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Aims: To evaluate whether plasma biomarkers of inflammation and endothelial dysfunction differed in Type 1 diabetic patients as compared with those in non-diabetic subjects, and to examine the association of these biomarkers with early stages of microvascular complications., Methods: Plasma biomarkers of inflammation [fibrinogen, hs-C-reactive protein (hs-CRP)] and endothelial dysfunction [von Willebrand factor (v-WF), intercellular adhesion molecule-1, plasminogen activator inhibitor-1 (PAI-1) activity] were measured in 88 non-smoking young patients with Type 1 diabetes without clinical macrovascular disease and in 40 healthy controls., Results: Plasma levels of hs-CRP, fibrinogen, v-WF, soluble intracellular adhesion molecule-1 (sICAM-1) and PAI-1 activity were markedly higher (P < 0.01 or less) in Type 1 diabetic patients than in healthy controls; these results were essentially unchanged when healthy controls were compared with patients without complications. After stratification by microvascular complication status, plasma biomarkers of inflammation and endothelial dysfunction were significantly increased in those with more advanced disease compared with those with early complications or without complications, respectively. However, while the significant differences in these biomarkers were little affected by adjustment for sex, age, BMI and blood pressure values, they were totally abolished after additional adjustment for diabetes duration and glycaemic control., Conclusions: These results indicate that in Type 1 diabetes there is a subclinical, chronic inflammation which is, at least partly, independent of clinically manifest macro- and microvascular complications, smoking or other traditional cardiovascular risk factors; this subclinical inflammation is closely correlated to the magnitude and duration of hyperglycaemia.

Objectives: To examine the association between nonalcoholic hepatic steatosis (HS) and the activity of the hypothalamo-pituitary-adrenal (HPA) axis, as evaluated by a low-dose dexamethasone suppression test, in obese subjects., Design and Patients: In a cross-sectional study, we examined 54 obese, otherwise healthy, individuals with a negligible or zero daily alcohol consumption., Measurements: HS (by ultrasonography), glucose tolerance status (by oral glucose load), insulin resistance [by homeostasis model assessment (HOMA)] and 1.0 mg postdexamethasone (postdex) suppression cortisol levels were measured., Results: Subjects with nonalcoholic HS (n = 39) had markedly less suppressed circulating cortisol levels than those without HS (n = 15) (21.9 +/- 2.6 vs. 11.0 +/- 1.4 nmol/l, P < 0.001). In addition, subjects with nonalcoholic HS had significantly higher values of HOMA-insulin resistance score and circulating liver enzymes than their counterparts without HS. Age, body mass index (BMI), waist/hip ratio, plasma glucose concentration (both at fasting and after glucose load), lipids and blood pressure values did not differ significantly between the groups. Females were more represented among those without HS. The marked differences in postdex suppression cortisol levels that were observed between the groups were little affected by adjustment for sex, age, BMI, waist/hip ratio, HOMA-insulin resistance score, plasma lipids and liver enzyme levels. Similarly, in a logistic regression analysis, cortisol levels significantly predicted the presence of nonalcoholic HS (P = 0.032), independently of potential confounders., Conclusions: These results suggest that nonalcoholic hepatic steatosis is closely correlated with a subtle, chronic activation of the HPA axis in obese, otherwise healthy, individuals.

Aim: To validate the Italian version of the World Health Organization (WHO)-Well-Being Questionnaire (WBQ) and the WHO-Diabetes Treatment Satisfaction Questionnaire (DTSQ) in Type 1 and Type 2 diabetic patients., Methods: The cultural adaptation of the questionnaires was performed by using standard forward/backward techniques. Internal consistency reliability was estimated by Cronbach's alpha coefficient. Construct validity was evaluated using the Short Form-36 (SF-36) Health Status Questionnaire. Finally, the discriminative properties of the questionnaires were evaluated relative to the patients' characteristics. The questionnaires were administered to a random sample of patients identified in twelve outpatient diabetes clinics., Results: Overall, 412 subjects were recruited, of whom 96 (23%) with Type 1 diabetes. Item-scale correlations were >0.40 for all the items. Cronbach's alpha coefficient was 0.86 for the WHO-DTSQ and ranged between 0.79 and 0.91 for the WHO-WBQ. High correlations were found between WHO-WBQ scales and the mental dimensions of the Short Form-36 (SF-36) questionnaire, but not between WHO-DTSQ and SF-36 scores. Women, obese subjects, those with longer diabetes duration and multiple complications showed a worse quality of life in all of the four areas of the WHO-WBQ. In Type 2 diabetic subjects, SF-36 scores, but not WHO-WBQ scores, were able to discriminate the population according to the treatment modalities. Lower levels of treatment satisfaction were related to female gender, longer diabetes duration, insulin treatment, presence of diabetes complications and HbA1c levels >7.0%. The flexibility of the treatement was perceived as a major problem even among patients treated with oral agents., Conclusions: The WHO-DTSQ can be considered as a valuable instrument to be used internationally for the description of diabetes treatment satisfaction. The WHO-WBQ also shows adequate psychometric properties, but additional data are needed to clarify whether it is more sensitive than SF-36, the most widely used generic instrument.

