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Ele Ferrannini

Publications and source records attributed to Ele Ferrannini.

88 records · Page 5Linked to original sources
PubMed2003

Insulin stimulates liver glucose uptake in humans: an 18F-FDG PET Study.

UNLABELLED: The liver is vital for the regulation of glucose metabolism, but inaccessibility of the organ for direct assessments has limited the study of its metabolic role in vivo. METHODS: The effect of insulin and insulin sensitivity (IS) on hepatic glucose uptake was investigated using PET, (18)F-FDG, and graphical analysis and 3-compartment modeling in humans. We studied 16 healthy sedentary men (normal IS), 8 athletes (high IS), and 7 patients with coronary artery disease (low IS) either during fasting (n = 14) or during euglycemic hyperinsulinemia (n = 24). RESULTS: Whole-body insulin-mediated glucose uptake was 35 +/- 7 micro mol/min/kg for normal-IS subjects, 65 +/- 8 micro mol/min/kg for high-IS subjects (P < 0.05 vs. normal IS), and 24 +/- 3 micro mol/min/kg for low-IS subjects (P < 0.05 vs. normal IS and high IS). Hyperinsulinemia enhanced hepatic glucose influx (2.3 +/- 0.9 vs. 1.5 +/- 0.7 micro mol x min(-1) x 100 mL(-1), P < 0.05) and phosphorylation rates (0.55 +/- 0.24 vs. 0.36 +/- 0.19 min(-1) x 10(-2), P < 0.05) similarly in insulin-sensitive and -resistant subjects. During hyperinsulinemia, however, the glucose phosphorylation-to-dephosphorylation ratio was significantly lower in the low-IS group than in normal-IS subjects (P < 0.05) or high-IS subjects (P < 0.01); correspondingly, whole-body insulin-mediated glucose disposal was directly related to this ratio (r = 0.45; P < 0.05). Furthermore, glucose influx rates were inversely correlated with fasting plasma free fatty acids (P < 0.05). Both compartmental modeling and the graphical approach accurately described the data, though the latter yielded slightly lower estimates of glucose influx rates during fasting. CONCLUSION: Our study provided evidence that physiologic hyperinsulinemia enhances hepatic glucose uptake and that IS is related to the glucose phosphorylation-to-dephosphorylation balance in the liver. Graphical analysis and modeling proved to be applicable and complementary tools for the investigation of glucose metabolism in the liver.

Adult↗
PubMed2002

Meal and oral glucose tests for assessment of beta -cell function: modeling analysis in normal subjects.

We investigated beta-cell function and its relationship to insulin sensitivity in 17 normal volunteers. For insulin secretion (derived by C-peptide deconvolution), a mathematical model was applied to 24-h triple-meal tests (MT) as well as oral glucose tolerance tests (OGTT); insulin sensitivity was assessed by the euglycemic insulin clamp technique. The beta-cell model featured a glucose concentration-insulin secretion dose response (characterized by secretion at 5 mM glucose and slope), a secretion component proportional to the glucose concentration derivative, and a time-dependent potentiation factor (modulating the dose response and accounting for effects of sustained hyperglycemia and incretins). The beta-cell dose-response functions estimated from the whole 24-h MT, the first 2 h of the MT, and the OGTT differed systematically, because a different potentiation factor was involved. In fact, potentiation was higher than average during meals (1.6 +/- 0.1-fold during the first meal) and had a different time course in the MT and OGTT. However, if potentiation was accounted for, the 24- and 2-h MT and the OGTT yielded similar dose responses, and most beta-cell function parameters were intercorrelated (r = 0.50-0.86, P < or = 0.05). The potentiation factor was found to be related to plasma glucose-dependent insulin-releasing polypeptide concentrations (r = 0.49, P < 0.0001). Among beta-cell function parameters, only insulin secretion at 5 mM glucose from MT correlated inversely with insulin sensitivity (24-h MT: r = -0.74, P < 0.001; 2-h MT: r = -0.52, P < 0.05), whereas the dose-response slope and the OGTT parameters did not. In nine other subjects, reproducibility of model parameters was evaluated from repeated MTs. Coefficients of variation were generally approximately 20%, but the derivative component was less reproducible. We conclude that our model for the multiple MT yields useful information on beta-cell function, particularly with regard to the role of potentiation. With cautious interpretation, a 2-h MT or a standard OGTT can be used as surrogates of 24-h tests in assessing spontaneous beta-cell function.

Adult↗
PubMed2002

Discordant effect of IFN-beta1a therapy on anti-IFN antibodies and thyroid disease development in patients with multiple sclerosis.

Interferon-beta1b (IFN-beta1b) therapy is associated with a relatively high risk of developing thyroid disease. IFN-beta1a is regarded as less immunogenic than IFN-beta1b because of its structural homology to natural IFN-beta. We assessed the effect of 1 year of IFN-beta1a treatment on thyroid function and autoimmunity in 14 multiple sclerosis (MS) patients. The results were compared with those obtained in a series of 31 MS patients treated with IFN-beta1b. The prevalence of positive binding antibody (BAb) titer and neutralizing (NAb) anti-IFN antibody titer in the two groups was also assessed. The BAb and NAb positivity rate in IFN-beta1a-treated patients was significantly lower than in the group submitted to IFN-beta1b therapy (7% vs. 84% and 0% vs. 30%, respectively). Although the incidence of thyroid dysfunction was slightly higher in IFN-beta1b-treated patients than in those undergoing IFN-beta1a treatment (33% vs. 23%, respectively), it did not reach statistical significance. Thyroid disease was unrelated to the presence of positive serum BAb or NAb titer in both the group undergoing IFN-beta1a therapy and in that treated with IFN-beta1b. In both groups, thyroid disease developed mostly in women (71%) against a background of preexisting thyroiditis and a diffuse hypoechoic ultrasound thyroid pattern (80%). IFN-beta1a treatment was associated with a significantly lower prevalence of both BAb and NAb-positive titers than was IFN-beta1b. Conversely, thyroid disease was similar and unrelated to the presence of positive anti-IFN-beta antibody titer. Therefore, routine thyroid assessment may be advised during IFN-beta1a treatment, especially in patients with preexisting thyroiditis.

Adult↗
PubMed2002

Metabolic effects of combined antihypertensive treatment in patients with essential hypertension.

Single-drug treatment of essential hypertension (HT) is often insufficient to normalize blood pressure (BP), and high doses of antihypertensive agents can have adverse effects on glucose tolerance (GT) and insulin sensitivity. This study tested whether aggressive BP lowering with combination treatment had any influence on GT or insulin action. In all, 29 nonobese (body mass index [BMI], <30 kg/m ), normolipidemic patients with established HT (159 +/- 3/99 +/- 1 mm Hg) but normal GT were recruited. Eleven normotensive (125 +/- 3/85 +/- 1 mm Hg) subjects were matched to the patients for both anthropometric and metabolic variables. Following baseline studies (serum lipid profile, oral GT, insulin release, and insulin sensitivity assessed by the insulin clamp technique), patients were randomized in a double-blind fashion to two combination regimens (verapamil 180 mg/day + trandolapril 2 mg/day or atenolol 50 mg/day + nifedipine 20 mg/day) and restudied 3 months later. Blood pressure was normalized in both groups (with decrements of 25 +/- 5/17 +/- 2 and 29 +/- 3/15 +/- 2 mm Hg, respectively). Lipid profile, GT, insulin release, and insulin sensitivity of both glucose uptake and lipolysis were unchanged following both treatments. The authors conclude that in nonobese, normolipidemic, glucose-tolerant hypertensive patients, BP normalization with combination therapy is feasible at no cost in terms of undesired effects on glucose and lipid metabolism and insulin sensitivity.

Antihypertensive Agents↗
PubMed2002

Regional myocardial blood flow and glucose utilization during fasting and physiological hyperinsulinemia in humans.

We investigated the effect of insulin on total and regional myocardial blood flow (MBF) and glucose uptake (MGU) in healthy subjects (50 +/- 5 yr) by means of positron emission tomography (PET) with oxygen-15-labeled water (H(2)(15)O) and fluorine-18 labeled fluorodeoxyglucose ((18)FDG) before and during physiological hyperinsulinemia (40 mU.min(-1).m(-2)). Twelve male subjects were included in the study. During hyperinsulinemia, MBF increased from 0.91 +/- 0.28 to 1.01 +/- 0.31 ml.min(-1).g(-1) (n = 7 patients, P = 0.05; n = 112 regions, P < 0.005). Intersubject variability ranged from -3.0 to +41%. MGU increased from 0.11 +/- 0.08 (n = 5) to 0.56 +/- 0.08 micromol.min(-1).g(-1) (P < 0.0001, n = 7). MBF and insulin-mediated MGU were higher in the septum and anterior and lateral wall along short-axis regions of the heart. During hyperinsulinemia, MBF was also higher in the apex and midventricle compared with the base. MBF and MGU were positively correlated before (r = 0.66, P < 0.0001) and during hyperinsulinemia (r = 0.24, P < 0.05). These results provide evidence that insulin stimulates MBF in normal human hearts and appears to involve mainly those regions of the heart where insulin-mediated MGU is higher. Furthermore, regional distribution of insulin-stimulated MBF and MGU does not appear to be uniform across the left ventricular wall of healthy subjects.

Coronary Circulation↗
PubMed2002

Metabolic effects of visceral fat accumulation in type 2 diabetes.

Visceral fat (VF) excess has been associated with decreased peripheral insulin sensitivity and has been suggested to contribute to hepatic insulin resistance. However, the mechanisms by which VF impacts on hepatic glucose metabolism and the quantitative role of VF in glycemic control have not been investigated. In the present study 63 type 2 diabetic subjects (age, 55 +/- 1 yr; fasting plasma glucose, 5.5-14.4 mmol/liter; hemoglobin A(1c), 6.1-11.7%) underwent measurement of 1) fat-free mass ((3)H(2)O technique), 2) sc and visceral abdominal fat area (magnetic resonance imaging), 3) insulin sensitivity (euglycemic insulin clamp), 4) endogenous glucose output ([(3)H]glucose infusion technique), and 5) gluconeogenesis ((2)H(2)O method). After adjustment for sex, age, body mass index, diabetes duration, ethnicity, and sc fat area, VF area was positively related to fasting hyperglycemia (partial r = 0.46; P = 0.001) as well as to hemoglobin A(1c) (partial r = 0.50; P = 0.0003). Insulin sensitivity was reciprocally related to VF independently of body mass index (partial r = 0.33; P = 0.01). In contrast, the relation of basal endogenous glucose output to VF was not statistically significant. This lack of association was explained by the fact that VF was positively associated with gluconeogenesis flux (confounder-adjusted, partial r = 0.45; P = 0.003), but was reciprocally associated with glycogenolysis (partial r = 0.31; P < 0.05). We conclude that in patients with established type 2 diabetes, VF accumulation has a significant negative impact on glycemic control through a decrease in peripheral insulin sensitivity and an enhancement of gluconeogenesis.

Adipose Tissue↗
PubMed2002

Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled study.

The relationship between subclinical hypothyroidism (SCH) and an atherogenic lipoprotein profile is still controversial. We measured lipoproteins in 49 SCH patients by comparison with 33 euthyroid controls. Total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDLc), apolipoprotein A(1), apolipoprotein B, and lipoprotein (a) [Lp(a)] were measured after an overnight fast. Patients were randomly assigned to levothyroxine therapy or placebo and re-evaluated after 6 months of euthyroidism. SCH patients showed significantly higher TC (P < 0.01), LDLc (P = 0.01), and apolipoprotein B (P = 0.001) levels than controls, positively correlated with baseline TSH levels (P = 0.003, P = 0.01, and P = 0.03, respectively). Elevated Lp(a) levels were significantly more frequent in SCH (P < 0.05) and associated with familial diabetes mellitus and/or coronary heart disease (P < 0.01). Levothyroxine treatment resulted in a significant decrease of both TC and LDLc concentrations (P = 0.003), in direct proportion to the respective baseline values (P < 0.05 and P < 0.01, respectively), whereas no change in Lp(a) level was observed. No changes occurred in the placebo group. In conclusion, only serum LDLc levels are increased specifically and reversibly in association with SCH. Altered Lp(a) values reflect a genetic influence rather than a reduced thyroid hormone action.

