Maddalena Trombetta

Metabolic Abnormalities Underlying the Different Prediabetic Phenotypes in Obese Adolescents

OBJECTIVE The aim of this study was to define the metabolic abnormalities underlying the prediabetic status of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG/IGT in obese youth. RESEARCH DESIGN AND METHODS We used state-of-the-art techniques (hyperinsulinemic-euglycemic and hyperglycemic clamps), applying a model of glucose-stimulated insulin secretion to the glucose and C-peptide concentration, in 40 normal glucose tolerance (NGT), 17 IFG, 23 IGT, and 11 IFG/IGT obese adolescents. Percent fat (by dual-energy x-ray absorptiometry), age, gender and ethnicity were comparable among groups. RESULTS Peripheral insulin sensitivity was similar between the IFG and NGT groups. In contrast, the IGT and IFG/IGT groups showed marked reductions in peripheral insulin sensitivity (P < 0.002). Basal hepatic insulin resistance index (basal hepatic glucose production x fasting plasma insulin) was significantly increased in IFG, IGT, and IFG/IGT (P < 0.009) compared with NGT. Glucose sensitivity of first-phase insulin secretion was progressively lower in IFG, IGT, and IFG/IGT compared with NGT. Glucose sensitivity of second-phase secretion showed a statistically significant defect only in the IFG/IGT group. In a multivariate regression analysis, glucose sensitivity of first-phase secretion and basal insulin secretion rate were significant independent predictors of FPG (total r(2) = 25.9%). CONCLUSIONS IFG, in obese adolescents, is linked primarily to alterations in glucose sensitivity of first-phase insulin secretion and liver insulin sensitivity. The IGT group is affected by a more severe degree of peripheral insulin resistance and reduction in first-phase secretion. IFG/IGT is hallmarked by a profound insulin resistance and by a new additional defect in second-phase insulin secretion.

Metabolic Effects of Aerobic Training and Resistance Training in Type 2 Diabetic Subjects A randomized controlled trial (the RAED2 study)

OBJECTIVE To assess differences between the effects of aerobic and resistance training on HbA1c (primary outcome) and several metabolic risk factors in subjects with type 2 diabetes, and to identify predictors of exercise-induced metabolic improvement. RESEARCH DESIGN AND METHODS Type 2 diabetic patients (n = 40) were randomly assigned to aerobic training or resistance training. Before and after 4 months of intervention, metabolic phenotypes (including HbA1c, glucose clamp–measured insulin sensitivity, and oral glucose tolerance test–assessed β-cell function), body composition by dual-energy X-ray absorptiometry, visceral (VAT) and subcutaneous (SAT) adipose tissue by magnetic resonance imaging, cardiorespiratory fitness, and muscular strength were measured. RESULTS After training, increase in peak oxygen consumption (VO2peak) was greater in the aerobic group (time-by-group interaction P = 0.045), whereas increase in strength was greater in the resistance group (time-by-group interaction P < 0.0001). HbA1c was similarly reduced in both groups (−0.40% [95% CI −0.61 to −0.18] vs. −0.35% [−0.59 to −0.10], respectively). Total and truncal fat, VAT, and SAT were also similarly reduced in both groups, whereas insulin sensitivity and lean limb mass were similarly increased. β-Cell function showed no significant changes. In multivariate analyses, improvement in HbA1c after training was independently predicted by baseline HbA1c and by changes in VO2peak and truncal fat. CONCLUSIONS Resistance training, similarly to aerobic training, improves metabolic features and insulin sensitivity and reduces abdominal fat in type 2 diabetic patients. Changes after training in VO2peak and truncal fat may be primary determinants of exercise-induced metabolic improvement.

Insulin Sensitivity Is Correlated with Subcutaneous but Not Visceral Body Fat in Overweight and Obese Prepubertal Children

AIM Our aim was to explore the relationship between insulin sensitivity, body fat distribution, ectopic (liver and skeletal muscle) fat deposition, adipokines (leptin and adiponectin), and inflammation markers (highly sensitive C-reactive protein, IL-6, IL-10, and TNF-alpha) in prepubertal children. SUBJECTS AND METHODS Thirty overweight and obese children (16 males and 14 females with body mass index z-score range of 1.1-3.2) were recruited. Body fat distribution and fat accumulation in liver and skeletal muscle were measured using magnetic resonance imaging. Insulin sensitivity was assessed by iv glucose tolerance test. RESULTS Insulin sensitivity was associated with sc abdominal adipose tissue (SAT) (r = -0.52; P < 0.01) and liver fat content (r = -0.44; P < 0.02) but not with visceral abdominal adipose tissue (VAT) (r = -0.193; P value not significant) and fat accumulation in skeletal muscle (r = -0.210; P value not significant). Adipokines, but not inflammation markers, were significantly correlated to insulin sensitivity. VAT correlated with C-reactive protein (r = 0.55; P < 0.01) as well as adiponectin (r = -0.53; P <0.01). Multiple regression analysis showed that only SAT and liver fat content were independently correlated to insulin sensitivity (P < 0.01; 20 and 16% of explained variance, respectively). CONCLUSIONS In overweight and moderately obese prepubertal children, insulin sensitivity was negatively correlated with SAT and liver fat content. Furthermore, contrary to adults, VAT and inflammation markers were not correlated with insulin sensitivity in children.