Background and Aim: Hepatic steatosis has recently been associated with insulin resistance and other metabolic abnormalities as a possible feature of the metabolic syndrome, but it is still uncertain how hepatic steatosis and insulin sensitivity are connected. Furthermore, obesity is a well characterized insulin resistant condition that is often associated with hepatic steatosis. The aim of this study was to verify whether hepatic steatosis further worsens insulin sensitivity in obese subjects by comparing the degree of insulin sensitivity in obese subjects with normal glucose tolerance on the basis of the presence or absence of hepatic steatosis., Methods and Results: We analyzed 86 obese patients whose alcohol intake was less than 20 g/day and who showed no signs of viral hepatopathy. All of the subjects had normal glucose tolerance as shown by an oral glucose tolerance test. Insulin resistance was estimated using the homeostasis model assessment (HOMA) method and the diagnosis of steatosis was determined by an ultrasound scan of the liver. The subjects were comparable in terms of body mass index (BMI), lipid profile and serum uric acid levels; those with hepatic steatosis were slightly older and tended to have higher systolic blood pressure and fasting glycemia levels. The HOMA values were significantly higher in the group with hepatic steatosis (4.48 +/- 2.22 vs 3.11 +/- 1.47, p=0.002). There was no linear correlation between HOMA and alanine aminotransferase (ALT) levels, but a close linear correlation between HOMA and BMI (r=0.40; p<0.001). The effect of hepatic steatosis on HOMA remained significant after adjusting for age and gender (covariance analysis, p=0.006). When BMI was added to the covariance analysis, hepatic steatosis retained its statistical significance., Conclusion: Our data suggest that hepatic steatosis can increase insulin resistance independently of obesity.

Objective: The aim of the present work was to compare mortality from site-specific malignancies in type 2 diabetic patients with those in the general population., Research Design and Methods: Mortality from site-specific cancers was assessed in a population-based cohort of 7,148 type 2 diabetic patients from Verona (Northern Italy) during a 10-year follow-up (1987-1996) by reviewing death certificates. Standardized mortality ratio (SMR) data were computed using as reference mortality rates in the general population of Verona., Results: During follow-up, 641 patients (378 men and 263 women) died of malignancies. The most common causes of death among site-specific malignancies were digestive tumors both in men (140 of 378, 37.0%) and women (105 of 263, 39.9%), respiratory tumors in men (103 of 378, 27.2%), and tumors of the reproductive system in women (79 of 263, 30.0%). A slight increase in the overall mortality from malignancies was observed in diabetic patients and achieved statistical significance in women (observed/expected = 1.16, 95% CI 1.02-1.30; P = 0.019) but not in men (observed/expected = 1.07, 0.97-1.19; P = 0.163). Excess mortality from hepatic cancer (SMR = 1.86, 1.44-2.38) was observed in both men and women. In addition, women with diabetes experienced a higher mortality from pancreatic tumors (observed/expected = 1.78, 1.13-2.67) and breast tumors (observed/expected = 1.40, 1.06-1.81). Excess mortality from breast cancer was confined to obese women with diabetes., Conclusions: Mortality from site-specific malignancies is different in type 2 diabetic patients than in the general population. Better control of body weight seems necessary to prevent the excess mortality from breast cancer in women.

