Association of macronutrient consumption with arterial aging in adults without clinically overt cardiovascular disease: a 5-year prospective cohort study.

PURPOSE: There is limited and inconsistent evidence regarding longitudinal effects of macronutrients on blood pressure (BP) haemodynamics and arterial aging in populations without cardiovascular disease (CVD). We aimed to prospectively investigate potential association of dietary macronutrients with long-term changes in peripheral and central haemodynamics and arterial stiffness. METHODS: One hundred and fifteen subjects (46.7 ± 8.73 years, 70 women), free of clinically overt CVD were consecutively recruited. Dietary macronutrient intake was evaluated using 3-day food records at baseline. Aortic stiffness and arterial wave reflections were assessed at baseline and in one follow-up visit 5 years later by pulse wave velocity (PWV) and augmentation index (AI), respectively. RESULTS: Individuals with the highest consumption of saturated fatty acids (SFA) presented the highest rate of progression in PWV, AI and aortic diastolic BP (p < 0.05 for all) after adjustment for age, gender, smoking, body mass index, hyperlipidemia, insulin resistance, changes in systolic BP and treatment with antihypertensive and hypolipidemic drugs. After similar multivariable adjustments, high consumption of carbohydrates was associated with higher progression of AI, whereas high consumption of monounsaturated fatty acids (MUFA) and fibre with lower progression in aortic and peripheral systolic and diastolic BP (p < 0.05 for all). CONCLUSIONS: In subjects without CVD, high consumption of SFA is related to accelerated arterial stiffening, while high consumption of MUFA and fibre and low intake of carbohydrates is associated with attenuated progression in blood pressure and arterial wave reflections, respectively. These findings expand current knowledge on the association of macronutrient consumption with arterial aging in the general population.

Avoiding hypoglycemia: the use of insulin pump combined with continuous glucose monitor in type 1 diabetes crossing a Rocky Gorge.

BACKGROUND: Continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring systems (CGMS) have been proven very effective in diabetes management. AIM: This study evaluated the usefulness of these devices during prolonged, intense physical activity in an uncontrolled natural environment away from the clinical research center. DESIGN: Non-randomized, prospective and observational study. METHODS: During the summer, 38 participants with type 1 diabetes crossed the Samaria gorge, the second largest gorge in Europe (17 km). Twenty subjects on CSII combined with real-time CGMS and 18 on multiple daily injections (MDI) combined with professional (retrospective) CGMS participated in the program. All participants were unsupervised during the event. RESULTS: All 38 participants managed to reach the destination point safely. There were no episodes of severe hypoglycemia. The duration of the exercise (mean ±SD) was 6.4 ± 1.3 h. The CSII group exhibited significantly lower hypoglycemic episodes during exercise (0.1 ± 0.3 vs. 0.4 ± 0.6; P = 0.047) as well as lower AUC below 70 mg/dl compared with the MDI, during the 24 h (0.61 ± 0.78 vs. 1.84 ± 1.55; P = 0.007). Individuals on CSII were significantly less likely to develop a hypoglycemic episode during exercise (P = 0.038). Exercise induced nocturnal hypoglycemia was not prevented effectively in neither group. CONCLUSIONS: CSII combined with CGMS is effective in controlling blood glucose levels in type 1 diabetics who perform prolonged strenuous exercise. The use of insulin pump technology in regions with hot Mediterranean climates is safe and can provide protection against exercise-induced hypoglycemia. Development of precise instructions for T1DM who occasionally get involved in exercise activities, requires further studies.

WHICH FACTORS MAY AFFECT THE QUALITY OF LIFE IN PATIENTS WITH TYPE 1 DIABETES MELLITUS USING THE MEDTRONIC VEO CONTINUOUS SUBCUTANEOUS INSULIN INFUSION PUMP?

