AIMS/HYPOTHESIS: Cardiovascular disease is a well-known severe complication of impaired glucose tolerance and Type II (non-insulin-dependent) diabetes mellitus. The independent contribution of glucose intolerance to cardiovascular disease and the underlying pathogenic mechanisms are still, however, not clear. METHODS: In this prospective population-based study, 826 subjects aged 40-79 years underwent high resolution duplex ultrasound examinations of carotid arteries and extensive clinical and laboratory screenings for potential vascular risk factors at baseline and 5 years later. The ultrasound protocol involved measurements of maximum axial diameter of atherosclerotic plaques, if any, in common and internal carotid arteries on both sides and enable differentiation of two main stages in carotid artery disease, termed early non-stenotic and advanced stenotic atherosclerosis. Intima-media thickness was assessed at the follow-up examination. RESULTS: Type II diabetes and, to a lesser extent, impaired glucose tolerance were found to be statistically significant risk predictors of 5-year changes in carotid atherosclerosis. These associations were in part independent of other vascular risk factors typically clustering with glucose intolerance. Both impaired glucose tolerance and Type II diabetes mellitus were not independently related to early non-stenotic atherosclerosis. In contrast, Type II diabetes mellitus was the strongest single risk predictor of advanced stenotic atherosclerosis [odds ratio 5.0 (95% confidence intervals 2.3-11.1)] and impaired glucose tolerance was of relevance as well [odds ratio 2.8 (1.2-6.4)] (p < 0.001). CONCLUSION/INTERPRETATION: Impaired glucose tolerance and, to a greater extent, Type II diabetes were strong independent predictors of advanced carotid atherosclerosis in our prospective population-based study.

Adult↗

PubMed2000

Effects of hyperglycaemia and hyperinsulinaemia on plasma amino acid levels in obese subjects with normal glucose tolerance.

OBJECTIVE: To investigate the effects of hyperglycaemia and hyperinsulinaemia on amino acid disposal in human obesity. DESIGN: Four sequential experimental conditions: (1) overnight fasting; (2) hyperglycaemia with hyperinsulinaemia (2 h hyperglycaemic clamp at 11 mmol/l); (3) hyperglycaemia with basal insulin (1 h hyperglycaemic clamp during somatostatin infusion), (4) hyperglycaemia with resuming hyperinsulinaemia (1 h hyperglycaemic clamp after somatostatin discontinuation). SUBJECTS: Seven non-obese and seven obese non-diabetic, normo-insulinaemic subjects. MEASUREMENTS: Glucose infused to maintain steady-state hyperglycaemia. Plasma insulin, glucagon, free fatty acid and amino acid concentrations in the last 20 min of the four experimental conditions. Net rates of plasma amino acid disappearance and appearance (micromol/l per hour), calculated as the slopes of the regression of amino acid concentration on time. RESULTS: The amount of glucose infused to maintain hyperglycaemia was reduced by nearly 50% in obese subjects. During hyperinsulinaemia, FFA suppression was lower in obese subjects. In all experimental conditions plasma amino acid levels were slightly, non-significantly higher in obese than in non-obese subjects. In both groups plasma amino acids decreased slightly with ongoing fasting, decreased remarkably during hyperglycaemia-hyperinsulinaemia, rose promptly when insulin concentration was suppressed by somatostatin infusion, and declined again after somatostatin discontinuation. Also the time-course of plasma branched-chain amino acids, which paralleled that of total amino acids, was similar in the two groups. The net rates of amino acid disappearance from plasma did not differ in obese and non-obese subjects both at fasting and during hyperglycaemia-hyperinsulinaemia. Also plasma amino acid appearance during hyperglycaemia with basal insulin was not different in the two groups. CONCLUSION: The net traffic of amino acids to and from plasma in relation to insulin drive and prevailing glucose is not impaired in obese subjects with normal glucose tolerance, in spite of a decreased insulin sensitivity of glucose and lipid metabolism.

Adult↗

PubMed2000

Distinct risk profiles of early and advanced atherosclerosis: prospective results from the Bruneck Study.