Objective: The relation between body weight and mortality in type II diabetic patients has not been fully elucidated. The aim of the present study was to evaluate the impact of body weight on mortality in a well-characterized type II diabetic cohort., Research Design and Methods: We examined a cohort of 3398 type II diabetic patients, alive on December 1986 and followed up for 10 years, to assess mortality and its causes and to investigate the relationship between body mass index (BMI) and mortality from all and specific causes. For this purpose, survival in the different quartiles of BMI was evaluated by a Cox model, controlling for sex, age, treatment, smoking, duration of diabetes, hypertension, and fasting plasma glucose. The Cox model was applied either excluding (model 1) or including (model 2) the last three variables., Results: During the 10 ys of follow-up, 1212 deaths (639 women, 573 men) occurred in the cohort under study. Since the interaction between BMI and age was statistically significant (P = 0.002), survival was studied separately in people aged <65 and > or =65 y (median age of the cohort = 65.9 y). Under 65 y, a significantly higher all-cause mortality was observed in obese patients, that is, in the IV quartile (BMI> or =30.9 kg/m(2); RR = 1.74; CI 95% = 1.26-2.40), in model 1. The inclusion of hypertension, duration of diabetes, and fasting plasma glucose in the model (model 2) slightly decreased the relative risk (RR = 1.52; CI 95% = 1.10-2.11). After 65 y, higher body weight was associated with a better outcome, especially in patients belonging to the IV quartile of BMI (RR = 0.74; CI 95% = 0.62-0.90)., Conclusions: In older type II diabetic patients, a moderate excess weight predicts a better survival, while obesity is a negative prognostic factor in patients younger than 65 y. In the latter patients, the effect of obesity on mortality seems to be partly mediated by hypertension, duration of diabetes, and fasting plasma glucose.

Evaluation of quality of life is important in treatment strategies of chronic illnesses, such as diabetes mellitus. The present study aimed at measuring the impact of self-reported exercise on quality of life in T1DM patients. Fifty-three young T1DM patients on intensive insulin-treatment regime who were regularly attending the Diabetes Clinic were selected. At the end of the scheduled clinic visit, they were asked to fill in an Italian version of the Diabetes Quality of Life (DQOL) questionnaire; 30 patients exercised regularly, whereas 23 were sedentary. Patients with clinical and laboratory evidence of major eye, renal and cardiovascular diseases were excluded. A significant difference in the scale of satisfaction (1.9 +/- 0.3 vs 2.2 +/- 0.5; p = 0.009), along with a better HbA1c level (7.0 +/- 1.0 vs 7.8 +/- 1.2; p = 0.014), was observed in physically active patients as compared to sedentary ones, whereas there were no differences between the 2 groups with respect to the impact and worry scale. Moreover, there were no significant correlations between glucose control parameters and the quality of life scores. In conclusion, we showed that self-reported exercise is associated with both a better quality of life and a better metabolic control in young T1DM patients. Further efforts should however be made to recognize all factors that can help motivate patients to exercise.

The purposes of this study were 1) to compare soluble tumor necrosis factor-alpha receptors, which are thought to reflect the degree of TNF-alpha activation, in nondiabetic subjects and type 1 diabetic patients, and 2) to evaluate the effects of smoking and microvascular complications on soluble tumor necrosis factor-alpha receptor levels in type 1 diabetic individuals. Plasma soluble tumor necrosis factor-alpha receptor levels (R1 and R2) were measured in 50 young type 1 diabetic patients without clinical macroangiopathy and in a matched group of 20 healthy volunteers. When diabetic patients were grouped according to smoking and microvascular complication status, the groups of patients had similar values of age, sex, body mass index, blood pressure, lipids, creatinine, and glycometabolic control. Nevertheless, soluble tumor necrosis factor-alpha receptor-R1 levels but not R2 levels, were markedly elevated (P < 0.05 or less) in complicated vs. uncomplicated (2.40 +/- 0.3 vs. 1.80 +/- 0.1 ng/ml) patients and in smokers vs. nonsmokers (2.66 +/- 0.4 vs. 1.76 +/- 0.1 ng/ml). In a two-factor ANOVA, both smoking (P < 0.01) and microvascular complications (P < 0.05) were independent predictors of soluble tumor necrosis factor-alpha receptor-R1. Soluble tumor necrosis factor-alpha receptor levels of diabetic patients who did not smoke or without complications were similar to those of healthy controls. In conclusion, smoking and microvascular complications seem to exert an additive and deleterious impact on TNF-alpha activation, as reflected by levels of soluble tumor necrosis factor-alpha receptors, in young adults with type 1 diabetes.

