The study investigated the diagnostic performance for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN) of the combined use of composite autonomic symptom score (COMPASS) 31, validated questionnaire for autonomic symptoms of CAN, and electrochemical skin conductance (ESC), proposed for detecting DPN and CAN. One-hundred and two participants with diabetes (age 57 ± 14 years, duration 17 ± 13 years) completed the COMPASS 31 before assessing cardiovascular reflex tests (CARTs), neuropathic symptoms, signs, vibratory perception threshold (VPT), thermal thresholds (TT), and ESC using Sudoscan. Two patterns were evaluated: (a) the combined abnormalities in both tests (COMPASS 31+ESC), and (b) the abnormality in COMPASS 31 and/or ESC (COMPASS 31 and/or ESC). CAN (≥1 abnormal CART) and confirmed CAN (≥2 abnormal CARTs) were present in 28.1% and 12.5%, DPN (two abnormalities among symptoms, signs, VPT, and TT) in 52%, abnormal COMPASS 31 (total weighted score >16.44) in 48% and abnormal ESC (hands ESC <50 μS and/or feet ESC <70 μS) in 47.4%. Both the patterns-COMPASS 31+ESC and COMPASS 31 and/or ESC-were associated with CAN and DPN (P < .01). COMPASS 31 and ESC reached a sensitivity of 75% and 83% for confirmed CAN, and a specificity of 65% and 67% for DPN. When combining the tests, the sensitivity for CAN rose by up to 100% for CAN and the specificity up to 89% for DPN. The combination of the tests can allow a stepwise screening strategy for CAN, by suggesting CAN absence with combined normality, and prompting to CARTs with combined abnormality

The diagnostic usefulness of the combined COMPASS 31 questionnaire and electrochemical skin conductance for diabetic cardiovascular autonomic neuropathy and diabetic polyneuropathy

The study investigated the diagnostic performance for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN) of the combined use of composite autonomic symptom score (COMPASS) 31, validated questionnaire for autonomic symptoms of CAN, and electrochemical skin conductance (ESC), proposed for detecting DPN and CAN. One-hundred and two participants with diabetes (age 57 ± 14 years, duration 17 ± 13 years) completed the COMPASS 31 before assessing cardiovascular reflex tests (CARTs), neuropathic symptoms, signs, vibratory perception threshold (VPT), thermal thresholds (TT), and ESC using Sudoscan. Two patterns were evaluated: (a) the combined abnormalities in both tests (COMPASS 31+ESC), and (b) the abnormality in COMPASS 31 and/or ESC (COMPASS 31 and/or ESC). CAN (≥1 abnormal CART) and confirmed CAN (≥2 abnormal CARTs) were present in 28.1% and 12.5%, DPN (two abnormalities among symptoms, signs, VPT, and TT) in 52%, abnormal COMPASS 31 (total weighted score >16.44) in 48% and abnormal ESC (hands ESC <50 μS and/or feet ESC <70 μS) in 47.4%. Both the patterns-COMPASS 31+ESC and COMPASS 31 and/or ESC-were associated with CAN and DPN (P < .01). COMPASS 31 and ESC reached a sensitivity of 75% and 83% for confirmed CAN, and a specificity of 65% and 67% for DPN. When combining the tests, the sensitivity for CAN rose by up to 100% for CAN and the specificity up to 89% for DPN. The combination of the tests can allow a stepwise screening strategy for CAN, by suggesting CAN absence with combined normality, and prompting to CARTs with combined abnormality

Low-density lipoprotein cholesterol levels are associated with first-phase insulin release

Aims: Prior studies provided evidence that low-density lipoprotein (LDL)-cholesterol-lowering statins reduce cardiovascular events while conveying an increased risk of type 2 diabetes. The aim of this study was to investigate the association between LDL levels and both insulin sensitivity and insulin secretion in a cohort of 356 adult first-degree relatives of patients with type 2 diabetes. Methods: Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp and first-phase insulin secretion was measured by both intravenous glucose tolerance test (IVGTT) and OGTT. Results: LDL-cholesterol levels were not independently associated with insulin-stimulated glucose disposal. After adjusting for several potential confounders, LDL-cholesterol concentration exhibited a positive independent association with acute insulin response (AIR) during IVGTT and with the OGTT derived Stumvoll first-phase insulin secretion index. When insulin release was adjusted for the underlying degree of insulin sensitivity, using the disposition index (AIR × insulin-stimulated glucose disposal), β-cell function was significantly associated with LDL-cholesterol levels, even after further adjusting for several potential confounders. Conclusions: The present results suggest that LDL cholesterol is a positive modulator of insulin secretion. The deterioration in glycemic control observed during treatment with statins might thus be explained by an impairment in insulin secretion due to the cholesterol-lowering effect of statins

Association between liver fibrosis and decreased myocardial mechano-energetic efficiency in individuals with different degree of glucose tolerance

Aim: Decreased myocardial mechano-energetic efficiency (MEEi) is associated with NAFLD and poorer prognosis in liver cirrhosis. We aim to investigate the association between liver fibrosis severity and MEEi in individuals participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study.Methods: Myocardial MEEi, assessed by an echocardiography-derived measure, and fibrosis severity, estimated by the fibrosis-4 index (FIB-4), were evaluated in 2383 subjects with different degree of glucose tolerance. Participants were divided into four groups according to FIB-4 index values: lowest risk of fibrosis (<1.3); low risk of fibrosis (>= 1.3 to < 1.67); moderate risk of fibrosis (>= 1.67 to < 2.67); high risk of fibrosis (>= 2.67).Results: Subjects with higher risk of liver fibrosis displayed a graded decrease in myocardial MEEi compare to those with the lowest risk of liver fibrosis. In a multivariable regression analysis, FIB-4 index was independently associated with MEEi (8 = -0.080, P < 0.001), along with total cholesterol (8 = -0.067, P = 0.01), hsCRP (8 = -0.081, P < 0.001), sex (8 = -0.099, P < 0.001), glucose tolerance status (8 = -0.109, <0.001) and HOMA-IR index (8 = -0.143, P < 0.001).Conclusion: Compromised myocardial MEEi is already reported in individuals with high risk of hepatic fibrosis suggesting that its assessment may help to identify among subjects with NAFLD those with worst prognosis

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features

Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS