Prediction of mortality and macrovascular complications in type 2 diabetes: validation of the UKPDS Outcomes Model in the Casale Monferrato Survey, Italy.

AIMS/HYPOTHESIS: The United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model can be used to estimate the lifetime occurrence of major diabetes-related complications in order to calculate health economic outcomes. The aim of the study was to assess the performance of the model by comparing the predicted and observed mortality and the incidence of macrovascular complications in an Italian population-based cohort with type 2 diabetes. METHODS: We used data from the Casale Monferrato Survey, a cohort enrolled in 1988 and surveyed in 1991 (n = 1,967) to assess the prevalence of cardiovascular risk factors. In 2000, a new survey included all the members of the original cohort who were still alive (n = 860), and in addition all individuals identified with a new diagnosis of type 2 diabetes since 1993 (n = 2,389). We compared the mortality predicted by the model for the 1991 survey over the subsequent 17-year period with the observed risk. The following outcomes were analysed in the 2000 survey: myocardial infarction (MI), other ischaemic heart disease, stroke, congestive heart failure (CHF) and amputation. RESULTS: For all-cause mortality, the predictions from the model at 5 and 10 years (23% and 47%, respectively) were identical to the observed risks. At 15 years, the risk of death was slightly overestimated (an estimate of 67% vs 64% observed, 95% CI 61%, 66%). The performance of the model was best for patients with a recent history of disease (duration <6 years). Among the complications, the predicted cumulative incidences of MI and CHF were very close to those observed. CONCLUSIONS/INTERPRETATION: External validation is essential to assess the accuracy of simulation models. The UKPDS Outcomes Model satisfactorily predicted a set of actual incidences of mortality and complications in an Italian diabetes cohort up to a duration of approximately 12 years. The longer term performance of such models should be carefully evaluated.

Diabetes-specific variables associated with quality of life changes in young diabetic people: the type 1 diabetes Registry of Turin (Italy).

BACKGROUND AND AIMS: Type 1 diabetes (T1DM) affects young people during the most active years of their life. Our aim was to assess quality of life (QoL) and associated variables in a large cohort of adults with childhood-onset and adult-onset T1DM. METHODS: A cohort of adult patients (18 years and older) from the T1DM Registry of Turin, Italy, was recruited. Clinical characteristics and Diabetes QoL (DQOL) questionnaire were assessed by standardized procedures. RESULTS: 310 adults completed the questionnaire. Age and diabetes duration at assessment (mean ± SD) were 32.8 ± 7.3 years and 17.3 ± 6.3 years, respectively. DQOL and its subscores were in the lower quartiles of their distributions, indicating a good level of QoL. However, scores were significantly higher in females than in males, particularly for the subscale of diabetes-related worries. In multivariate analysis, lower QoL was independently associated with female sex (ß = 1.07, 95% CI 1.03-1.11, p = 0.003), higher age at onset (ß = 1.03, 1.00-1.05, p = 0.009), lower schooling (ß = 1.05, 1.00-1.09, p = 0.02), higher fasting plasma glucose (ß = 1.03, 1.01-1.05, p = 0.008), daily SMBG >4 (ß = 1.06, 1.01-1.10, p = 0.01), severe hypoglycemia over the last year (ß = 1.06, 1.01-1.11, p = 0.02), lower numbers of diabetologic visits (ß = 1.07, 1.01-1.13, p = 0.02) and hypertension (ß = 1.06, 1.02-1.10, p = 0.005). Autonomic neuropathy was associated with diabetes impact. Female sex (ß = 4.36, 2.43-7.83) and daily SMBG >4 (ß = 3.77, 1.72-8.30) were independently associated with worst level and CSII with better level (ß = 0.22, 0.07-0.68) of diabetes-related worries. CONCLUSIONS: The impact of T1DM on QoL may depend on demographic, metabolic control-related variables, presence of complications and insulin delivery modality.

The ghrelin gene products and exendin-4 promote survival of human pancreatic islet endothelial cells in hyperglycaemic conditions, through phosphoinositide 3-kinase/Akt, extracellular signal-related kinase (ERK)1/2 and cAMP/protein kinase A (PKA) signalling pathways.

AIMS/HYPOTHESIS: Pancreatic islet microendothelium exhibits unique features in interdependent relationship with beta cells. Gastrointestinal products of the ghrelin gene, acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin (Ob), and the incretin, glucagon-like peptide-1 (GLP-1), prevent apoptosis of pancreatic beta cells. We investigated whether the ghrelin gene products and the GLP-1 receptor agonist exendin-4 (Ex-4) display survival effects in human pancreatic islet microendothelial cells (MECs) exposed to chronic hyperglycaemia. METHODS: Islet MECs were cultured in high glucose concentration and treated with AG, UAG, Ob or Ex-4. Apoptosis was assessed by DNA fragmentation, Hoechst staining of the nuclei and caspase-3 activity. Western blot analyses and pharmacological inhibition of protein kinase B (Akt) and extracellular signal-related kinase (ERK)1/2 pathways, detection of intracellular cAMP levels and blockade of adenylyl cyclase (AC)/cAMP/protein kinase A (PKA) signalling were performed. Levels of NO, IL-1ß and vascular endothelial growth factor (VEGF)-A in cell culture supernatant fractions were measured. RESULTS: Islet MECs express the ghrelin receptor GHS-R1A as well as GLP-1R. Treatment with AG, UAG, Ob and Ex-4 promoted cell survival and significantly inhibited glucose-induced apoptosis, through activation of PI3K/Akt, ERK1/2 phosphorylation and intracellular cAMP increase. Moreover, peptides upregulated B cell lymphoma 2 (BCL-2) and downregulated BCL-2-associated X protein (BAX) and CD40 ligand (CD40L) production, and significantly reduced the secretion of NO, IL-1ß and VEGF-A. CONCLUSIONS/INTERPRETATION: The ghrelin gene-derived peptides and Ex-4 exert cytoprotective effects in islet MECs. The anti-apoptotic effects involve phosphoinositide 3-kinase (PI3K)/Akt, ERK1/2 and cAMP/PKA pathways. These peptides could therefore represent a potential tool to improve islet vascularisation and, indirectly, islet cell function.

The rs553668 polymorphism of the ADRA2A gene predicts the worsening of fasting glucose values in a cohort of subjects without diabetes. A population-based study.

AIMS: Single-nucleotide polymorphisms in the human ADRA2A gene have been associated with increased risk of Type 2 diabetes. The associations between the rs553668 polymorphism and fasting glucose concentrations both cross-sectionally and longitudinally after 6-year follow-up were evaluated in an adult Caucasian population-based cohort. METHODS: From a cohort of 1658 individuals, after excluding patients with diabetes, those who died and those whose blood samples were not available for genotyping, data of 1345 individuals were analysed. RESULTS: Subjects homozygous for the A allele showed significantly increased baseline fasting glucose values and a significant worsening of fasting glucose (ß = 0.48; 95% CI 0.10-0.86) and insulin secretion (ß =-20.75; -32.67 to -8.82 for homeostasis model assessment for ß-cell function) at follow-up by using generalized estimating equations. Incidence of impaired fasting glucose and diabetes was almost twofold higher in subjects homozygous for the A allele (respectively: incident impaired fasting glucose 7.6-8.2, 16.1%, incident diabetes 1.7-2.3, 3.2% in GG, AG, AA carriers). CONCLUSIONS: Our results suggested that the rs553668 polymorphism is associated with glucose worsening in subjects without diabetes at baseline.

Direct costs in diabetic and non diabetic people: the population-based Turin study, Italy.

BACKGROUND AND AIMS: We compared direct costs of diabetic and non diabetic people covered by the Italian National Health System, focusing on the influence of age, sex, type of diabetes and treatment. METHODS AND RESULTS: Diabetic people living in Turin were identified through the Regional Diabetes Registry and the files of hospital discharges and prescriptions. Data sources were linked to the administrative databases to assess health care services used by diabetic (n = 33,792) and non diabetic people(n = 863,123). Data were analyzed with the two-part model; the estimated direct costs per person/year were €3660.8 in diabetic people and €895.6 in non diabetic people, giving a cost ratio of 4.1. Diabetes accounted for 11.4% of total health care expenditure. The costs were attributed to hospitalizations (57.2%), drugs (25.6%), to outpatient care (11.9%), consumable goods (4.4%) and emergency care (0.9%). Estimated costs increased from € 2670.8 in diabetic people aged <45 years to € 3724.1 in those aged >74 years, the latter representing two third of the diabetic cohort; corresponding figures in non diabetic people were € 371.6 and € 2155.9. In all expenditure categories cost ratios of diabetic vs non diabetic people were higher in people aged <45 years, in type 1 diabetes and in insulin-treated type 2 diabetes. CONCLUSION: Direct costs are 4-fold higher in diabetic than in non diabetic people, mainly due to care of the elderly and inpatient care. In developed countries, demographic changes will have a profound impact on costs for diabetes in next years.

Is left ventricular hypertrophy a low-level inflammatory state? A population-based cohort study.

BACKGROUND AND AIMS: Cross-sectional studies have shown that chronic sub-clinical inflammation is associated with left ventricular hypertrophy (LVH), but results are conflicting. We investigated the association between baseline LVH and high-sensitivity C-reactive protein (CRP) values, both cross-sectionally and after a six-year-follow-up, in a population-based cohort (n = 1564) and a subgroup from this cohort (n = 515), without obesity, diabetes, metabolic syndrome or any drugs. METHODS AND RESULTS: ECG tracings at baseline were interpreted according to the Cornell voltage-duration product criteria: 166/1564 subjects (10.6%) showed LVH. Patients with baseline LVH showed increased BMI, waist circumference, blood pressure, and a worse metabolic pattern. Their CRP values both at baseline and at follow-up were almost two-fold higher than in patients without LVH. Similar results were found in the healthier sub-sample. In a multiple regression model, CRP at follow-up was directly associated with baseline LVH (expressed as Cornell voltage-duration product) in the whole cohort (ß = 0.0003; 95%CI 0.0002-0.0006; p < 0.001) and in the sub-sample (ß = 0.0003; 0.0002-0.0004; p < 0.001), after adjusting for age, sex, BMI, waist circumference, smoking, exercise levels, blood pressure and baseline CRP values. CONCLUSION: Baseline LVH, which is associated with systemic inflammation, predicts increased CRP values at follow-up, independently of cardiovascular and metabolic risk factors, both in a population-based cohort and a healthier sub-sample. The inflammatory consequences of LVH might be an intriguing subject for further researches.

Contributors to the obesity and hyperglycemia epidemics. A prospective study in a population-based cohort.

OBJECTIVE: Relatively unexplored contributors to the obesity and diabetes epidemics may include sleep restriction, increased house temperature (HT), television watching (TW), consumption of restaurant meals (RMs), use of air conditioning (AC) and use of antidepressant/antipsychotic drugs (ADs). DESIGN AND SUBJECTS: In a population-based cohort (n=1597), we investigated the possible association among these conditions, and obesity or hyperglycemia incidence at 6-year follow-up. Subjects with obesity (n=315) or hyperglycemia (n=618) at baseline were excluded, respectively, 1282 and 979 individuals were therefore analyzed. RESULTS: At follow-up, 103/1282 became obese; these subjects showed significantly higher body mass index, waist circumference, saturated fat intake, RM frequency, TW hours, HT, AC and AD use, and lower fiber intake, metabolic equivalent of activity in h per week (METS) and sleep hours at baseline. In a multiple logistic regression model, METS (odds ratio=0.94; 95% confidence interval (CI) 0.91-0.98), RMs (odds ratio=1.47 per meal per week; 1.21-1.79), being in the third tertile of HT (odds ratio=2.06; 1.02-4.16) and hours of sleep (odds ratio=0.70 per h; 0.57-0.86) were associated with incident obesity. Subjects who developed hyperglycemia (n=174/979; 17.8%) had higher saturated fat intake, RM frequency, TW hours, HT, AC and AD use at baseline and lower METS and fiber intake. In a multiple logistic regression model, fiber intake (odds ratio=0.97 for each g per day; 0.95-0.99), RM (1.49 per meal per week; 1.26-1.75) and being in the third tertile of HT (odds ratio=1.95; 1.17-3.26) were independently associated with incident hyperglycemia. CONCLUSIONS: Lifestyle contributors to the obesity and hyperglycemia epidemics may be regular consumption of RM, sleep restriction and higher HT, suggesting potential adjunctive non-pharmacological preventive strategies for the obesity and hyperglycemia epidemics.

The incidence of type 1 diabetes is increasing in both children and young adults in Northern Italy: 1984-2004 temporal trends.