Review article: type 2 diabetes and chronic liver disease in the Verona diabetes study

Non‐alcoholic liver steatosis is associated with metabolic syndrome and type 2 diabetes. The prevalence of this condition in type 2 diabetes is estimated to be between 28 and 55%. Non‐alcoholic liver steatosis is not a benign disease because of its potential progression to liver fibrosis, cirrhosis and cancer. The Verona diabetes study, a population‐based observational study, on 7148 type 2 diabetic patients after 5 years of follow‐up has reported an increased risk of death from gastrointestinal diseases, particularly from chronic liver cirrhosis. Moreover, in the same population after 10 years of follow‐up a higher risk of mortality from liver cancer was observed and this risk increased significantly in obese patients (body mass index >30 kg/m2). Of note is that obese diabetic patients suffer an even higher prevalence of non‐alcoholic liver steatosis. In conclusion, the Verona diabetes study showed an increased risk of mortality from liver cirrhosis and liver cancer in type 2 diabetic patients. Diverse pathophysiological mechanisms can be responsible, i.e. higher alcohol consumption, hepatitis and others but, considering the high prevalence of non‐alcoholic liver steatosis in these patients, it is plausible to hypothesize that non‐alcoholic liver steatosis may play a significant role in predisposing the liver of diabetics to chronic diseases.

Elevated 1-hour postload plasma glucose levels identify subjects with normal glucose tolerance but impaired β-cell function, insulin resistance, and worse cardiovascular risk profile: the GENFIEV study

CONTEXT In subjects with normal glucose tolerance (NGT) 1-hour postload plasma glucose (1-h oral glucose tolerance test [OGTT]) of >155 mg/dL predicts type 2 diabetes (T2DM) and is associated with subclinical atherosclerosis. OBJECTIVE The purpose of this study was to evaluate β-cell function, insulin resistance, and cardiovascular risk profile in subjects with NGT with a 1-h OGTT glucose of >155 mg/dL. PATIENTS AND METHODS The GENFIEV (Genetics, PHYsiopathology, and Evolution of Type 2 diabetes) study is a multicenter study recruiting individuals at high risk of T2DM. A total of 926 subjects underwent a 75-g OGTT for assessment of plasma glucose and C-peptide for mathematical modeling of β-cell function (derivative and proportional control). Fasting insulin, lipid profile, and clinical parameters were determined as well. RESULTS A 1-hour OGTT glucose of >155 mg/dL was found in 39% of subjects with NGT, 76% with impaired fasting glucose (IFG), 90% with impaired glucose tolerance (IGT), and 99% and 98% with IFG + IGT or newly diagnosed T2DM, respectively. Among subjects with NGT (n = 474), those with 1-hour OGTT glucose of >155 mg/dL were more insulin-resistant and had worse β-cell function than those with 1-hour OGTT glucose of ≤155 mg/dL. Moreover, glycosylated hemoglobin, blood pressure, low-density lipoprotein cholesterol, and triglycerides were higher in subjects with NGT with 1-hour OGTT glucose of >155 mg/dL, whereas high-density lipoprotein cholesterol was lower compared with that in subjects with NGT with 1-hour OGTT glucose of ≤155 mg/dL. Compared with subjects with IGT, those with NGT with 1-hour OGTT glucose of >155 mg/dL had comparable cardiovascular risk profile and insulin resistance but slightly better β-cell function. CONCLUSIONS Among subjects with NGT, those with 1-hour OGTT glucose of >155 mg/dL showed lower insulin sensitivity, impaired β-cell function, and worse cardiovascular risk profile and therefore are at greater risk of developing T2DM and cardiovascular disease.

Nonalcoholic Fatty Liver Disease Is Independently Associated With an Increased Incidence of Chronic Kidney Disease in Patients With Type 1 Diabetes

OBJECTIVE There is no information about the role of nonalcoholic fatty liver disease (NAFLD) in predicting the development of chronic kidney disease (CKD) in type 1 diabetes. RESEARCH DESIGN AND METHODS We studied 261 type 1 diabetic adults with preserved kidney function and with no macroalbuminuria at baseline, who were followed for a mean period of 5.2 years for the occurrence of incident CKD (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 and/or macroalbuminuria). NAFLD was diagnosed by ultrasonography. RESULTS At baseline, patients had a mean eGFR of 92 ± 23 mL/min/1.73 m2; 234 (89.7%) of them had normoalbuminuria and 27 (10.3%) microalbuminuria. NAFLD was present in 131 (50.2%) patients. During follow-up, 61 subjects developed incident CKD. NAFLD was associated with an increased risk of incident CKD (hazard ratio [HR] 2.85 [95% CI 1.59–5.10]; P < 0.001). Adjustments for age, sex, duration of diabetes, hypertension, A1C, and baseline eGFR did not appreciably attenuate this association (adjusted HR 2.03 [1.10–3.77], P < 0.01). Results remained unchanged after excluding those who had microalbuminuria at baseline (adjusted HR 1.85 [1.03–3.27]; P < 0.05). Addition of NAFLD to traditional risk factors for CKD significantly improved the discriminatory capability of the regression models for predicting CKD (e.g., with NAFLD c statistic 0.79 [95% CI 0.73–0.86] vs. 0.76 [0.71–0.84] without NAFLD, P = 0.002). CONCLUSIONS This is the first study to demonstrate that NAFLD is strongly associated with an increased incidence of CKD. Measurement of NAFLD improves risk prediction for CKD, independently of traditional cardio-renal risk factors, in patients with type 1 diabetes.

