Clinical Outcomes of Switching to Insulin Glargine 300 U/ml from Other Basal Insulins in People with Type 2 Diabetes in Italy: A Real-World Study.

INTRODUCTION: Primary aim was to provide real-world evidence of the outcomes after the switch to glargine 300 U/ml (Gla-300) from other basal insulins (first or second generation) in Italy. METHODS: Multicenter, observational, retrospective study based on electronic medical records. RESULTS: Overall, 953 T2DM insulin ± OAD treated people switched to Gla-300 or Gla-100 from January 2015 to July 2018. Three clinically relevant cohorts were identified: patients switching to Gla-300 from first-generation basal insulin (cohort 1), patients switching to Gla-300 from degludec-100 (Deg-100) (cohort 2), and those switching to Gla-100 from any basal insulin (cohort 3). The three cohorts differed in terms of age, diabetes duration, and metabolic control. HbA1c changes after 6 months from the switch were - 0.27% (95% CI - 0.38; - 0.16), - 0.06% (95% CI - 0.31; 0.19), and - 0.30% (95% CI - 0.51; - 0.09) in the three cohorts, respectively. FPG significantly decreased in cohort 1 (- 14.07 mg/dl, 95% CI - 20.25; - 7.89), while body weight significantly decreased in cohort 2 (- 1.47 kg, 95% CI - 2.55; - 0.39). Doses of insulin marginally changed during the follow-up (+ 0.89 U in basal insulin daily dose in cohort 1 and + 2.07 U in short-acting insulin daily dose in cohort 2). CONCLUSIONS: Switching to Gla-300 from first-generation basal insulin in the real world is associated with improvements in metabolic control despite a suboptimal titration of both basal and short-acting insulins. Inertia in insulin titration documented in the Gla-100 cohort is also observed with the second-generation basal insulin. The switch to Gla-300 from Deg-100 was associated with a decrease in body weight of - 1.47 kg despite a slight increase in short-acting insulin daily doses of about + 2 U.

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 diet + either 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 (-7.5% in the vitamin D group and -10% 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 36.7 ± 13.2 nmol/L to 74.8 ± 18.7 nmol/L; P < 0.001). Insulin sensitivity in the vitamin D group improved (from 4.6 ± 2.0 to 6.9 ± 3.3 mg·kg-1 ·min-1 ; P < 0.001), whereas no changes were observed in the placebo group (from 4.9 ± 1.1 to 5.1 ± 0.3 mg·kg-1 ·min-1 ; P = 0.84). 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.

FL-926-16, a novel bioavailable carnosinase-resistant carnosine derivative, prevents onset and stops progression of diabetic nephropathy in db/db mice.

BACKGROUND AND PURPOSE: The advanced glycation end products (AGEs) participate in the pathogenesis of diabetic nephropathy (DN) by promoting renal inflammation and injury. L-carnosine acts as a quencher of the AGE precursors reactive carbonyl species (RCS), but is rapidly inactivated by carnosinase. In this study, we evaluated the effect of FL-926-16, a carnosinase-resistant and bioavailable carnosine derivative, on the onset and progression of DN in db/db mice. EXPERIMENTAL APPROACH: Adult male db/db mice and coeval db/m controls were left untreated or treated with FL-926-16 (30 mg·kg-1 body weight) from weeks 6 to 20 (prevention protocol) or from weeks 20 to 34 (regression protocol). KEY RESULTS: In the prevention protocol, FL-926-16 significantly attenuated increases in creatinine (-80%), albuminuria (-77%), proteinuria (-75%), mean glomerular area (-34%), fractional (-40%) and mean (-42%) mesangial area in db/db mice. This protective effect was associated with a reduction in glomerular matrix protein expression and cell apoptosis, circulating and tissue oxidative and carbonyl stress, and renal inflammatory markers, including the NLRP3 inflammasome. In the regression protocol, the progression of DN was completely blocked, although not reversed, by FL-926-16. In cultured mesangial cells, FL-926-16 prevented NLRP3 expression induced by RCS but not by the AGE Nε -carboxymethyllysine. CONCLUSION AND IMPLICATIONS: FL-926-16 is effective at preventing the onset of DN and halting its progression in db/db mice by quenching RCS, thereby reducing the accumulation of their protein adducts and the consequent inflammatory response. In a future perspective, this novel compound may represent a promising AGE-reducing approach for DN therapy.

A rare case of ectopic adrenocorticotropic hormone syndrome caused by a metastatic neuroendocrine tumor of the pancreas detected by 68Ga-DOTANOC and 18F-FDG PET/CT.

We report a rare case of ectopic adrenocorticotropic hormone (ACTH) syndrome caused by a metastatic neuroendocrine tumor (NET) of the pancreas detected by PET/CT using different tracers. A 43-year-old female patient with Cushing syndrome (CS) by suspected ectopic ACTH secretion underwent a 68Ga-DOTANOC and a 18F-FDG PET/CT. Both these functional imaging techniques revealed increased tracer uptake in a pancreatic mass and multiple liver metastases. Histology showed the presence of a mildly differentiated pancreatic NET. 68Ga-DOTANOC PET/CT may be a useful functional imaging method, complementary to 18F-FDG PET/CT, in detecting ACTH-secreting pancreatic NETs.