Continuous Subcutaneous Insulin Infusion (CSII) is considered an effective therapeutic approach to the treatment of patients with Type 1 Diabetes Mellitus (T1DM). Literature offers limited information regarding the quality of life (QoL) in patients using CSII. The aim of the study was to investigate the impact of diabetes related factors on the QoL of patients with T1DM on CSII treatment, in a Greek urban population. A cross-sectional study was conducted on 80 patients with T1DM using CSII. [(Mean±SD) age: 35.9±11.4 years, duration of diabetes: 24.2±10.3 years, BMI: 24.6±3.5kg/m2, duration of Insulin pump use: 7.1±3.9 years, HbA1c: 7.7±1.1%, gender: 37 males-43 females)]. QoL was assessed using the patient self-administered EuroQol EQ 5D validated in Greek. Correlation and regression analyses were performed to examine the relationship between EQ index - EQ VAS scores and diabetes related factors. Hypoglycemia Awareness was measured using Clarke and Gold Score questionnaires, Hypoglycemic Episodes were expressed as number of episodes per week and the Fear of Hypoglycemia was measured using the worry subscale of the Hypoglycemia Fear Survey (HFS-W). Results were as follows: Gold score: 2.8±1.5, Clarke score: 2.8±2.1, Hypoglycemia Fear Score: 20.6±11.2, Number of hypoglycemic Episodes per week: 4.3±2.9, VAS score: 68.7±18.1, EQ index: 0.79±0.24. In univariate analyses QoL was negatively correlated with Hypoglycemic episodes, HbA1c, Hypoglycemia Fear Score and Hypoglycemia Awareness status. After regression analysis, only HbA1c and the number of hypoglycemic episodes per week remained independently related to QoL scores. Prevention of hypoglycemia and glycemic control should be emphasized in order to improve QoL in patients with T1DM with CSII.

Eating frequency predicts changes in regional body fat distribution in healthy adults.

Background: Eating frequency (EF) has been associated with generalized obesity. Aim: We aimed to prospectively investigate potential associations of frequency of eating episodes with regional fat layers. Design: EF was evaluated at baseline in 115 subjects free of clinically overt cardiovascular disease (54 ± 9.1 years, 70 women) in a prospective, observational study. Methods: Metabolic parameters known to be associated with dietary factors and anthropometric markers including ultrasound assessment of subcutaneous (Smin) and pre-peritoneal (Pmax) fat and their ratio Smin/Pmax (AFI) were evaluated at baseline and at follow-up, 5 years later. Results: EF at baseline positively correlated with Pmax, even after adjustment for potential confounders. EF above median was also an independent predictor for Pmax (beta coefficient = -0.192, P = 0.037) and AFI (beta coefficient = 0.199, P = 0.049) at follow up. Multivariable linear mixed models analysis demonstrated that subjects with increased EF presented a lower progression rate of Pmax (beta = -0.452, P = 0.006) and a higher progression rate of AFI (beta = 0.563, P = 0.003) over time, independently of age, sex, progression of BMI, energy intake, smoking and changes in parameters of glucose metabolism. Conclusions: High EF is associated with lower progression rate of pre-peritoneal fat accumulation. Future interventional studies should further investigate the clinical utility of these findings.

Fasting insulin at baseline influences the number of cardiometabolic risk factors and R-R interval at 3years in a healthy population: the RISC Study.

AIM: This was a cross-sectional and longitudinal study of factors contributing to the number of cardiometabolic risk factors, common carotid artery intima-media thickness (CCA-IMT) and R-R interval in clinically healthy subjects without diabetes. METHODS: Anthropometric and cardiometabolic parameters were measured in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) Study cohort at baseline (n=1211) and 3years later (n=974). At baseline, insulin sensitivity was assessed by the euglycaemic clamp technique. The CCA-IMT was echographically measured and the R-R interval was electrocardiographically evaluated at baseline and at the 3-year follow-up. RESULTS: Higher baseline BMI, fasting insulin and tobacco use as well as greater changes in BMI and fasting insulin but lower adiponectin levels, were associated with a greater number of cardiometabolic risk factors at the 3-year follow-up independently of insulin sensitivity (all P<0.02). The CCA-IMT increased with the number of cardiometabolic risk factors (P=0.008), but was not related to fasting insulin, whereas higher fasting insulinaemia and its 3-year changes were significantly associated with a smaller R-R interval (P=0.005 and P=0.002, respectively). These relationships were independent of baseline age, gender, BMI, adiponectin, insulin sensitivity, tobacco use and physical activity. CONCLUSION: In clinically healthy subjects, fasting insulinaemia, adiponectin and lifestyle parameters are related to the presence of one or two cardiometabolic risk factors before criteria for the metabolic syndrome are met. These results underline the importance of fasting insulinaemia as an independent cardiometabolic risk factor at an early stage of disease development in a healthy general population.

