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Lispro insulin in people with non-alcoholic liver cirrhosis and type 2 diabetes mellitus.
Gentile, S, Guarino, G, Strollo, F, Romano, M, Genovese, S, Masarone, M, Ceriello, A
Diabetes research and clinical practice. 2016;:179-86
Abstract
AIMS: To compare metabolic control under lispro and recombinant regular human insulin (RHI) in people with diet-unresponsive type 2 diabetes mellitus (T2DM) and compensated non-alcoholic liver disease (CLD).
METHODS 108 people with T2DM and CLD were randomly allocated to RHI or lispro according to a 12+12 week cross-over protocol. A 1-week continuous glucose monitoring (CGM) session was performed at the end of each treatment period followed by a standard meal test with a 12IU lispro or RHI shot ahead.
RESULTS CGM showed higher glycemic excursions under RHI than under lispro (p<0.01) with lower glucose levels in the late post-absorption phase (p<0.05) and even more during the night (p<0.01). Post-challenge incremental areas under the curve (ΔAUC) were undistinguishable for insulin but lower for glucose, while insulin peaked higher and earlier and glycemic excursions were lower with lispro than with RHI (0.05
CONCLUSIONS Lispro granted lower early postprandial glucose levels and late postprandial hypoglycemic rates and therefore might represent the treatment of choice for people with T2DM and compensated CLD. This might depend on its faster/shorter-living effects, as well as, on the lower liver glucose output expected from its earlier hepatic distribution.
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Simultaneous GLP-1 and insulin administration acutely enhances their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes.
Ceriello, A, Novials, A, Canivell, S, La Sala, L, Pujadas, G, Esposito, K, Testa, R, Bucciarelli, L, Rondinelli, M, Genovese, S
Diabetes care. 2014;(7):1938-43
Abstract
OBJECTIVE To test the hypothesis that the simultaneous administration of GLP-1 and insulin may increase their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes. RESEARCH DESIGN AND METHODS In two groups of persons with type 2 diabetes, two sets of experiments were performed. The first group had two normoglycemic-normoinsulinemic clamps with or without GLP-1 and two normoglycemic-hyperinsulinemic clamps with or without GLP-1. The second group had two hyperglycemic-normoinsulinemic clamps and two hyperglycemic-hyperinsulinemic clamps with or without GLP-1. RESULTS During the normoglycemic-hyperinsulinemic clamp, flow-mediated dilatation (FMD) increased, while soluble intercellular adhesion molecule (sICAM-1), plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), nitrotyrosine, and interleukin (IL)-6 decreased compared with normoglycemic-normoinsulinemic clamp. Similar results were obtained with the infusion of GLP-1 during the normoglycemic-normoinsulinemic clamp. The combination of hyperinsulinemia and GLP-1 in normoglycemia was accompanied by a further FMD increase and sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 decrease. During the hyperglycemic-normoinsulinemic clamp, FMD significantly decreased, while sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 significantly increased. When hyperglycemia was accompanied by hyperinsulinemia or by the simultaneous infusion of GLP-1, these phenomena were attenuated. The simultaneous presence of hyperinsulinemia and GLP-1 had an increased beneficial effect. CONCLUSIONS Our results show that the combination of insulin and GLP-1 is more effective than insulin or GLP-1 alone in improving endothelial dysfunction, inflammation, and oxidative stress in type 2 diabetes.
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Effect of pioglitazone versus metformin on cardiovascular risk markers in type 2 diabetes.