AIMS/HYPOTHESIS: A shift towards younger age at onset of diabetes in susceptible people has been suggested as a possible explanation for the increasing temporal trend in incidence of type 1 diabetes. We aimed to test this hypothesis by assessing trends in incidence rates in the period 1984-2004 in children and young adults in Northern Italy. METHODS: The study bases were: (1) children resident in the Province of Turin in the period 1984-2004 and in the remaining areas of the Piedmont Region in the period 1990-2004; and (2) young adults (15-29 years) resident in the Province of Turin in the period 1984-2003. Temporal trends in rates were analysed using Poisson regression models. RESULTS: A total of 1,773 incident cases were identified. Overall incidence rates/100,000 person-years in the age groups 0-14 and 15-29 years were 11.3 (95% CI 10.7-12.0) and 7.1 (95% CI 6.6-7.7), respectively, with sex differences among young adults only (incidence rate ratio [IRR] in males vs females 1.41 [95% CI 1.20-1.64]). Average annual increases in incidence rates were similar in children and young adults at 3.3% (95% CI 2.5-4.1). Compared with the period 1984-89, in 2000-2004 a 60% higher risk was found in both age 0-14 years (IRR 1.60, 95% CI 1.31-1.95) and 15-29 years (IRR 1.57, 95% CI 1.26-1.96) groups. The Poisson modelling showed no interaction between calendar period and age at onset. CONCLUSIONS/INTERPRETATION: Incidence of type 1 diabetes in Northern Italy is increasing over time in both children and young adults, not supporting the hypothesis of a shift towards younger age as the main explanation for the increasing temporal trend in children.

ANTI-HSP60 and ANTI-HSP70 antibody levels and micro/ macrovascular complications in type 1 diabetes: the EURODIAB Study.

OBJECTIVES: The heat shock proteins 60 and 70 (HSP60, HSP70) play an important role in cytoprotection. Under stress conditions they are released into the circulation and elicit an immune response. Anti-HSP60 and anti-HSP70 antibody levels have been associated with cardiovascular disease. Type 1 diabetes is associated with a greatly increased risk of micro- and macrovascular complications. Therefore, we investigated whether anti-HSP60 and anti-HSP70 antibody levels were associated with micro- and macrovascular complications in type 1 diabetic patients. DESIGN: A cross-sectional nested case-control study from the EURODIAB Study of 531 type 1 diabetic patients was performed. SUBJECTS: Cases (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were all those with no evidence of any complication. We measured anti-HSP60 and anti-HSP70 antibody levels and investigated their cross-sectional associations with diabetic complications. RESULTS: Anti-HSP70 antibody levels were significantly greater in control than in case subjects, whereas anti-HSP60 antibody levels were similar in the two groups. In logistic regression analysis, anti-HSP70 levels in the upper quartiles were associated with a 47% reduced odds ratio of micro/macrovascular complications, independently of conventional risk factors, markers of inflammation and endothelial dysfunction [odds ratio (OR) = 0.53, 95% confidence intervals (CI): 0.28-1.02]. CONCLUSIONS: In this large cohort of type 1 diabetic subjects, we found an independent and inverse association between serum anti-HSP70 antibody levels and diabetic micro/macrovascular complications. This suggests that anti-HSP70 antibody levels may be a novel marker of protection from chronic diabetic complications.

What predicts the occurrence of the metabolic syndrome in a population-based cohort of adult healthy subjects?

BACKGROUND: Metabolic syndrome (MS), the concurrence of hyperglycaemia, dyslipidaemia, hypertension and visceral obesity, increases cardiovascular risk and mortality. Predictors of MS were previously evaluated in patients without the full syndrome, but with some of its traits. This might confound the resulting associations. METHODS: The relationship between baseline variables and MS development was evaluated in healthy middle-aged subjects without any MS component at baseline, over a 4.5-year follow-up. RESULTS: From a population-based cohort of 1658 subjects, 241 individuals showed no MS components and 201 (83.4%) of them participated in a follow-up screening. At baseline, patients who developed the MS (n = 28/201; 13.9%) showed significantly higher Homeostasis Model Assessment-Insulin Resistance score (HOMA-IR) and C-reactive protein (CRP) values, and lower exercise level than subjects who did not. In a multiple logistic regression analysis, after multiple adjustments, the only baseline variable significantly (p < 0.01) associated with the MS was CRP (OR = 4.05; 95% CI 2.23-7.38; p < 0.001). Results did not change after adjusting for weight gain. The area under the receiver-operating curve was 0.83 for CRP after multiple adjustments. The optimal cut-off point of baseline CRP values was 2.1 mg/L, with 86% (95% CI 81-90) sensitivity and 75% (69-81) specificity in predicting the MS. Baseline CRP resulted associated with after-study glucose values in a multiple regression model (beta = 0.14; 0.08-0.20; p < 0.001). CONCLUSIONS: Higher baseline CRP values confer a significant increased risk of developing the MS in healthy subjects, independently of weight gain.

Short-term mortality risk in children and young adults with type 1 diabetes: the population-based Registry of the Province of Turin, Italy.