Glucose and arterial blood pressure variability in Obstructive Sleep Apnea Syndrome.

INTRODUCTION: Current evidence supports an association between Obstructive Sleep Apnea Syndrome (OSAS), insulin resistance, type 2 diabetes mellitus (DM) and cardiovascular disorders. The relationship is complex and still remains poorly understood. AIM: The aim of this study was to examine the potential correlation of sleep characteristics with glucose and arterial pressure values variability in non - diabetic, non-hypertensive patients with OSAS. SUBJECTS AND METHODS: We examined 22 subjects, 11 men and 11 women (mean age 54 ± 14,5 years), recently diagnosed with OSAS (Apnea - Hypopnea Index (AHI) ≥ 5 apneas/hypopneas per hour of sleep) by full night polysomnography (PSG). Fasting and postprandial after a 2 hour oral glucose tolerance test (OGTT) glucose and insulin levels were measured, and homeostatic model assessment of insulin resistance (HOMA(IR)) index profile as well as Matsuda insulin sensitivity index (ISI) were calculated. A 24 hour glucose monitoring with subcutaneous measurements every 5 minutes and a 24-hour arterial blood pressure (ABP) monitoring (Holter monitoring) were evaluated. RESULTS: AHI, a widely accepted marker of the severity of OSAS, was correlated with HOMA and Matsuda index (p = 0.016 and p = 0.022, respectively), Standard Deviation (SD) of glucose measurements (p = 0.05) and mean diastolic blood pressure (p = 0.007). Percentage of sleep time with saturation of hemoglobin with oxygen, as measured by pulse oximetry, (SpO2) < 90% was also correlated with HOMA and Matsuda index (p = 0.014 and p = 0.012, respectively), coefficient of variation (CV) of glucose measurements (p = 0.009) and SD of 24-hour systolic blood pressure. Moreover, minimum SpO2 was correlated with glucose levels (p = 0.018), Matsuda index (p = 0.30) and SD of 24-hour diastolic and systolic blood pressure (p = 0.005 and p = 0.022, respectively). CONCLUSIONS: Glucose and arterial pressure variability were associated with markers of OSAS severity (AHI, % sleep time with SpO2 < 90%, min SpO2), among nondiabetic patients. Thus, glucose and arterial pressure variability in OSAS may be an additional marker of cardiovascular risk as well as of future diabetes in these subjects. Nevertheless, the clinical significance of our observations remains to be confirmed by prospective studies.

Association of fasting glucagon and proinsulin concentrations with insulin resistance.

AIMS/HYPOTHESIS: Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) in non-diabetic individuals. METHODS: We measured IR [by a euglycaemic-hyperinsulinaemic (240 pmol min(-1) m(-2)) clamp technique] in 1,296 non-diabetic (on a 75 g OGTT) individuals [716 women and 579 men, mean age 44 years, BMI 26 kg/m(2) (range 18-44 kg/m(2))] recruited at 19 centres in 14 European countries. IR was related to fasting proinsulin or pancreatic glucagon concentrations in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control. RESULTS: In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with it (all p < 0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was approximately 2 for both glucagon (p = 0.05) and proinsulin (p = 0.02) and 0.36 for adiponectin (p < 0.0001). CONCLUSIONS/INTERPRETATION: Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a result of IR at the level of alpha cells and beta cells in pancreatic islets.

Leptin and adiponectin responses in overweight inactive elderly following resistance training and detraining are intensity related.