Objective: The aim of the present study was to evaluate the impact of hypothyroidism on the autonomic regulation of the cardiovascular system by analysing separately sympathetic and parasympathetic influences on the heart., Design: In seven newly diagnosed untreated hypothyroid patients we analysed power spectral density of heart rate cyclic variations at rest, while lying, and while standing. The same protocol was repeated after the induction of stable euthyroidism by levothyroxine (L-T(4)) treatment. The results were also compared with those obtained from seven age-, sex- and body mass index-matched control subjects., Methods: Heart rate variability was evaluated by autoregressive power spectral analysis (PSA). This method allows reliable quantification of low frequency (LF) and high frequency (HF) components of the heart rate power spectral density. These are considered to be under mainly sympathetic and purely parasympathetic control respectively. In addition, heart rate variations during deep breathing, lying to standing, and Valsalva's manoeuvre were assessed., Results: PSA showed a sharp reduction in the HF (parasympathetic) component in hypothyroid subjects compared with controls (lying, 29.4+/-5.4 vs 47.7+/-6.3 normalized units (NU) (means +/- s.e.m.), P<0.05; standing, 14.0+/-3.5 vs 32.1+/-3.6NU, P<0.005). Conversely, the LF (mainly sympathetic) component was higher in hypothyroid subjects than in controls (lying, 61.6+/-6.4 vs 45.4+/-6.7 NU; standing, 71.7+/-8.0 vs 53.1+/-5.6NU), this difference being significant in the standing position. Hence, the LF/HF ratio, which is considered an index of sympathovagal balance, was increased in hypothyroid subjects while both lying (2.75+/-0.6 vs 1.16+/-0.3; P<0.05) and standing (10.0+/-3.7 vs 1.85+/-0.3; P<0. 02). Total heart rate variability, expressed as total power spectral density, was lower in hypothyroid patients than in control subjects, this difference being significant in the lying position (574+/-126 vs 2302+/-994ms(2), P<0.05). In patients re-examined after L-T(4) therapy, complete normalization of cardiovascular parameters was observed (LF/HF ratio, lying, 1.26+/-0.4; standing, 2.56+/-0.8, both P<0.01 vs baseline values). The response to conventional cardiovascular autonomic tests was not significantly different between hypothyroid patients and healthy controls, and did not change in patients after therapy., Conclusions: These results suggest that, contrary to the clinical picture, thyroid hormone deficiency is associated with an increased sympathetic influence on the autonomic cardiovascular system. The changes in sympathetic function could be explained by a secondary adaptation to an altered cardiovascular responsiveness.

Objective: To examine the 10-year mortality and effect of diabetes duration on overall and cause-specific mortality in diabetic subjects in the Verona Diabetes Study (VDS)., Research Design and Methods: Records from diabetes clinics, family physicians, and a drug consumption database were used to identify 5,818 subjects > or =45 years of age with type 2 diabetes who were alive and residing in Verona, Italy on 31 December 1986. Vital status of each subject was ascertained on 31 December 1996. Underlying causes of death were determined from death certificates. Death rates and death rate ratios (DRRs) were computed and standardized to the population of Verona in 1991., Results: During the study, 2,328 subjects died; 974 deaths were attributable to cardiovascular disease, 517 to neoplasms, 324 to diabetes-related diseases, 134 to digestive diseases, 250 to other natural causes, and 48 to external causes. There were 81 subjects who died of unknown causes. Death rates from natural causes were higher in men than in women (DRR 1.4, 95% CI 1.2-1.5) and rose in both sexes with increasing duration of diabetes (P = 0.001). Among the natural causes of death, those for diabetes-related diseases were strongly related to diabetes duration (P = 0.001). a modest relationship with duration was also found for ischemic heart disease in men (P = 0.07)., Conclusions: Cardiovascular disease was the principal cause of death among people with type 2 diabetes in the VDS. Rates for natural causes of death rose with increasing duration of diabetes. Deaths from diabetes-related diseases in both sexes and from ischemic heart disease in men were largely responsible for this increase.

Objective: The purposes of this study were to compare plasma total homocysteine (tHcy) levels, a recognized cardiovascular risk factor, in nondiabetic subjects and type 1 diabetic patients, and to evaluate whether chronic cigarette smoking had a deleterious effect on plasma tHcy levels in type 1 diabetic patients., Research Design and Methods: Plasma tHcy concentrations were measured in 60 young type 1 diabetic patients without clinical evidence of macroangiopathy and in 30 healthy control subjects who were matched for age, sex, BMI, and smoking habit., Results: Plasma tHcy levels were significantly higher in type 1 diabetic patients than in control subjects (12.5 +/- 4.8 vs. 10.3 +/- 2.2 micromol/l, P = 0.01). After stratification by smoking status, diabetic smokers had values for age, sex, BMI, lipids, creatinine, blood pressure, glycometabolic control, diabetes duration, and microvascular complications that were superimposable on their nonsmoking counterparts. Nevertheless, plasma tHcy levels were markedly elevated in diabetic smokers versus nonsmokers (15.5 +/- 5.7 vs. 10.6 +/- 3 pmol/l, P < 0.0001) in a dose-dependent fashion (P < 0.0001, by analysis of variance when subjects were categorized for the number of cigarettes smoked daily)., Conclusions: Chronic cigarette smoking seems to adversely affect plasma tHcy levels in young adults with type 1 diabetes.