Most epidemiological surveys on risk factors of atherosclerosis were cross-sectional in design and did not consider the existence of pathologically distinct processes. The Bruneck Study is a prospective survey in the general community (age range, 40 to 79 years). The baseline examination and first reevaluation were performed in the summers of 1990 and 1995 (participation, 92%; follow-up, 96%). Carotid atherosclerosis was monitored with high-resolution duplex ultrasound. Early (incidence and/or extension of nonstenotic lesions) and advanced (incidence and/or progression of stenosis >40%) stages of atherogenesis were differentiated. The risk profile of early atherogenesis consists of traditional risk factors, such as hypertension, hyperlipidemia, and cigarette smoking (pack-years), supplemented by a variety of less well-established risk conditions, including high body iron stores, hypothyroidism, microalbuminuria, and high alcohol consumption. In contrast, the risk profile of advanced atherogenesis includes markers of enhanced prothrombotic capacity, attenuated fibrinolysis, and clinical conditions known to interfere with coagulation: high fibrinogen, low antithrombin, factor V Leiden mutation, lipoprotein(a) >0.32 g/L, high platelet count, cigarette smoking, and diabetes. Hyperlipidemia and hypertension were of only minor relevance. These findings, along with the epidemiological features of advanced atherogenesis and emergence of an elevated fibrin turnover, suggest atherothrombosis to be a key mechanism in the development of advanced stenotic atherosclerosis. Supplementary 6-category logistic regression models illustrate the changing association between major risk predictors and atherosclerosis of increasing severity and substantiate appropriateness of the 40% threshold applied for the definition of advanced stenotic atherosclerosis. Atherosclerosis is a heterogeneous process that subsumes etiologically and epidemiologically distinct disease entities. The multifactorial etiology of atherosclerosis, which goes far beyond the traditional risk factors, has not yet achieved adequate attention in clinical practice and disease prevention.

Adult↗

PubMed2000

Antiandrogen drugs lower serum prostate-specific antigen (PSA) levels in hirsute subjects: evidence that serum PSA is a marker of androgen action in women.

Assay by ultrasensitive methods of serum prostate-specific antigen (PSA) recently demonstrated that many women have detectable levels of this molecule. Interestingly, serum PSA concentrations were higher in hirsute than in nonhirsute subjects, suggesting that, also in females, PSA may be regulated by androgens. To establish the potential for this assay as a biochemical marker of androgen action in women, we studied 40 hirsute subjects recruited in a double-blind, placebo-controlled, 6-month trial assessing the effects of 3 different antiandrogen drugs: spironolactone, flutamide, or finasteride. In each subject, serum PSA, free testosterone, and 3alpha-androstanediol glucuronide were determined at baseline and at the end of treatments. At baseline, PSA concentrations were higher in these 40 women than in 19 nonhirsute healthy controls (12.9+/-1.5 vs. 4.9+/-0.7 pg/mL, P = 0.03) and significantly correlated with serum free testosterone (r = 0.37, P<0.005). After treatments, the 29 hirsute subjects given active drugs showed significant reduction of serum PSA levels (7.2+/-1.4 vs. 14.7+/-3.0 pg/mL, P = 0.002). This phenomenon was correlated to baseline PSA values. No change was found in the placebo group. In conclusion, serum PSA is increased in many hirsute women. A 6-month course of antiandrogen treatments with spironolactone, flutamide, or finasteride determines a reduction of PSA levels in these subjects. These results suggest that serum PSA is a biochemical marker of androgen action in tissues of female subjects.

Adult↗

PubMed2000

Comparison of spironolactone, flutamide, and finasteride efficacy in the treatment of hirsutism: a randomized, double blind, placebo-controlled trial.

To compare objectively the efficacies of spironolactone (100 mg/day), flutamide (250 mg/day), and finasteride (5 mg/day) in the treatment of hirsutism, 40 hirsute women were randomly assigned to double blind treatments with 1 of these 3 drugs or placebo for 6 months. Before and at the end of treatment, hirsutism was quantitatively measured in each subject by determination, by computer-assisted light microscopy, of the largest diameter of 5 hairs plucked from the linea alba. These measurements were averaged to produce a mean hair shaft diameter. For each subject, baseline and posttreatment assessments were carried out at the same time by an investigator blinded to both time and type of therapy. In addition, a semi-quantitative clinical evaluation was carried out by a modification of the Ferriman-Gallwey (F-G) scoring method, performed by a single investigator. At baseline the 4 groups of women had similar hair diameters and F-G scores. After 6 months of therapy all groups of subjects given active drugs showed reductions of their hair diameters, without statistically significant differences among groups (mean change +/- SEM, -11.7+/-5.6%, -18.0+/-6.1%, and -12.6+/-6.7%, respectively, in the spironolactone, flutamide, and finasteride groups). F-G scores were also significantly reduced in women receiving antiandrogen drugs, again without differences among groups (mean change, -41.0+/-5.5%, -38.9+/-7.2%, and -31.6+/-3.7%, respectively). No significant changes from baseline values were recorded by either hair diameter (-1.4+/-5.2%) or F-G score (+5.4+/-3.7%) assessment in the placebo group. In conclusion, spironolactone, flutamide, and finasteride are all effective in the treatment of hirsutism. After a 6-month course of therapy, the clinical efficacies of these drugs, at least at the doses used, are similar.