Variability of body weight, pulse pressure and glycaemia strongly predict total mortality in elderly type 2 diabetic patients. The Verona Diabetes Study.

Ageing is characterized by a decreased functional reserve, a concept defined as homeostenosis. We assessed the impact of long‐term exposure to the average value (mean) or to the variability (coefficient of variation) of fasting glycaemia, body mass index (BMI) and pulse pressure on total mortality in a cohort of type 2 diabetic patients.

Increased prevalence of chronic kidney disease in patients with Type 1 diabetes and non‐alcoholic fatty liver

Diabet. Med. 29, 220–226 (2012)

Variants and Haplotypes of TCF7L2 Are Associated with β-Cell Function in Patients with Newly Diagnosed Type 2 Diabetes: The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 1

CONTEXT Intronic variants of TCF7L2 are confirmed genetic risk factors for type 2 diabetes and are associated to alterations in beta cell function in nondiabetic individuals. OBJECTIVE The objective of the study was to test whether TCF7L2 variability may affect β-cell function also in patients with type 2 diabetes. DESIGN This was a cross-sectional association study. SETTING The study was conducted at a university hospital referral center for diabetes. PATIENTS Patients included 464 (315 males and 149 females) glutamic acid decarboxylase-negative patients [age: median 59 yr (interquartile range: 52-65); body mass index: 29.3 kg/m(2) (26.5-32.9); fasting plasma glucose: 7.0 mmol/liter (6.1-8.0)] with newly diagnosed type 2 diabetes. INTERVENTION(S) Interventions included frequently sampled oral glucose tolerance test and euglycemic insulin clamp. MAIN OUTCOME MEASURE(S) β-Cell function (derivative control and proportional control); insulin sensitivity; genotypes of the following TCF7L2 single-nucleotide polymorphisms: rs7901695, rs7903146, rs11196205, and rs12255372. RESULTS Both rs7901695 and rs7903146 diabetes risk alleles were associated with reduced proportional control of β-cell function (P = 0.019 and P = 0.022, respectively). Two low-frequency haplotypes were associated with extreme (best and worst) phenotypes of β-cell function (P < 0.01). No associations between TCF7L2 genotypes and insulin sensitivity were detected. CONCLUSIONS TCF7L2 diabetes risk variants, either as single-nucleotide polymorphisms or as haplotypes, detrimentally influence β-cell function and might play a role in determining the metabolic phenotype of patients with newly diagnosed type 2 diabetes.

Differences in the Acute Effects of Aerobic and Resistance Exercise in Subjects with Type 2 Diabetes: Results from the RAED2 Randomized Trial

Objective Both aerobic (AER) and resistance (RES) training, if maintained over a period of several months, reduce HbA1c levels in type 2 diabetes subjects. However, it is still unknown whether the short-term effects of these types of exercise on blood glucose are similar. Our objective was to assess whether there may be a difference in acute blood glucose changes after a single bout of AER or RES exercise. Study Design Twenty-five patients participating in the RAED2 Study, a RCT comparing AER and RES training in diabetic subjects, were submitted to continuous glucose monitoring during a 60-min exercise session and over the following 47 h. These measurements were performed after 10.9+0.4 weeks of training. Glucose concentration areas under the curve (AUC) during exercise, the subsequent night, and the 24-h period following exercise, as well as the corresponding periods of the non-exercise day, were assessed. Moreover, the low (LBGI) and high (HBGI) blood glucose indices, which summarize the duration and extent of hypoglycaemia or hyperglycaemia, respectively, were measured. Results AER and RES training similarly reduced HbA1c. Forty-eight hour glucose AUC was similar in both groups. However, a comparison of glucose AUC during the 60-min exercise period and the corresponding period of the non-exercise day showed that glucose levels were lower during exercise in the AER but not in the RES group (time-by-group interaction p = 0.04). Similar differences were observed in the nocturnal periods (time-by-group interaction p = 0.02). Accordingly, nocturnal LBGI was higher in the exercise day than in the non-exercise day in the AER (p = 0.012) but not in the RES group (p = 0.62). Conclusions Although AER and RES training have similar long-term metabolic effects in diabetic subjects, the acute effects of single bouts of these exercise types differ, with a potential increase in late-onset hypoglycaemia risk after AER exercise. Trial registration ClinicalTrials.gov NCT01182948