Objective: In the present study, we evaluated whether the coefficient of variation (CV) of fasting plasma glucose (FPG) over a 3-year period was a significant predictor of mortality in type 2 diabetic patients aged 56-74 years., Research Design and Methods: All type 2 diabetic patients (n = 1,409) aged 56-74 years attending the Verona Diabetes Clinic and having at least two FPG determinations in each of the years 1984-1986 were followed for 10 years (1987-1996) to assess total and cause-specific mortality Patients were grouped into tertiles of mean and CV of FPG during 1984-1986. These parameters as well as sex, age, diabetes duration, insulin treatment, smoking, hypertension, and hypercholesterolemia were included in multivariate survival analyses., Results: During the follow-up, 468 patients died. The CV of FPG was an independent predictor of total, cardiovascular, and cancer mortality. Mean FPG was a predictor of total mortality only when the CV of FPG was not included in the analyses., Conclusions: Long-term variability of fasting glucose is an independent predictor of mortality in patients with type 2 diabetes. The CV of FPG might be considered a useful additional parameter in the management of these patients.

Objective: The purposes of this study were to compare plasma concentrations of circulating intercellular adhesion molecule 1 (cICAM-1), a marker of endothelial dysfunction, in nondiabetic subjects and type 1 diabetic patients and to evaluate whether chronic cigarette smoking had a deleterious effect on plasma cICAM-1 levels in type 1 diabetic patients., Research Design and Methods: Plasma cICAM-1 concentrations were measured in 54 young type 1 diabetic patients without clinical macroangiopathy and in 20 healthy control subjects who were matched for age, sex, BMI, and smoking habit., Results: Type 1 diabetic patients had significantly higher plasma levels of cICAM-1 than control subjects (280.4 +/- 59 vs. 224 +/- 53.6 ng/ml, respectively) (P < 0.001). After stratification by smoking status, diabetic smokers had values for age, sex, BMI, lipids, blood pressure, glycemic control, diabetes duration, and chronic complications of diabetes that were super-imposable on their nonsmoking counterparts. Nevertheless, plasma cICAM-1 levels were markedly elevated in type 1 diabetic smokers (321.4 +/- 64.2 vs. 257.3 +/- 41.5 ng/ml, respectively) (P < 0.001) in a dose-dependent fashion (P < 0.001 by analysis of variance when subjects were categorized by number of cigarettes smoked per day)., Conclusions: Chronic cigarette smoking has a deleterious effect on plasma cICAM-1 levels in young type 1 diabetic patients, which further supports the clinical importance of discouraging the initiation of smoking and promoting its cessation in people with type 1 diabetes.

Objective: This population-based study, carried out in the framework of the Verona Diabetes Study, investigated mortality from specific causes in known type 2 diabetic patients., Research Design and Methods: A cohort of 7,148 known type 2 diabetic patients (3,366 men and 3,782 women) was identified on 31 December 1986 and followed up for 5 years (1987-1991). Underlying causes of death were obtained from death certificates and were coded according to the International Classification of Diseases, Ninth Revision. Cause-specific death rates of diabetic subjects were compared with those of the inhabitants of Verona. By 31 December 1991, 1,550 diabetic subjects (744 men and 806 women) had died., Results: The standardized mortality ratio (SMR) for all causes of death was 1.42 (95% CI 1.35-1.50). The highest SMRs were for the following specific causes: diabetes (SMR 4.47 [3.91-5.10]), gastrointestinal diseases (1.83 [1.50-2.21])--particularly liver cirrhosis (2.52 [1.96-3.20])--and cardiovascular diseases (1.34 [1.23-1.44]), particularly cerebrovascular (1.48 [1.25-1.73]) and ischemic heart diseases (1.41 [1.24-1.62]). A significantly higher than expected risk of mortality for cardiovascular causes was already present in the first 5 years after diagnosis and decreased with age. Type 2 diabetic patients treated with insulin had a higher risk of dying than those treated orally or by diet., Conclusions: The highest SMRs in the diabetic cohort were for diabetes and liver cirrhosis. The mortality risk for cardiovascular diseases, although significantly higher than expected, was much lower in Italian type 2 diabetic patients than that reported for American patients. The evidence of an early effect on mortality suggests that prevention, early diagnosis, and treatment should be improved.