Adult↗

PubMed2000

Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation.

In the last few years some studies assessed the effects of attenuation of hyperinsulinemia and insulin resistance, obtained by insulin sensitizing agents, in women with polycystic ovary syndrome (PCOS), suggesting potential scope for these drugs in treating the whole spectrum of reproductive, endocrine, and metabolic abnormalities found in such subjects. However, the results of these studies, mostly uncontrolled and short-term, are still inconclusive, and there is no long-term follow-up. In the present study, 23 PCOS subjects [mean (+/- SE) body mass index 30.0+/-1.1 kg/m2] were randomly assigned to double-blind treatment with metformin (500 mg tid) or placebo for 6 months, while maintaining their usual eating habits. Before and after treatment, menstrual history, endocrine and metabolic profiles, serum 17-hydroxyprogesterone response to GnRH-agonist testing, and insulin sensitivity measured by the glucose clamp technique were assessed. Eighteen of these women, as well as 14 additional PCOS patients, were subsequently given metformin in an open trial for 11.0+/-1.3 months (range 4-26), to assess long-term effects of treatment and baseline predictors of metformin efficacy on reproductive abnormalities. After metformin treatment, mean frequency of menstruation improved (P = 0.002), due to striking amelioration of menstrual abnormalities in about 50% of subjects. Women given metformin showed reduced plasma insulin (at fasting: P = 0.057; during the clamp studies: P<0.01) and increased insulin sensitivity (P<0.05). Concurrently, ovarian hyperandrogenism was attenuated, as indicated by significant reductions in serum free testosterone (P<0.05) and in the 17-hydroxyprogesterone response to GnRH-agonist testing (P<0.05). No changes were found in the placebo group. Only comparable minor changes in body mass index were found both in the metformin group and in the placebo group. In the open, long-term trial 17 women (54.8%) showed striking improvements of their menstrual abnormalities and were considered as responders. Logistic regression analysis of baseline characteristics in responders and nonresponders showed that plasma insulin, serum androstenedione, and menstrual history were independent predictors of the treatment's clinical efficacy. In 10 subjects whose menses proved regular after treatment, the great majority of cycles became ovulatory (32 out of 39 assessed, 79%). In conclusion, in women with PCOS metformin treatment reduced hyperinsulinemia and hyperandrogenemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation. Higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities are baseline predictors of clinical response to metformin.

17-alpha-Hydroxyprogesterone↗

PubMed2000

Power spectral analysis of heart rate in hypothyroidism.

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.

Electrocardiography↗

PubMed2000

Effects of glucosamine infusion on insulin secretion and insulin action in humans.

Glucose toxicity (i.e., glucose-induced reduction in insulin secretion and action) may be mediated by an increased flux through the hexosamine-phosphate pathway. Glucosamine (GlcN) is widely used to accelerate the hexosamine pathway flux, independently of glucose. We tested the hypothesis that GlcN can affect insulin secretion and/or action in humans. In 10 healthy subjects, we sequentially performed an intravenous glucose (plus [2-3H]glucose) tolerance test (IVGTT) and a euglycemic insulin clamp during either a saline infusion or a low (1.6 micromol x min(-1) x kg(-1)) or high (5 micromol x min(-1) x kg(-1) [n = 5]) GlcN infusion. Beta-cell secretion, insulin (SI*-IVGTT), and glucose (SG*) action on glucose utilization during the IVGTT were measured according to minimal models of insulin secretion and action. Infusion of GlcN did not affect readily releasable insulin levels, glucose-stimulated insulin secretion (GSIS), or the time constant of secretion, but it increased both the glucose threshold of GSIS (delta approximately 0.5-0.8 mmol/l, P < 0.03-0.01) and plasma fasting glucose levels (delta approximately 0.3-0.5 mmol/l, P < 0.05-0.02). GlcN did not change glucose utilization or intracellular metabolism (glucose oxidation and glucose storage were measured by indirect calorimetry) during the clamp. However, high levels of GlcN caused a decrease in SI*-IVGTT (delta approximately 30%, P < 0.02) and in SG* (delta approximately 40%, P < 0.05). Thus, in humans, acute GlcN infusion recapitulates some metabolic features of human diabetes. It remains to be determined whether acceleration of the hexosamine pathway can cause insulin resistance at euglycemia in humans.