Short-term mortality risk in young diabetic people is an indicator of quality of care. We assessed this in the Italian incident population-based registry of Turin. The study base included 1210 incident cases (n=677 aged 0-14 years and n=533 aged 15-29 years) with diabetes, onset period 1974-2000 in the Province of Turin, Italy. The relevant timescale for analysis was the time since the onset of diabetes to death, or till 31 December 2003. Standardized mortality ratio (SMR) for all-cause mortality was computed using the Italian population as a standard, by 5 years, age group, sex, and calendar period. Mean attained age of the incident cohort was 29.7 years (range 5.2-49.7 years). During a mean follow-up period of 15.8 years (range 2.0-29.9 years), there were 19 deaths in 15,967. Nine person-years of observation (n=9.5 expected deaths), giving an all-cause mortality rate of 1.19/1000 person-years (95% CI 0.76-1.87) and an SMR of 1.96 (1.25-3.08). In no cases did death occur at the onset of diabetes or in childhood. Out of 19 deaths, 9 were diabetes related (n=6 coma and n=3 end-stage renal disease). In Cox regression analysis, the hazard ratio (HR) was higher in adult-onset than in childhood-onset diabetes (HR=3.90, 95% CI 1.14-13.39), independently of calendar period and gender. (1) Children and young adults with type 1 diabetes experienced a two-fold higher short-term mortality risk than Italian people of similar age and sex and (2) the risk was higher in adult-onset than in childhood-onset diabetes. The quality of diabetes care should be improved to prevent early deaths.

Plasma visfatin concentrations after a lifestyle intervention were directly associated with inflammatory markers.

BACKGROUND AND AIMS: The biological activity and regulation of the novel adipokine visfatin are still largely unknown. Our aim was to evaluate if visfatin plasma concentrations may be influenced by a lifestyle intervention. METHODS AND RESULTS: Out of 335 dysmetabolic patients from a population-based cohort, randomized to receive a lifestyle intervention program (intervention group) or family physician usual care (controls), 20 patients per group were randomly selected for plasma visfatin determination. The before-after variation (Delta) in visfatin concentration at 1-year from randomization, and the correlations between (Delta)visfatin and intervention-induced changes in waist circumference, fasting glucose, markers of inflammation, and oxidative stress were evaluated. The intervention group showed a significant improvement in waist circumference, and many metabolic/inflammatory variables, while the controls worsened. Visfatin concentrations slightly decreased in the former and significantly increased in the controls ((Delta)visfatin=-2.4 vs 66.0 ng/ml, p<0.001). In robust regression models, the following variables resulted associated with (Delta)visfatin: (Delta)waist circumference, (Delta)fasting glucose, (Delta)hs-CRP (high-sensitivity C-reactive protein) and (Delta)TNFalpha (tumor necrosis factor-alpha). Significant effects on (Delta)visfatin of (Delta)TNFalpha (beta=16.8; 6.1-25.6; p=0.003) and, modified by group, of (Delta)hs-CRP (beta=29.8; 95% CI 15.4-44.2; p<0.001 and beta=4.2; 2.9-5.5; p<0.001 in the control and intervention group, respectively) were detected. By controlling for (Delta)waist, the effects of (Delta)TNFalpha and of (Delta)hs-CRP on (Delta)visfatin by group did not change, while (Delta)waist was no longer associated. The association between (Delta)visfatin and (Delta)glucose was no longer significant, after adjusting for (Delta)hs-CRP. CONCLUSION: Visfatin values increased with waist circumference and were associated with variations of inflammatory markers, suggesting participation in inflammatory mechanisms.

Associations between serum uric acid and adipokines, markers of inflammation, and endothelial dysfunction.

AIM: Serum uric acid is associated with the metabolic syndrome and its components, while its relationship with cardiovascular disease is controversial. The aim of the study was to evaluate the association between uric acid and adipokines, markers of inflammation, oxidative stress, and endothelial dysfunction, which are all linked to cardiovascular disease. METHODS: The associations between uric acid and adiponectin, resistin, leptin, high-sensitivity-C-reactive protein (hs-CRP), interleukin-6, tumor necrosis factor-alpha, nitrotyrosine, Total Antioxidant Status (TAS), E-selectin, vascular adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) were cross-sectionally evaluated in a randomly collected sample of 100 men from a population-based cohort. RESULTS: Subjects within the highest uric acid quartile showed a worse metabolic pattern and a higher prevalence of the metabolic syndrome [odds ratio (OR)=3.6; 95% confidence interval (CI) 1.6-8.2; p<0.001 for each 50 micromol/l uric acid increment in a logistic regression model after multiple adjustments]. Nitrotyrosine and adiponectin were significantly lower, while TAS, hs-CRP, E-selectin, ICAM-1, and VCAM-1 were higher in the groups with increased uric acid levels. In a multiple regression model, after adjustments for multiple confounders, uric acid levels were inversely associated with nitrotyrosine (p<0.001) and adiponectin (p=0.02), and directly with TAS (p<0.001), and E-selectin (p=0.006). CONCLUSION: Serum uric acid showed opposite relationships, being associated with both beneficial (inverse association with nitrotyrosine, direct association with TAS) and detrimental (inverse association with adiponectin, direct association with E-selectin) markers, thus providing a possible explanation for the previously reported controversial and not linear association between uric acid and cardiovascular disease.

Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR).

Insulin resistance and insulin hypersecretion are established features of obesity. Their prevalence, however, has only been inferred from plasma insulin concentrations. We measured insulin sensitivity (as the whole-body insulin-mediated glucose uptake) and fasting posthepatic insulin delivery rate (IDR) with the use of the euglycemic insulin clamp technique in a large group of obese subjects in the database of the European Group for the Study of Insulin Resistance (1,146 nondiabetic, normotensive Caucasian men and women aged 18-85 yr, with a body mass index (BMI) ranging from 15 to 55 kg.m-2). Insulin resistance, defined as the lowest decile of insulin sensitivity in the lean subgroup (608 subjects with a mean BMI of 29 kg.m-2). Insulin sensitivity declined linearly with BMI at an age- and sex-adjusted rate of 1.2 micromol.min-1.kg FFM-1 per BMI unit (95% confidence intervals = 1.0-1.4). Insulin hypersecretion, defined as the upper decile of IDR, was significantly (P<0.0001) more prevalent (38%) than insulin resistance in the obese group. In the whole dataset, IDR rose as a function of both BMI and insulin resistance in a nonlinear fashion. Neither the waist circumference nor the waist-to-hip ratio, indices of body fat distribution, was related to insulin sensitivity after adjustment for age, gender, and BMI; both, however, were positively associated (P<0.001) with insulin hypersecretion, particularly in women. In nondiabetic, normotensive obese subjects, the prevalence of insulin resistance is relatively low, and is exceeded by the prevalence of insulin hypersecretion, particularly in women with central obesity. In the obese with preserved insulin sensitivity, risk for diabetes, cardiovascular risk, and response to treatment may be different than in insulin resistant obesity.

An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects.

Prednisone-induced insulin resistance may depend on either reduced sensitivity (receptor defect) or reduced response to insulin (postreceptor defect). To clarify the mechanism of prednisone-induced insulin resistance, a [3H]glucose infusion (1 microCi/min) was performed for 120 min before and during a euglycemic clamp repeated at approximately 100, approximately 1,000, and approximately 10,000 microU/ml steady state plasma insulin concentration in 10 healthy, normal weight subjects, aged 35 +/- 7 yr. Each test was repeated after 7-d administration of placebo or prednisone (15 plus 15 mg/d per subject), in a randomized sequence with an interval of 1 mo between the two tests. Mean fasting blood glucose (89.5 +/- 2.1 vs. 83.7 +/- 1.9 mg/dl) and mean fasting plasma insulin values (17.8 +/- 1.2 vs. 14.3 +/- 0.8 microU/ml) were significantly higher (P less than 0.01) after prednisone. The insulin sensitivity index (glucose metabolic clearance rate in ml/kg per min) was significantly lower (P less than 0.001) after prednisone at all three steady state plasma insulin levels: 2.8 +/- 0.3 vs. 7.4 +/- 1.1 at approximately 100 microU/ml; 6.0 +/- 0.5 vs. 12.2 +/- 1.1 at approximately 1,000 microU/ml; 7.4 +/- 0.6 vs. 14.4 +/- 0.5 at approximately 10,000 microU/ml. Fasting glucose production (in mg/kg per min) was significantly higher after prednisone: 3.7 +/- 0.2 vs. 2.9 +/- 0.2, P less than 0.001. Suppression of glucose production at steady state plasma insulin level of approximately 100 microU/ml was less after prednisone (1.01 +/- 0.35 vs. 0.14 +/- 0.13, NS), and total at approximately 1,000 and approximately 10,000 microU/ml after both prednisone and placebo. The metabolic kinetic parameters of insulin after prednisone were not significantly different from those after placebo. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro on fat cells from 16 normal-weight surgical candidates aged 40 +/- 8 yr (10 treated with placebo and 6 with prednisone as above). No significant difference was observed with regard to specific insulin binding (tested with 1 ng/ml hormone only), whereas significant transport differences were noted at the basal level (0.40 +/- 0.10 vs. 0.54 +/- 0.12 pmol/10(5) cells, P less than 0.05), and at increasing concentrations up to the maximum stimulation values (5 ng/ml): 0.59 +/- 0.04 vs. 0.92 +/- 0.12 pmol/10(5) cells, P less than 0.005. These results suggest that (a) administration of an anti-inflammatory dose of prednisone for 7 d induces insulin resistance in man; (b) this is more dependent on depressed peripheral glucose utilization than on increased endogenous production; (c) total insulin binding on isolated adipocytes is not significantly affected; (d) insulin resistance is primarily the outcome of postreceptor defect (impaired glucose transport).