Background: The aim of the present study was to compare specific causes of death in Type 2 diabetic patients attending and not attending the diabetes center., Methods: The study was carried out within the framework of the Verona Diabetes Study, a population-based survey of known diabetes prevalence with a 10-year mortality follow-up. On 31 December 1986, 7148 Type 2 diabetic patients were identified in Verona, north-east Italy. Among them 4047 regularly attended the diabetes center, while 3101 did not attend the diabetes center. On 31 December 1996, life status was determined and the underlying cause of death was coded according to the ICD-9. During the follow-up, 2896 subjects died. Difference in mortality from specific causes between attenders and non-attenders were evaluated by a Cox model, controlling for sex, age, diabetes treatment and place of residence (downtown vs suburbs)., Results: Mortality was lower in subjects who attended the diabetes center (38. 6% vs 43.0%, p<0.001). This phenomenon was mainly due to lower cardiovascular (p=0.002) and digestive (p=0.047) mortality., Conclusions: These data support the conclusion that attending the diabetes center reduces cardiovascular and, to a lesser extent, digestive mortality., (Copyright 1999 John Wiley & Sons, Ltd.)

Monocytes bear insulin receptors similar to those expressed in other tissues, but insulin action in these cells remains unclear. There is evidence that adhesion, by generating a complex array of irreversible transformations, may modify the response of cells to other stimuli, such as hormones. The present study aimed to characterise the pattern of insulin induced tyrosine phosphorylation of monocytes in suspension. Monocytes in suspension were obtained by sequential gradient centrifugation and the tyrosine phosphoproteins were analyzed by immunoblot with antiphosphotyrosine antibodies. The major result of the study is that in suspended monocytes insulin induced a dose and time dependent dephosphorylation of a protein with a molecular mass of about 92 kDa without stimulating the tyrosine phosphorylation of the Insulin Receptor Substrat-1 (IRS-1). In conclusion, we showed that in monocytes in suspension insulin seems to activate a tyrosine phosphatase, which, in turn, dephosphorylates a protein with an apparent molecular weight of 92 kDa.

Background: We recently reported that long-term fasting plasma glucose (FPG) instability predicts all-cause mortality in elderly patients with non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present study was to evaluate whether glucose instability, as represented by the coefficient of variation of FPG concentrations (CV-FPG) measured during a 3-year period, can predict specific causes of death in the subsequent 5 years., Methods and Results: Five hundred sixty-six elderly patients with NIDDM were followed up for 5 years to assess mortality and causes of death. All FPG determinations of the 3 years preceding the follow-up available in the clinical records were collected and analyzed. Patients were grouped in tertiles of mean FPG, CV-FPG, and the slope of FPG. These parameters of glucose control, as well as sex, age, duration of diabetes, insulin treatment, cigarette smoking, hypertension, and total cholesterol, were included in a multivariate analysis of mortality. During the follow-up, 63 men and 128 women died. Diabetes- and malignancy-related mortality were not independently associated with any parameter of glucose control, whereas cardiovascular-related mortality was independently associated with CV-FPG (P=.007) but not with the mean or the slope of FPG. In particular, the relative risk of cardiovascular mortality in subjects in tertile III versus tertile I of CV-FPG was 2.40 (95% CI, 1.28 to 4.53)., Conclusions: These results indicate that FPG instability is a predictor of cardiovascular-related mortality in elderly patients with NIDDM and suggest that glucose stability might be a goal in the management of these patients.

Objective: To measure plasma malondialdehyde (MDA) concentration, a product of lipid peroxidation, both in IDDM patients and in healthy control subjects and to examine whether smoking has a negative impact on the plasma MDA levels in diabetic patients., Research Design and Methods: Plasma total MDA concentration (as a thiobarbituric acid adduct by high-performance liquid chromatography) was measured in 56 young IDDM patients and in a group of 32 age-, sex-, BMI-, and smoking habit-matched healthy subjects., Results: Plasma MDA concentration in IDDM patients was significantly higher than that in healthy control subjects (mean +/- SE: 0.95 +/- 0.03 vs. 0.54 +/- 0.03 mumol/l; P < 0.0001). After stratification by smoking status, it was seen that diabetic smokers had values of age, BMI, serum lipids, blood pressure, metabolic control, and diabetes duration and its chronic complications superimposable on those of their nonsmoking counterparts. Nevertheless, plasma MDA concentration was significantly higher in IDDM patients who smoked than in IDDM patients who didn't smoke (1.03 +/- 0.4 vs. 0.87 +/- 0.03 mumol/l; P = 0.002), without any sex difference with regard to MDA levels., Conclusions: These data show an increase in circulating products of lipid peroxidation in young diabetic smokers, thus further supporting the clinical importance of discouraging the initiation of smoking as well as promoting its cessation in people with IDDM.