CONTEXT: Adiponectin and leptin are closely related to weight control and energy balance, whereas exercise affects elderly metabolic regulation and functional capacity. OBJECTIVE: The objective of this study was to investigate leptin and adiponectin responses in elderly males after exercise training and detraining. DESIGN: The study design was a 1-yr randomized controlled trial. SETTING: The study was performed at the Laboratory of Physical Education and Sport Science Department. PARTICIPANTS: Fifty inactive men [age, 65-78 yr; body mass index (BMI), 28.7-30.2 kg/m2] were recruited from a volunteer database by word of mouth and fliers sent to medical practitioners, physiotherapists, and nursing homes in the local community. INTERVENTION(S): Participants were randomly assigned to a control (n = 10), low-intensity (n = 14), moderate-intensity (n = 12), or high-intensity training (HI; n = 14) group. Resistance training (6 months, 3 d/wk, 10 exercises/three sets) was followed by 6 months of detraining. MAIN OUTCOME MEASURE(S): Strength, exercise energy cost, skinfold sum, body weight, maximal oxygen consumption, resting metabolic rate (RMR), and plasma leptin and adiponectin were determined at baseline and after training and detraining. RESULTS: Strength, maximal oxygen consumption, RMR, and exercise energy cost increased (P < 0.05) after training in an intensity-dependent manner. Skinfold sum and BMI were reduced by resistance training (P < 0.05), with HI being more effective (P < 0.05) than moderate-intensity/low-intensity training. Leptin was diminished (P < 0.05) by all treatments, whereas adiponectin increased (P < 0.05) only in HI. Detraining maintained training-induced changes only in HI. The percent leptin decrease was associated (P < 0.05) with the percent BMI decrease and the percent RMR increase, whereas the percent adiponectin increase was associated (P < 0.05) with the percent BMI decrease. CONCLUSIONS: Resistance training and detraining may alter leptin and adiponectin responses in an intensity-dependent manner. Leptin and adiponectin changes were strongly associated with RMR and anthropometric changes.

Increased renal glucose metabolism in Type 1 diabetes mellitus.

AIMS: In poorly controlled diabetes, increased renal glucose uptake has been implicated in the pathogenesis of diabetic nephropathy by promoting nonenzymatic glycosylation of proteins, activation of protein kinase C, and increased polyol pathway flux. However, whether glucose uptake by the diabetic kidney is actually increased, especially in patients with Type 1 diabetes, is unclear. METHODS: To examine this question, we used a combination of net balance and isotopic techniques to compare renal glucose uptake in 12 subjects with Type 1 diabetes before and after restoration of near normoglycaemia by infusion of insulin with that in 15 postabsorptive nondiabetic volunteers. RESULTS: Prior to insulin infusion, the diabetic subjects were markedly hyperglycaemic (arterial glucose 15.8 +/- 0.9 vs. 4.4 +/- 0.1 mm) and their renal tissue glucose uptake (i.e. total glucose disappearance across the kidney minus glycosuria) was increased more than 2 1/2-fold (388 +/- 43 vs. 148 +/- 12 micromol/min, P < 0.001). This was wholly explained by the mass action effects of hyperglycaemia since the diabetic subjects had normal renal blood flow (1575 +/- 82 vs. 1492 +/- 68 mL/min, P = 0.46) and reduced renal tissue glucose fractional extraction (1.7 +/- 0.2 vs. 2.3 +/- 0.1%, P = 0.027). Insulin infusion for three hours, which restored near normoglycaemia (arterial glucose 7.6 +/- 0.7 mm), reduced renal tissue glucose uptake toward normal (258 +/- 41 micromol/min, P = 0.006) without altering renal blood flow (1557 +/- 110, P = 0.63) or renal tissue glucose fractional extraction (2.1 +/- 0.3%, P = 0.35). Renal and hepatic glucose release, which had been increased (419 +/- 49 and 960 +/- 54 vs. 204 +/- 9 and 734 +/- 32 micromol/min, both P < 0.001), were suppressed by insulin to 138 +/- 22 and 520 +/- 53 micromol/min, respectively (both P < 0.001). CONCLUSIONS: In poorly controlled Type 1 diabetes, renal glucose uptake is markedly increased, which provides a link between hyperglycaemia and biochemical processes implicated in the pathogenesis of diabetic nephropathy. Its reversal by restoration of near normoglycaemia with insulin may explain the benefit of intensive insulin therapy in preventing diabetic nephropathy.