Adult↗
PubMed2002

Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion.

Obesity is a frequent cause of insulin resistance and poses a major risk for diabetes. Abnormal fat deposition within skeletal muscle has been identified as a mechanism of obesity-associated insulin resistance. We tested the hypothesis that dietary lipid deprivation may selectively deplete intramyocellular lipids, thereby reversing insulin resistance. Whole-body insulin sensitivity (by the insulin clamp technique), intramyocellular lipids (by quantitative histochemistry on quadriceps muscle biopsies), muscle insulin action (as the expression of Glut4 glucose transporters), and postprandial lipemia were measured in 20 morbidly obese patients (BMI = 49 +/- 8 [mean +/- SD] kg x m(-2)) and 7 nonobese control subjects. Patients were restudied 6 months later after biliopancreatic diversion (BPD; n = 8), an operation that induces predominant lipid malabsorption, or hypocaloric diet (n = 9). At 6 months, BPD had caused the loss of 33 +/- 10 kg through lipid malabsorption (documented by a flat postprandial triglyceride profile). Despite an attained BMI still in the obese range (39 +/- 8 kg x m(-2)), insulin resistance (23 +/- 3 micromol/min per kg of fat-free mass; P < 0.001 vs. 53 +/- 13 of control subjects) was fully reversed (52 +/- 11 micromol/min per kg of fat-free mass; NS versus control subjects). In parallel with this change, intramyocellular-but not perivascular or interfibrillar-lipid accumulation decreased (1.63 +/- 1.06 to 0.22 +/- 0.44 score units; P < 0.01; NS vs. 0.07 +/- 0.19 of control subjects), Glut4 expression was restored, and circulating leptin concentrations were normalized. In the diet group, a weight loss of 14 +/- 12 kg was accompanied by very modest changes in insulin sensitivity and intramyocellular lipid contents. We conclude that lipid deprivation selectively depletes intramyocellular lipid stores and induces a normal metabolic state (in terms of insulin-mediated whole-body glucose disposal, intracellular insulin signaling, and circulating leptin levels) despite a persistent excess of total body fat mass.

Adult↗
PubMed2002

Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance.

Clustering of classical cardiovascular risk factors is insufficient to account for the excess coronary artery disease (CAD) of patients with diabetes, and chronic hyperglycemia and insulin resistance (IR) are obvious culprits. Whole-body and skeletal muscle IR is characteristic of patients with type 2 diabetes, but whether it extends to the normally contracting cardiac muscle is controversial. We investigated whether type 2 diabetes is associated with myocardial IR independent of CAD in a case-control series (n = 55) of male nondiabetic and diabetic (type 2 and type 1) patients with or without angiographically documented CAD. Baseline blood flow ((15)O-water) and insulin-stimulated glucose uptake ((18)F-fluoro-deoxyglucose) during euglycemic (5.6 mmol/l), physiological hyperinsulinemia (40 mU x min(-1) x m(-2) insulin clamp) were measured by positron emission tomography in skeletal muscle and normally contracting myocardium. Skeletal muscle glucose uptake was reduced in association with both CAD and type 2 diabetes. In regions with normal baseline perfusion, insulin-mediated myocardial glucose uptake was reduced in non-CAD type 2 diabetic (0.36 +/- 0.14 micro mol x min(-1). g(-1)) and nondiabetic CAD patients (0.44 +/- 0.15 micro mol x min(- 1) x g(-1)) in comparison with healthy control subjects (0.61 +/- 0.08) or with non-CAD type 1 diabetic patients (0.80 +/- 0.13; P < 0.001 for both CAD and diabetes). Neither basal skeletal muscle nor basal myocardial blood flow differed across groups; both skeletal muscle and myocardial IR were directly related to whole-body IR. We conclude that type 2 diabetes is specifically associated with myocardial IR that is independent of and nonadditive with angiographic CAD and proportional to skeletal muscle and whole-body IR.