Genovese, S, De Berardis, G, Nicolucci, A, Mannucci, E, Evangelista, V, Totani, L, Pellegrini, F, Ceriello, A
Advances in therapy. 2013;(2):190-202
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Abstract
INTRODUCTION Besides its critical role in metabolic homeostasis, peroxisome proliferator-activated receptor (PPAR)-γ modulates several cellular responses involved in atherothrombosis. This multicenter, double-blind, randomized study investigated the effects of two oral hypoglycemic agents on markers of inflammation, platelet activation, thrombogenesis, and oxidative stress in patients with type 2 diabetes. METHODS AND RESULTS The primary objective of this study was to evaluate the effect on C-reactive protein (CRP) after a 16-week treatment period with either pioglitazone or metformin. Additionally, markers of vascular inflammatory response, platelet activation, thrombogenesis, oxidative stress, glucose, and lipid metabolism, as well as liver function, were measured. In total, 50 patients completed the study. Pioglitazone-treated patients were found to have statistically significantly larger decreases in mean CRP levels (-0.4 mg/dL) compared to those treated with metformin (-0.2 mg/dL) (P=0.04), as well as greater reductions in levels of mean fasting plasma glucose (-27 vs. -9 mg/dL; P=0.01), serum insulin (-2 vs. -1.9 mU/L; P=0.014), homeostatic model assessment (HOMA) (-1.2 vs. -0.9; P=0.015), and E-selectin (-12.4 vs. +3.4 μg/mL; P=0.01). Mean glycated hemoglobin (HbA1c) levels decreased in both treatment groups from baseline to week 16 (-0.4% in the pioglitazone group, -0.2% in the metformin group; P=0.36). Pioglitazone treatment was also found to be associated with a statistically significant increase in total cholesterol levels (+10 mg/dL in the pioglitazone arm, -3 mg/dL in the metformin arm; P=0.05) and a decrease in liver enzyme levels. CONCLUSIONS The favorable changes in markers of systemic and vascular inflammatory response with pioglitazone suggest that it may positively influence the atherothrombotic process in type 2 diabetes.
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Effects of a Mediterranean-style diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: a randomized trial.
Esposito, K, Maiorino, MI, Ciotola, M, Di Palo, C, Scognamiglio, P, Gicchino, M, Petrizzo, M, Saccomanno, F, Beneduce, F, Ceriello, A, et al
Annals of internal medicine. 2009;(5):306-14
Abstract
BACKGROUND Low-carbohydrate and low-fat calorie-restricted diets are recommended for weight loss in overweight and obese people with type 2 diabetes. OBJECTIVE To compare the effects of a low-carbohydrate Mediterranean-style or a low-fat diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes. DESIGN Single-center, randomized trial. Randomization was computer-generated and unstratified. Allocation was concealed in sealed study folders held in a central, secure location until participants gave informed consent. Participants and investigators were aware of treatment assignment, and assessors of the primary outcome were blinded. SETTING Teaching hospital in Naples, Italy. PATIENTS 215 overweight people with newly diagnosed type 2 diabetes who were never treated with antihyperglycemic drugs and had hemoglobin A(1c) (HbA(1c)) levels less than 11%. INTERVENTION Mediterranean-style diet (<50% of daily calories from carbohydrates) (n = 108) or a low-fat diet (<30% of daily calories from fat) (n = 107). MEASUREMENTS Start of antihyperglycemic drug therapy, defined by protocol as indicated for follow-up HbA(1c) level greater than 7% (primary outcome), and changes in weight, glycemic control, and coronary risk factors (secondary outcomes). RESULTS After 4 years, 44% of patients in the Mediterranean-style diet group and 70% in the low-fat diet group required treatment (absolute difference, -26.0 percentage points [95% CI, -31.1 to -20.1 percentage points]; hazard ratio, 0.63 [CI, 0.51 to 0.86]; hazard ratio adjusted for weight change, 0.70 [CI, 0.59 to 0.90]; P < 0.001). Participants assigned to the Mediterranean-style diet lost more weight and experienced greater improvements in some glycemic control and coronary risk measures than did those assigned to the low-fat diet. LIMITATIONS Investigators responsible for initiating drug therapy were not blinded to treatment assignment. Dietary intake was self-reported. CONCLUSION Compared with a low-fat diet, a low-carbohydrate, Mediterranean-style diet led to more favorable changes in glycemic control and coronary risk factors and delayed the need for antihyperglycemic drug therapy in overweight patients with newly diagnosed type 2 diabetes. PRIMARY FUNDING SOURCE Second University of Naples.