Mechanism of insulin resistance in human liver cirrhosis. Evidence of a combined receptor and postreceptor defect.

Insulin resistance in liver cirrhosis may depend on either reduced sensitivity (receptor defect) and/or reduced response to insulin (postreceptor defect). To clarify the mechanism of such resistance, a [3H]glucose infusion (0.2 microCi/min) was performed for 120 min before and during a euglycemic clamp at approximately 100, 1,000, and 10,000 microU/ml steady state plasma insulin concentration in 18 compensated cirrhotics with portal hypertension and impaired glucose tolerance, and 18 healthy volunteers with no family history of diabetes, matched for sex, age, and weight. Mean fasting plasma insulin (29.2 +/- 3.4 SEM vs. 14.8 +/- 1.1 microU/ml) was significantly higher (P less than 0.001) in cirrhotics, while fasting plasma glucose was much the same in the two groups. Glucose use (milligrams per kilogram per minute) was significantly lower in cirrhotics at all three steady state plasma insulin levels: 3.04 +/- 0.34 vs. 7.72 +/- 0.61 (P less than 0.001) at approximately 100; 6.05 +/- 1.07 vs. 11.45 +/- 1.24 (P less than 0.001) at approximately 1,000; and 11.69 +/- 0.69 vs. 14.13 +/- 0.74 (P less than 0.05) at approximately 10,000 microU/ml. Mean plasma C-peptide was significantly higher in cirrhotics both basally and during the steady states (P less than 0.001); it was completely suppressed at approximately 10,000 microU/ml in controls and only 57.5% of the baseline in cirrhotics. Endogenous glucose production (milligrams per kilogram per minute) was much the same in the two groups in the fasting state and almost entirely suppressed in the controls (0.10 +/- 0.05 vs. 0.48 +/- 0.11, P less than 0.001) at approximately 100 microU/ml; at approximately 1,000 microU/ml a residual glucose production, 0.07 +/- 0.05, was observed in the cirrhotics only. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro in six cirrhotics and six controls. Insulin binding to circulating monocytes and isolated adipocytes was significantly lower (P less than 0.025) in cirrhotics in all insulin concentration studies. Glucose transport values on isolated adipocytes were significantly lower in cirrhotics both basally (P less than 0.001) and at maximal insulin concentration (P less than 0.05). These results suggest that insulin resistance in human cirrhosis is more dependent on depressed peripheral glucose use than on increased endogenous glucose production, and that a combined receptor and postreceptor defect in insulin action on target cells seems to be present.

Lung Ultrasound and Pulmonary Function Test in Cirrhotic Patients.

Lung ultrasound (LU) is useful in the diagnosis of pulmonary interstitial-alveolar syndrome (IAS) when B-lines are detected. Its prevalence and effect in lung function is not well studied in cirrhotic patients. The objective of this study was to detect the prevalence of interstitial-alveolar involvement with LU and correlate with pulmonary function test to distinguish the effect of ascites and B-lines in pulmonary function. This was an observational single-center study with 49 patients listed for liver transplantation submitted for LU and pulmonary function tests. Patients were divided into 4 groups: no ascites and no B-lines (n = 19), B-lines only (n = 19), ascites only (n = 6), and ascites and B-lines (n = 5). There was a worse forced vital capacity (FVC) in patients with B-lines only (76.1% ± 9.2; P = .0058) and ascites only (66.8% ± 10.2; P = .0010). 1-second forced expiratory volume (FEV1) also was lower in patients with B-lines only (78.5% ± 10.3; P = .0001), ascites only (71.3% ± 13.2; P = .0004), and B-lines and ascites (74.2% ± 7.6; P = .0035). Model for End-Stage Liver Disease score was worse in the group with ascites and B-lines (22.4 ± 10.1; P = .0229). B-Lines reduced FVC and FEV1 in our study and may be an independent factor in worsening pulmonary function in these patients.