Adult↗

PubMed2000

Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study.

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.

Aged↗

PubMed2000

Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity.

OBJECTIVE: To evaluate whether the homeostasis model assessment (HOMA) is a reliable surrogate measure of in vivo insulin sensitivity in humans. RESEARCH DESIGN AND METHODS: In the present study, we compared insulin sensitivity as assessed by a 4-h euglycemic (approximately 5 mmol/l) hyperinsulinemic (approximately 300 pmol/l) clamp with HOMA in 115 subjects with various degrees of glucose tolerance and insulin sensitivity. RESULTS: We found a strong correlation between clamp-measured total glucose disposal and HOMA-estimated insulin sensitivity (r = -0.820, P<0.0001), with no substantial differences between men (r = -0.800) and women (r = -0.796), younger (aged <50 years, r = -0.832) and older (r = -0.800) subjects, nonobese (BMI <27 kg/m2, r = -0.800) and obese (r = -0.765) subjects, nondiabetic (r = -0.754) and diabetic (r = -0.695) subjects, and normotensive ( r = -0.786) and hypertensive (r = -0.762) subjects. Also, we found good agreement between the two methods in the categorization of subjects according to insulin sensitivity (weighted k = 0.63). CONCLUSIONS: We conclude that the HOMA can be reliably used in large-scale or epidemiological studies in which only a fasting blood sample is available to assess insulin sensitivity

Adult↗

PubMed2000

Cigarette smoking and plasma total homocysteine levels in young adults with type 1 diabetes.

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.

Adult↗

PubMed2000

Capture-recapture method in the epidemiology of type 2 diabetes: a contribution from the Verona Diabetes Study.

OBJECTIVE: The present investigation used data from the Verona Diabetes Study to verify a main assumption of the capture-recapture method (source independence) and to characterize the subgroup of known diabetic patients missed by all sources whose number is estimated by the capture-recapture method. RESEARCH DESIGN AND METHODS: The Verona Diabetes Study identified 7,148 type 2 diabetic patients on 31 December 1986 using 3 different sources: family physicians, a diabetes center, and a drug prescription database. Completeness of ascertainment was estimated with traditional methods based on the hypergeometric distribution and with a log-linear model. RESULTS: Identification sources were not independent because the drug prescription database was positively related to family physicians and negatively related to the diabetes center (P < 0.001). Thus, completeness of ascertainment was overestimated (87.5% [95% CI 86.3-88.8]) when using only family physicians and the drug prescription database and underestimated (45.9% [43.9-48.1]) when using only the diabetes center and the drug prescription database. Because of characteristics contributing to variable "catchability" (probability of ascertainment), the estimated proportion of ascertainment increased with increasing time since diagnosis from 65.6% in the first tertile (<6 years) to 91.5% in the third tertile (>12 years); moreover, the ascertainment was estimated to be nearly complete (97.9%) for insulin-treated patients and scanty (28.9%) for diet-treated patients. CONCLUSIONS: Because identification sources are likely to be dependent, the capture-recapture method should be used with caution in diabetes epidemiology and possibly when at least 3 sources are available. The subgroup of diabetic patients whose existence is inferred by this technique likely consists of newly diagnosed patients with mild disease severity.

Aged↗

PubMed2000

Diabetes duration and cause-specific mortality in the Verona Diabetes Study.

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.

Adolescent↗

PubMed2000

Glycemic control and cardiovascular diseases in Type 2 diabetes mellitus. Beyond fasting glycemia and glycosylated hemoglobin.

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Blood Glucose↗