Adult↗
PubMed2002

Effect of acute hyperglycemia on insulin secretion in humans.

First-phase insulin response to intravenous glucose is impaired both in type 2 diabetic patients and in subjects at risk for the disease. Hyperglycemia can modify beta-cell response by either inhibiting or potentiating both first- and second-phase insulin release. In normal subjects, the effect of acute hyperglycemia on insulin secretion is controversial. We measured (in 13 healthy volunteers) insulin secretion (by deconvolution of plasma C-peptide concentrations) during three consecutive 30-min hyperglycemic steps (2.8, 2.8, and 5.6 mmol/l), followed by an intravenous arginine bolus. First-phase insulin secretion in response to the first hyperglycemic step (456 +/- 83 pmol.min(-1).m(-2)) was significantly larger than that in response to the second step (311 +/- 37 pmol.min(-1).m(-2), P < 0.01); the subsequent increase in glycemia failed to stimulate first-phase secretion any further (377 +/- 60 pmol.min(-1).m(-2), NS vs. the previous value). This inhibition was also evident when insulin release rates were corrected for the respective increments (absolute or percentage) in plasma glucose levels and was not due to beta-cell exhaustion because the arginine bolus still elicited a large peak of insulin secretion (4,790 +/- 2,330 pmol.min(-1).m(-2)). In contrast, second-phase insulin secretion was related to the prevailing glucose levels across the three hyperglycemic steps in a direct quasilinear manner. We conclude that first-phase insulin secretion is inhibited by short-term modest hyperglycemia, whereas the second-phase insulin secretion increases linearly with hyperglycemia.

Acute Disease↗
PubMed2002

Assessing insulin secretion by modeling in multiple-meal tests: role of potentiation.

We developed a mathematical model of the glucose control of insulin secretion capable of quantifying beta-cell function from a physiological meal test. The model includes a static control, i.e., a secretion component that is a function of plasma glucose concentration (the dose-response function), and a dynamic control, i.e., a secretion component that is proportional to the positive values of the glucose concentration derivative. Furthermore, the dose-response function is assumed to be modulated by a time-varying potentiation factor. To test the model, nine nondiabetic control subjects and nine type 2 diabetic patients received three standardized mixed meals over a period of 14-15 h. Blood samples were drawn for the measurement of glucose, insulin, and C-peptide concentration. The dose-response function, the parameter of the dynamic control, and the potentiation factor were determined by fitting the model to glucose and C-peptide concentrations. In diabetic patients, the dose-response function was shifted to the right (glucose concentration at a reference insulin secretion of 300 pmol.min(-1).m(-2) was 11.7 +/- 1.1 vs. 7.2 +/- 0.7 mmol/l; P < 0.05), and decreased in slope (53 +/- 15 vs. 148 +/- 38 pmol.min(-1).m(-2).mmol(-1).l; P < 0.05) and the parameter of the dynamic control was decreased (220 +/- 67 vs. 908 +/- 276 pmol.m(-2).mmol(-1).l; P < 0.05) compared with the nondiabetic control subjects. Furthermore, potentiation was markedly blunted and delayed: maximum potentiation was observed at the first meal in normal subjects and at the second meal (about 4 h later) in diabetic subjects; the mean time for the potentiation factor was higher (7.1 +/- 0.2 vs. 5.9 +/- 0.2 h; P < 0.01), and the size of potentiation was reduced (2.6 +/- 0.5 vs. 7.2 +/- 1.5 fold increase; P < 0.005). In conclusion, our model of insulin secretion extracts multiple indexes of beta-cell function from a physiological meal test. Use of the model in patients with type 2 diabetes retrieves known defects in insulin secretion but also uncovers new facets of beta-cell dysfunction.