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Enteral nutritional support and use of diabetes-specific formulas for patients with diabetes: a systematic review and meta-analysis.
Elia, M, Ceriello, A, Laube, H, Sinclair, AJ, Engfer, M, Stratton, RJ
Diabetes care. 2005;(9):2267-79
Abstract
OBJECTIVE The aim of this systematic review was to determine the benefits of nutritional support in patients with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS Studies utilizing an enteral nutritional support intervention (oral supplements or tube feeding) were identified using electronic databases and bibliography searches. Comparisons of interest were nutritional support versus routine care and standard versus diabetes-specific formulas (containing high proportions of monounsaturated fatty acids, fructose, and fiber). Outcomes of interest were measures of glycemia and lipid status, medication requirements, nutritional status, quality of life, complications, and mortality. Meta-analyses were performed where possible. RESULTS A total of 23 studies (comprising 784 patients) of oral supplements (16 studies) and tube feeding (7 studies) were included in the review, and the majority compared diabetes-specific with standard formulas. Compared with standard formulas, diabetes-specific formulas significantly reduced postprandial rise in blood glucose (by 1.03 mmol/l [95% CI 0.58-1.47]; six randomized controlled trials [RCTs]), peak blood glucose concentration (by 1.59 mmol/l [86-2.32]; two RCTs), and glucose area under curve (by 7.96 mmol.l(-1).min(-1) [2.25-13.66]; four RCTs, i.e., by 35%) with no significant effect on HDL, total cholesterol, or triglyceride concentrations. In addition, individual studies reported a reduced requirement for insulin (26-71% lower) and fewer complications with diabetes-specific compared with standard nutritional formulas. CONCLUSIONS This systematic review shows that short- and long-term use of diabetes-specific formulas as oral supplements and tube feeds are associated with improved glycemic control compared with standard formulas. If such nutritional support is given long term, this may have implications for reducing chronic complications of diabetes, such as cardiovascular events.
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Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy.
Ceriello, A, Morocutti, A, Mercuri, F, Quagliaro, L, Moro, M, Damante, G, Viberti, GC
Diabetes. 2000;(12):2170-7
Abstract
There is an individual susceptibility to diabetic nephropathy, and oxidative stress is believed to play an important role in the pathogenesis of diabetic complications. Active oxygen species induce antioxidant enzyme expression in tissues, an effect considered to be a defensive mechanism. To test whether altered intracellular antioxidant enzyme production might explain the predisposition to diabetic nephropathy, we studied the effect of long-term (12 weeks) exposure to normal (5 mmol/l) or high (22 mmol/l) glucose concentrations on fibroblast antioxidant enzyme gene expression and protein activity in type 1 diabetic patients with and without nephropathy, nondiabetic nephropathic patients, and nondiabetic control subjects. Under conditions of normal glucose concentration in the culture media, CuZnSuperoxide-dismutase, MnSuperoxide-dismutase, catalase, and glutathione-peroxidase activity and mRNA expression were not different among the four groups. Under high-glucose conditions, CuZnSuperoxide-dismutase mRNA and activity increased similarly in all groups (P < 0.001 vs. basal), whereas MnSuperoxide-dismutase did not change. In contrast, catalase mRNA and activity as well as glutathione-peroxidase mRNA and activity increased in fibroblasts from type 1 diabetic patients without nephropathy (P < 0.001), in fibroblasts from nondiabetic nephropathic patients (P < 0.001), and in fibroblasts from nondiabetic control subjects (P < 0.001), but not in fibroblasts from type 1 diabetic patients with nephropathy. Exposure to high glucose concentrations significantly increased lipid peroxidation in cells, higher levels being found in cells from diabetic patients with nephropathy (P < 0.001). These data, while confirming that exposure to high glucose concentrations induces an antioxidant defense in skin fibroblasts from normal subjects, demonstrate a failure of this defensive mechanism in cells from type 1 diabetic patients with nephropathy, whereas skin fibroblasts from diabetic patients without complications or from nondiabetic nephropathic patients have an intact antioxidant response to glucose-induced oxidative stress.