Mononuclear cells are largely used in clinical studies on insulin action because of their accessibility. Insulin acts in monocytes in different ways than it does in other cells, i.e. adipocytes and muscular cells. Therefore, it still remains unclear whether monocytes reflect the same changes that occur in insulin receptors at the level of the major insulin target tissues during different pathophysiologic states. We have studied the phosphotyrosine protein profiles in intact human monocytes after insulin and IGF-1 stimulation with the aim of identifying substrate/s of these receptors and of comparing them to the substrates already described in major insulin target tissues. Mononuclear cells were prepared from peripheral blood by centrifugation on Ficoll Hypaque and by adhesion to tissue-culture plates. Cell stimulation, lysis, immunoprecipitation and western blotting were carried out following the protocol described by P. L. Rothenberg in 1991 and the immunoreactive proteins visualized on film by chemiluminescence. Insulin and IGF-1 rapidly increased the tyrosine phosphorylation of the 95 Kdal beta-subunit of their own receptors. Under our experimental conditions insulin and IGF-1 were not able to stimulate the phosphorylation of IRS-1, a major substrate of the insulin receptor kinase.

In the present study we measured the activity of some cytosolic enzymes involved in intracellular glucose metabolism in mononuclear leukocytes from 77 obese subjects of which 39 were nondiabetic and 38 had newly-diagnosed untreated type II diabetes mellitus. 28 subjects (19 nondiabetic and 18 diabetic) had also a study of insulin binding to monocytes. 35 subjects (14 nondiabetic, 21 diabetic) underwent an insulin tolerance test for the evaluation of in vivo insulin action. Mononuclear leukocytes from diabetic obese patients showed significantly lower activities of hexokinase (HK), 6-phosphofructokinase (PFK) and glucose-6-phosphate dehydrogenase (G6PDH), while pyruvate kinase (PK) and 6-phosphogluconate dehydrogenase (6PGDH) activities were similar in the two groups. In the whole population HK and G6PDH activities inversely correlated with fasting and 2-h OGTT plasma glucose levels. Neither plasma insulin levels nor maximal specific insulin binding to monocytes were significantly correlated with any of the enzyme activities measured. Conversely, the parameter of insulin action generated by insulin tolerance test significantly correlated with HK, G6PDH and 6PGDH. These results indicate that in obese subjects the presence of diabetes is associated with a reduced activity of some enzymes of glucose metabolism in mononuclear leukocytes. This multiple enzymatic defect is correlated with the impairment of in vivo insulin action.

To study the role of membrane lipids in signal transduction by the insulin receptor, we have studied the effect of phospholipase C (Clostridium perfringens) and a phosphatidylinositol-specific phospholipase (Staphylococcus aureus) on insulin binding, a function of the alpha-subunit, and tyrosine kinase activity, a function of the beta-subunit in IM-9 lymphocytes and NIH 3T3 fibroblasts transfected with the human insulin receptor. Treatment of the cells with phospholipase C at concentrations up to 3.4 U/ml did not affect specific insulin binding, but reduced insulin-stimulated receptor phosphorylation by 50%. This effect of phospholipase C was observed within 10 min of treatment and occurred with no change in the basal level of phosphorylation. Pre-treatment of cells with insulin for 5 min prior to enzyme addition prevented any change in kinase activity. Insulin-stimulated phosphorylation of pp 185, the presumed endogenous substrate for the insulin receptor kinase, was also reduced following phospholipase C treatment, with an almost complete loss of insulin stimulation after exposure of cells to enzyme at concentrations as low as 0.6 U/ml. In contrast to these effects of phospholipase C on intact cells, receptor autophosphorylation was not affected in insulin receptors purified on wheat germ agglutinin-agarose from phospholipase C treated cells. Likewise, the phospholipase C effect was reduced by the addition of phosphatidylcholine, but not by the addition of the protease inhibitors, aprotinin and phenylmethylsulfonyl fluoride, to the incubation indicating its dependence on phospholipid hydrolysis. Treatment of cells with the phosphatidylinositol-specific phospholipase C did not affect any of the parameters studied.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanism of action of sulphonylureas is not completely understood. In the present study we evaluated the effects of gliquidone, a second-generation compound, on several metabolic parameters in 22 patients with untreated newly-diagnosed type II (noninsulin-dependent) diabetes mellitus. After either 1 or 6 months of treatment with gliquidone plus isocaloric diet we observed: 1) a significant decrease in fasting plasma glucose and glycemic profile after oral glucose load; 2) unchanged fasting and postglucose plasma insulin levels; 3) no change in fasting C-peptide levels but a significant increase in C-peptide concentrations after glucose challenge; 4) a significant increase in glucose disappearance rate from plasma following iv insulin injection; 5) an increase in the insulin-induced reduction of plasma levels of free-fatty acids; 6) no change in plasma C-peptide levels following iv insulin injection; 7) a significant increase in specific insulin binding to monocytes. After 6 but not 1 month of gliquidone therapy we also found an increase in the activity of hexokinase in circulating mononuclear leukocytes. These results suggest that the hypoglycemic effect of gliquidone occurs through either an increased beta cell response to glucose stimulus or an enhanced insulin sensitivity. The latter effect seems to depend on both receptor and postreceptor mechanisms.