D-Carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation.

BACKGROUND AND PURPOSE: Lipoxidation-derived reactive carbonyl species (RCS) such as 4-hydroxy-2-nonenal (HNE) react with proteins to form advanced lipoxidation end products (ALEs), which have been implicated in both atherosclerosis and renal disease. L-carnosine acts as an endogenous HNE scavenger, but it is rapidly inactivated by carnosinase. This study aimed at assessing the effect of the carnosinase-resistant, D-carnosine, on HNE-induced cellular injury and of its bioavailable prodrug D-carnosine octylester on experimental atherosclerosis and renal disease. EXPERIMENTAL APPROACH: Vascular smooth muscle cells (VSMCs) were exposed to HNE or H2O2 plus D-carnosine. ApoE null mice fed a Western, pro-atherogenic diet were treated with D-carnosine octylester for 12 weeks. KEY RESULTS: In vitro, D-carnosine attenuated the effect of HNE, but not of H2O2, on VSMCs. In vivo, D-carnosine octylester-treated mice showed reduced lesion area and a more stable plaque phenotype compared with untreated animals, with reduced foam cell accumulation, inflammation and apoptosis and increased clearance of apoptotic bodies and collagen deposition, resulting in decreased necrotic core formation. Likewise, renal lesions were attenuated in D-carnosine octylester-treated versus untreated mice, with lower inflammation, apoptosis and fibrosis. This was associated with increased urinary levels of HNE-carnosine adducts and reduced protein carbonylation, circulating and tissue ALEs, expression of receptors for these products, and systemic and tissue oxidative stress. CONCLUSIONS AND IMPLICATIONS: These data indicate RCS quenching with a D-carnosine ester was highly effective in attenuating experimental atherosclerosis and renal disease by reducing carbonyl stress and inflammation and that this may represent a promising therapeutic strategy in humans.

Single-fiber conduction velocity test allows earlier detection of abnormalities in diabetes.

INTRODUCTION: The purpose of this study was to determine whether single-fiber conduction velocity (SF-CV) of a small number of axons increases sensitivity for identification of motor nerve conduction alterations in patients with diabetes. METHODS: Twenty-one consecutive diabetic patients in good metabolic control were studied. For each patient, conventional (C-CV) and SF-CV results were correlated with the presence of neuropathic symptoms. RESULTS: Nine of 21 patients reported symptoms suggestive of mild nerve impairment. Three patients had abnormal sural nerve CV, 1 of whom also had abnormal motor nerve conduction. Eighteen patients had normal findings on conventional tests, 3 of whom had slowing of SF-CV. CONCLUSIONS: SF-CV is able to detect mild myelin damage with higher sensitivity than conventional tests. The use of SF-CV may be a helpful tool in the early identification of diabetic polyneuropathy, and it may be useful for tailoring an approach to diabetic polyneuropathy.

The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause-effect relationship?

CONTEXT: Adrenal incidentalomas (AI) have often been associated with a high prevalence of insulin resistance (IR) and cardiovascular risk factors, although direct measurement of insulin sensitivity (IS) has never been carried out. OBJECTIVE: We aimed to investigate whether the morphological and hormonal features of AI correlate with the presence and severity of IR, using the hyperinsulinaemic euglycaemic clamp (HEC). DESIGN AND MEASUREMENTS: Forty patients with AI (22 women) with a mean age of 58.5±11.1 years underwent hormonal and morphological evaluation. Nineteen patients with AI without known history of diabetes mellitus (DM) or impaired glucose tolerance (IGT) and 17 matched controls underwent oral glucose tolerance test (OGTT) and hyperinsulinaemic euglycaemic clamp (HEC). RESULTS: Diabetes mellitus was observed in 13 patients (33%), while three (8%) had IGT. Thirty-one of the AI were nonfunctioning (82.5%), whereas two (5%) secreted cortisol (Cushing's syndrome) and seven (12.5%) showed subclinical secretion of cortisol. The 19 patients with nonfunctioning AI were more insulin resistant than controls (glucose up-take: 4.58±1.80 vs 5.85±2.48 mg/kg/min respectively; P=0.01); IS was inversely related to the mass size (r=-0.57; P=0.04), free urinary cortisol (r=-0.68; P=0.01), serum cortisol after 1-mg dexamethasone suppression (-0.65; P=0.02) and percentage of trunk fat mass (-0.77; P=0.02) and directly related to serum adreno cortico tropic hormone (ACTH) (r=0.62; P=0.03). After performing multivariate regression, the mass size was found to be the most powerful predictor of IR. CONCLUSION: Our study showed a high prevalence of insulin resistance in patients with nonfunctioning AI and suggests its possible involvement in AI growth.