Relative conributions of beta-cell function and tissue insulin sensitivity to fasting and postglucose-load glycemia.

We performed hyperglycemic clamps in 283 nondiabetic Caucasians and, with multiple linear regression, determined the contribution of beta-cell function and tissue insulin sensitivity to variations in glycemia and insulinemia during oral glucose tolerance tests (OGTTs). Impaired glucose tolerance (IGT) subjects had reduced insulin sensitivity (P < .02) and beta-cell function (P < .0001). Normal glucose tolerance (NGT) subjects with first-degree type 2 diabetic relatives had reduced first and second phase insulin secretion (both, P < .05), but normal insulin sensitivity (P = .37). Beta-Cell function and insulin sensitivity accounted for one fourth of the variability in glucose tolerance. Fasting plasma glucose in subjects with NGT (n = 185) was a function of both phases of insulin secretion and of insulin sensitivity (all, P < .05), whereas, in IGT subjects (n = 98), it was a function of first phase insulin secretion and insulin sensitivity (P < .01). Two-hour glycemia was a function of second phase secretion and insulin sensitivity (P < .01). Fasting and 2-hour plasma insulin levels were determined by insulin sensitivity (and glycemia) in NGT subjects (P < .001), but by second phase secretion in IGT (P < .001). We conclude that beta-cell function is reduced in subjects with IGT; glycemia and insulinemia are not regulated by the same mechanisms in IGT and NGT; insulin sensitivity does not contribute to insulinemia in IGT; family history of diabetes influences beta-cell function, but not insulin sensitivity in Caucasians.

Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.

OBJECTIVE: The oral glucose tolerance test (OGTT) has often been used to evaluate apparent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be predicted from an OGTT is unclear. RESEARCH DESIGN AND METHODS: We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear regression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps. RESULTS: The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P < 0.00005) and ISI (r = 0.79, P < 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P < 0.00005) and 2nd PH (r = 0.79, P < 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the delta30-min insulin/delta30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT. CONCLUSIONS: We thus conclude that predicting insulin sensitivity and insulin release with reasonable accuracy from simple demographic parameters and values obtained during an OGTT is possible. The derived equations should be used in various clinical settings in which the use of clamps or the minimal model would be impractical.

Important role of the kidney in human carbohydrate metabolism.

Recent studies using a combination of isotope and balance techniques have shown that, in the postabsorptive state, the human kidney contributes substantially to overall glucose production and consumption. The kidney may contribute as much as the liver to gluconeogenesis and play an important role in the counterregulation of hypoglycemia. Furthermore, increased renal glucose production may contribute to fasting hyperglycemia found in type I and type II diabetes mellitus. Finally, loss of renal tissue as a consumer of glucose could explain the insulin resistance of uremia. We hypothesize that the human kidney may play a more important role in human carbohydrate metabolism than previously appreciated.

Reduced beta-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness.

OBJECTIVE: We tested the hypothesis that impaired tissue sensitivity to catecholamines contributes to hypoglycemia unawareness in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 21 subjects with type 1 diabetes underwent a standardized insulin infusion protocol to produce a stepwise decrease in plasma glucose to 45-min plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l. Glycemic thresholds, maximum responses for adrenergic and neuroglycopenic symptoms, and counterregulatory hormones were determined. Patients were classified as hypoglycemia unaware if the initiation of adrenergic symptoms occurred at a plasma glucose level 2 SD below that of nondiabetic volunteers. beta-Adrenergic sensitivity was measured as the dose of isoproterenol required to produce an increment in heart rate of 25 beats per minute above baseline (I25) in resting subjects. RESULTS: Subjects with type 1 diabetes and hypoglycemia unawareness experienced the onset of adrenergic symptoms at a lower plasma glucose level than did those with awareness (2.5+/-0.1 vs. 3.7+/-0.1 mmol/l, P < 0.001), whereas neuroglycopenic symptoms occurred at similar glucose levels (2.7+/-0.2 vs. 2.8+/- 0.1 mmol/l). The plasma glucose levels for counterregulatory hormone secretion (epinephrine 2.9+/-0.2 vs. 4.1+/-0.2 mmol/l; norepinephrine 2.7+/-0.1 vs. 3.2+/-0.2 mmol/l; cortisol 2.5+/-0.2 vs. 3.3+/-0.2 mmol/l, P < 0.01) were also lower in subjects with unawareness. The maximal epinephrine (1,954+/-486 vs. 5,332+/- 1,059 pmol/l, P < 0.01), norepinephrine (0.73 +/- 0.14 vs. 1.47+/-0.21 nmol/l, P = 0.04), and cortisol (276+/-110 vs. 579+/-83 nmol/l, P < 0.01) responses were reduced in the unaware group. I25 was greater in unaware subjects than in subjects without unawareness (1.5+/-0.3 vs. 0.8+/-0.2 microg), where I25 was not different from that of controls (0.8 +/-0.2 microg). CONCLUSIONS: We conclude that subjects with type 1 diabetes and hypoglycemia unawareness have reduced beta-adrenergic sensitivity, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.

Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients.

OBJECTIVE: The recent EURODIAB Study has identified autonomic neuropathy as an independent risk factor for severe hypoglycemia in patients with type 1 diabetes. We tested the hypothesis that counterregulatory catecholamine responses and awareness of hypoglycemia are impaired to a greater extent in type 1 diabetic patients with autonomic neuropathy (AN+) than in those without autonomic neuropathy (AN-). RESEARCH DESIGN AND METHODS: We studied 22 type 1 diabetic patients (8 AN+, 14 AN-) matched for age, duration of diabetes, glycemic control, and history of hypoglycemic episodes. We also studied 33 nondiabetic control subjects using the stepped hypoglycemic clamp technique and determined glycemic thresholds and magnitudes of counterregulatory hormone responses and of hypoglycemia symptoms. RESULTS: Both groups of diabetic patients had reduced awareness of hypoglycemia as evidenced by an elevated glycemic threshold for autonomic symptoms > or =2 SD above normal but neither the magnitude nor thresholds for symptoms differed in AN+ patients and AN-patients. Both groups also had impaired glucagon, epinephrine, norepinephrine, growth hormone and cortisol responses to hypoglycemia. However, in AN+ patients compared with AN-patients, magnitudes of epinephrine and norepinephrine responses (194+/-49 vs. 784+/-206 pmol/l, P < 0.007, and 316+/-56 vs. 610+/-87 pmol/l, P < 0.02, respectively) and epinephrine and norepinephrine glycemic thresholds (2.33+/- 0.10 vs. 2.82+/-0.10 mmol/l, P < 0.009 and 2.34+/-0.06 vs. 2.79+/-0.10 mmol/l, P < 0.008, respectively) were impaired to a greater extent. This was associated with a 50% greater requirement of exogenous glucose to prevent more severe hypoglycemia during the 2.3 mmol/l glycemic plateau (P < 0.002). No differences were observed between other counterregulatory hormone responses in AN+ and AN- patients. CONCLUSIONS: We conclude that in patients with type 1 diabetes, autonomic neuropathy further reduces counterregulatory catecholamine responses. Since this should increase the risk for severe hypoglycemia, one might consider safer therapeutic goals in these patients.

Long-term effectiveness of a new alpha-glucosidase inhibitor (BAY m1099-miglitol) in insulin-treated type 2 diabetes mellitus.

In a double-blind, randomized study, miglitol (BAY m 1099), an alpha-glucosidase inhibitor, 100 mg tds or placebo was given orally with meals for a period of 24 weeks in 117 patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) treated with insulin. Fasting and 1 h postprandial plasma glucose and C-peptide were measured at the beginning and at the end of each 4-week interval and glycosylated haemoglobin was determined at day 0 and at the end of the 12th and 24th week. One hour postprandial plasma glucose was significantly lower in the miglitol group at the end of the 24th week (placebo: 11.6 +/- 1.5 vs miglitol: 8.2 +/- 1.5 mmol l-1, mean +/- SD, p = 0.001). Diabetes control improved in the same group as the HbA1 was lowered by 16% (p = < 0.0001) at the end of the treatment. Mild reversible adverse effects were observed in 37 patients of the miglitol group (mainly flatulence and mild hypoglycaemia) and 2 of the placebo group. Urinary glucose was rendered negative in 41 patients in the miglitol group only. Thus miglitol appears to be a safe and effective adjunct in the management of Type 2 DM, in association with insulin.

Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus.

Release of glucose by liver and kidney are both increased in diabetic animals. Although the overall release of glucose into the circulation is increased in humans with diabetes, excessive release of glucose by either their liver or kidney has not as yet been demonstrated. The present experiments were therefore undertaken to assess the relative contributions of hepatic and renal glucose release to the excessive glucose release found in type 2 diabetes. Using a combination of isotopic and balance techniques to determine total systemic glucose release and renal glucose release in postabsorptive type 2 diabetic subjects and age-weight-matched nondiabetic volunteers, their hepatic glucose release was then calculated as the difference between total systemic glucose release and renal glucose release. Renal glucose release was increased nearly 300% in diabetic subjects (321+/-36 vs. 125+/-15 micromol/min, P < 0.001). Hepatic glucose release was increased approximately 30% (P = 0.03), but increments in hepatic and renal glucose release were comparable (2.60+/-0.70 vs. 2.21+/-0.32, micromol.kg-1.min-1, respectively, P = 0.26). Renal glucose uptake was markedly increased in diabetic subjects (353+/-48 vs. 103+/-10 micromol/min, P < 0.001), resulting in net renal glucose uptake in the diabetic subjects (92+/-50 micromol/ min) versus a net output in the nondiabetic subjects (21+/-14 micromol/min, P = 0.043). Renal glucose uptake was inversely correlated with renal FFA uptake (r = -0.51, P < 0.01), which was reduced by approximately 60% in diabetic subjects (10. 9+/-2.7 vs. 27.0+/-3.3 micromol/min, P < 0.002). We conclude that in type 2 diabetes, both liver and kidney contribute to glucose overproduction and that renal glucose uptake is markedly increased. The latter may suppress renal FFA uptake via a glucose-fatty acid cycle and explain the accumulation of glycogen commonly found in the diabetic kidney.

The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age; it is associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. This study was designed to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile in women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. Seventeen women with PCOS (10 obese and 7 lean) were studied. All subjects received a 12-week course of oral flutamide (500 mg/day). The baseline and posttreatment evaluations included lipid profile, androgen levels, insulin sensitivity, and serum catecholamine determinations. The primary outcome was the change in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). Treatment with flutamide was associated with a significant decrease in the LDL/HDL ratio by 23% (P = 0.005), in total cholesterol by 18% (P < 0.0001), in LDL by 13% (P = 0.002), and in triglycerides by 23% (P = 0.002). Flutamide treatment was also associated with a trend toward an increase in HDL (by 14%; P = 0.14). The effects on lipid profile were found regardless of obesity and were not associated with a change in weight. Furthermore, actions of flutamide on lipid metabolism were not associated with significant changes in circulating adrenaline or noradrenaline, glucose metabolism, or insulin sensitivity. This report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile and that this effect may be due to direct inhibition of androgenic actions.

Renal glucose production and utilization: new aspects in humans.

According to current textbook wisdom the liver is the exclusive site of glucose production in humans in the postabsorptive state. Although many animal and in vitro data have documented that the kidney is capable of gluconeogenesis, production of glucose by the human kidney in the postabsorptive state has generally been regarded as negligible. This traditional view is based on net balance measurements which, other than after a prolonged fast or during metabolic acidosis, showed no significant net renal glucose release. However, recent studies have refuted this view by combining isotopic and balance techniques, which have demonstrated that renal glucose production accounts for 25% of systemic glucose production. Moreover, these studies indicate that glucose production by the human kidney is stimulated by epinephrine, inhibited by insulin and is excessive in diabetes mellitus. Since renal glucose release is largely, if not exclusively, due to gluconeogenesis, it is likely that the kidney is as important a gluconeogenic organ as the liver. The most important renal gluconeogenic precursors appear to be lactate, glutamine and glycerol. The implications of these recent findings on the understanding of the physiology and pathophysiology of human glucose metabolism are discussed.