Adult↗
PubMed2002

Prolonged in vitro exposure to autoantibodies against CD38 impairs the function and survival of human pancreatic islets.

Autoantibodies against CD38 (adenosine-5'-diphosphate[ADP]-ribosyl cyclase/cyclic ADP-ribose hydrolase) have been described in 10-12% of patients with type 2 diabetes. In human islets, anti-CD38 autoantibodies (CD38Abs) acutely stimulate insulin release (IR) and increase the cytosolic calcium concentration ([Ca(2+)](i)). Whether CD38Abs affect human islet cell function and survival upon prolonged in vitro exposure is not known. We cultured human islets for up to 7 days in the presence of sera from 10 patients with type 2 diabetes that had neither CD38Ab- nor [Ca(2+)](i)-mobilizing activity (-/-), sera from 6 patients with type 2 diabetes that was CD38Ab-positive and had [Ca(2+)](i)-mobilizing activity (+/+), or no sera (control). At baseline, +/+ sera caused a significant (P < 0.002) acute stimulation of IR (IR at 3.3 mmol/l glucose was 45 +/- 19, 84 +/- 24, and 34 +/- 12 micro U/ml in control, +/+, and -/- sera, respectively; the corresponding IR at 16.7 mmol/l glucose was 72 +/- 25, 204 +/- 56, and 80 +/- 32 micro U/ml). At 3 days, IR at 3.3 mmol/l glucose was 42 +/- 18, 27 +/- 11, and 43 +/- 24 micro U/ml (P = 0.0003) for control, +/+, and -/- sera, respectively, whereas at 16.7 mmol/l glucose, it was 95 +/- 76, 45 +/- 35, and 76 +/- 42 micro U/ml, respectively. After 7 days of exposure, the corresponding IR at 3.3 mmol/l glucose was 40 +/- 11, 28 +/- 12, and 35 +/- 15 micro U/ml, respectively, whereas at 16.7 mmol/l glucose it was 79 +/- 39, 39 +/- 17, and 62 +/- 39 micro U/ml. At both 3 and 7 days, IR still increased when switching from 3.3 to 16.7 mmol/l glucose (P < 0.0003), and incubation with +/+ sera induced a significant decrease in the insulin response (P < 0.002). At 7 days, the number of dead cells (as evaluated by an enzyme-linked immunosorbent assay technique) differed significantly between control (1.2 +/- 0.3 OD units) cells, islets exposed to -/- sera (1.4 +/- 0.1), and islets coincubated with +/+ sera (1.9 +/- 0.4, P < 0.01). We conclude that prolonged exposure of human islets to sera positive for the presence of CD38Abs with [Ca(2+)](i)-mobilizing activity impairs beta-cell function and viability in cultured human pancreatic islets.

ADP-ribosyl Cyclase↗
PubMedDate not supplied

[Extrahepatic manifestations of hepatitis C virus: the thyroid disorders].

The prevalence of thyroid disorders has been studied in patients with chronic hepatitis C virus (HCV) infection by many studies. In general, thyroid dysfunction in chronic C hepatitis may include all forms of thyroid alterations, i.e. hypothyroidism and hyperthyroidism, Hashimoto's disease and isolated increases in antithyroid autoantibodies. The prevalence of various thyroid disorders and serum anti-thyroid autoantibodies is generally higher in chronic hepatitis type C than in hepatitis B or D or control series. The results of most studies in patients with hepatitis C confirm a higher prevalence of autoimmune thyroid involvement and hypothyroidism than in controls. More recently, some epidemiological studies have suggested a possible association between HCV and thyroid cancer. These last data need to be confirmed by other studies, but seem to be sufficient to suggest careful thyroid monitoring during the follow-up of patients with HCV infection.

Europe↗