The vestibular hair cells: post-transductional signal processing.

Hair cells in mechanosensory systems transduce mechanical stimuli into biological signals to be presented to and analyzed by the brain. Vestibular hair cells transduce stimuli primarily associated with the organism's orientation and motion in space. When examined superficially it may appear that the hair cells act as passive transducers whereby mechanical stimulation of their hair bundle results in transmitter release at their afferent synapses. In fact, hair cell functions are more complicated, and the mechanical signals are heavily processed even before being encoded in afferent nerve activity. Hair cells are different from one another in morphology, biophysics, transmitter and transmitter receptor complements, not only across different organs (as one might expect), but even in the same organ. This review focuses on hair cell morpho-physiological properties, ionic conductances, neurotransmitters/modulators and their receptors, second messengers and effectors. Special features of hair cell neurotransmission, as the synaptic body and the presence of autoreceptors and local circuits, are also discussed, as is the possibility of a differential modulation of hair cell transmitter release in the resting and mechanically-stimulated states.

Preserved insulin sensitivity and {beta}-cell activity, but decreased glucose effectiveness in normal-weight women with the polycystic ovary syndrome.

Insulin resistance and hyperinsulinemia are often considered intrinsic features of the polycystic ovary syndrome (PCOS). Nevertheless, conflicting results of insulin sensitivity and secretion have been obtained in the subgroup of normal-weight women with PCOS. Differences in body composition, ethnicity, and diet composition and a family history of metabolic diseases may act as confounding variables in women with PCOS. In the present study, insulin sensitivity and secretion were estimated by an iv glucose tolerance test (IVGTT), analyzed by minimal models, in 20 normal-weight healthy women with PCOS and no family history of type 2 diabetes mellitus and in 20 normally ovulating women, matched for age and body mass index. Insulin sensitivity [mean (95% confidence intervals); PCOS 4.0 (2.8-5.1) vs. controls 4.5 (3.5-5.4) 10(-4) min(-1)/microU.ml], and insulin secretion, expressed as the acute insulin response to glucose [PCOS 3.7 (3.3-4.2) vs. controls 3.7 (3.4-4.0) microU/ml] were similar in the two groups. The women with PCOS showed an increased proportion of total body fat (PCOS 29% vs. controls 27.2%; P < 0.01). They also showed decreased glucose effectiveness, i.e. the proportion of glucose uptake independent from insulin activity [PCOS 2.6 (2.1-3.0) vs. controls 3.8 (3.0-4.6) mg x 100 min(-1); P = 0.01]. The levels of insulin sensitivity and of glucose effectiveness did not correlate in either group. Whether the isolated finding of decreased glucose effectiveness could reflect an early stage in the development of the metabolic aberrations often associated with the syndrome remains to be clarified.

PAI-1 and factor VII activity are higher in IDDM patients with microalbuminuria.

Microalbuminuria is associated with an increased risk of cardiovascular disease (CVD) in insulin-dependent diabetes mellitus (IDDM) patients, but the pathophysiological basis of this association is not clear. To see whether or not hemostatic dysfunctions might contribute to explain this association, we measured tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), factor VII activity, plasma fibrinogen, and plasma endothelin-1 (ET-1) in 13 microalbuminuric (albumin excretion rate [AER], 20-200 micrograms/min) and in 13 comparable normoalbuminuric (< 20 micrograms/min) IDDM patients. t-PA and ET-1 were similar in the two groups, whereas PAI-1 activity (5.65 +/- 1.92 vs. 0.85 +/- 0.58 IU/ml, P < 0.05), factor VII (87.85 +/- 4.94 vs. 76.54 +/- 2.31%, P < 0.05), and plasma fibrinogen (3.38 +/- 0.21 vs. 2.65 +/- 0.13 g/l, P < 0.05) were significantly higher in microalbuminuric than in normoalbuminuric patients. Plasma fibrinogen was related to AER (r2 = 0.23, P < 0.05), whereas triglycerides and factor VII were related to PAI-1 (r2 = 0.39, P < 0.001 and r2 = 0.10, P < 0.05). These results suggest that microalbuminuria is associated with a hypercoagulative and hypofibrinolytic state. Hemostatic dysfunctions might be a pathogenetic link between microalbuminuria and CVD.