The exact relationship between EGF-stimulated tyrosine phosphorylation, induction of the cellular proto-oncogenes c-myc and c-fos, and DNA synthesis remains uncertain. Madin-Darby Canine Kidney (MDCK) cells possess EGF receptor sites with high binding capacity, and in contrast to A431 cells, respond to EGF by increasing DNA synthesis. Following EGF stimulation of intact MDCK cells, there was a rapid and marked increase in the autophosphorylation of the EGF receptor. This was associated with an increase in the tyrosine phosphorylation of a 120 kDa phosphoprotein believed to be an endogenous substrate of this receptor kinase. The ED50 for stimulation of phosphorylation of pp120 was approximately 0.05 nM versus 1.0 nM for receptor autophosphorylation, consistent with amplification of signalling at this step in EGF action. Stimulation of DNA synthesis occurred after 12 to 24 hours and revealed even further amplification with an ED50 of about 0.1 nM. Intermediate between these events was a time-dependent activation of c-fos and c-myc gene expression. However, the ED50 for these processes was approximately 10 nM, indicating a relatively lower sensitivity of EGF for stimulation of proto-oncogene expression. Tyrphostin (RG 50864), a compound reported to inhibit specifically the EGF receptor kinase, completely blocked EGF stimulation of proto-oncogene induction. Interestingly, under the same experimental conditions, EGF receptor autophosphorylation was decreased only 60%. These data, along with the dose-response studies, indicate that proto-oncogene induction requires near maximal stimulation of EGF receptor autophosphorylation. They also suggest that, in MDCK cells, the EGF dependent induction of the c-fos and c-myc genes is not strictly correlated to the extent of EGF receptor autophosphorylation or EGF-stimulated DNA synthesis, and that EGF stimulation of DNA synthesis likely involves additional rate-limiting intermediate steps.

The aim of the present study was to evaluate whether the inhibitory effect on pancreatic A-cell exerted by hyperglycemic hyperinsulinemia and/or by somatostatin administration is impaired in human obesity. For this purpose plasma glucagon concentrations were measured in 8 obese and 8 nonobese nondiabetic subjects during a 4-h hyperglycemic clamp. Synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min during the third hour of the study. Fasting plasma glucagon was higher in obese than in nonobese subjects (242 +/- 32 vs 163 +/- 15 pg/ml, p less than 0.05) (mean +/- SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100-120 min of the study) plasma glucagon averaged 195 +/- 26 pg/ml in obese and 122 +/- 13 pg/ml in nonobese subjects (p less than 0.05), with a reduction of 19 +/- 3% in the former and 28 +/- 4% in the latter (p = n.s.). In both groups somatostatin infusion did not result in a further decrease in plasma glucagon, which averaged 192 +/- 27 pg/ml in obese and 123 +/- 16 pg/ml in nonobese subjects (p less than 0.05) in the 160-180 min period of the study. Also after discontinuing somatostatin infusion plasma glucagon levels did not change. These results suggest that in human obesity hyperglycemic hyperinsulinemia has a normal inhibitory effect on pancreatic A-cell and that somatostatin administration has no additive effect on hyperglycemia and hyperinsulinemia in either obese or nonobese nondiabetic subjects.