Developing risk stratification charts for diabetic and nondiabetic subjects.

AIMS: To provide estimates of the 10-year risk of coronary heart disease events for diabetic and nondiabetic men and women with different levels of risk factors and, for diabetic subjects, with and without microalbuminuria. METHODS: Use of risk coefficients derived from the Framingham Study and a meta-analysis of the influence of microalbuminuria on cardiovascular disease. The risk of a coronary heart disease event has been calculated for men and women with and without diabetes mellitus, and among diabetic subjects, with and without microalbuminuria, according to age, systolic blood pressure and the ratio of total to high density lipoprotein cholesterol. RESULTS: These risk estimates have been developed as a series of colour charts. The use of Framingham estimates of risk have been validated by comparing them with estimates derived from the Dundee Risk Disk and from the PROCAM Study, these estimates providing reasonable agreement despite the geographical and temporal differences in their development. CONCLUSIONS: These charts permit the overall level of risk to be derived, which can inform decision making about thresholds for therapeutic interventions, as well as assisting in patient education.     

Relationship of plasma amino acids to nitrogen balance and portal-systemic encephalopathy in alcoholic liver disease

Plasma amino acids were compared in three groups of patients with alcoholic liver disease including stable cirrhosis, acute alcoholic hepatitis without portal-systemic encephalopathy, and cirrhosis with encephalopathy. In addition, plasma amino acids were correlated with nitrogen balance in patients with acute alcoholic hepatitis and with clinical improvement in patients with encephalopathy. Significant differences in plasma amino acids within these groups were present. Plasma amino acids did not change with improvement in portal-systemic encephalopathy, and abnormalities of plasma amino acids did not prevent maintenance or attainment of positive nitrogen balance in patients with acute alcoholic hepatitis.This work was supported by the Veterans Administration.     

Hepatic uptake and release of glucose, lactate, and amino acids in acutely uremic dogs

This study evaluated the potential contribution of the liver to glucose intolerance and insulin resistance in acute uremia. Eight bilaterally nephrectomized dogs and eight sham-operated dogs were studied, while awake, 24 to 30 hours after surgery. Blood levels and hepatic balance of glucose, lactate, and amino acids were measured during a baseline period and during a 90-minute infusion of glucose and insulin that maintained plasma glucose at 9 to 10 mmol/L. During the basal state, the acutely uremic dogs, in comparison to control dogs, displayed decreased femoral artery plasma glucose, whole blood total amino acids, and elevated blood lactate. In the liver of the uremic dogs, there was lower glucose output, less uptake of alanine, greater uptake of glutamine, and similar uptake of lactate, as compared with controls during the basal state. In the control dogs during the hyperglycemic clamp, the liver took up glucose and released lactate; the hepatic uptake of alanine diminished, and the hepatic output of glutamine persisted. In contrast, during the hyperglycemic clamp in the uremic dogs, there was no hepatic uptake of glucose; the hepatic uptake of alanine, glutamine, and lactate persisted, and the hepatic uptake of total amino acids was greater than in controls. Peripheral glucose uptake was also impaired in the acutely uremic dogs. Moreover, the uremic dogs had insulin resistance, as indicated by a low ratio of the glucose infusion rate to the plasma insulin levels, and a higher urea nitrogen appearance. Thus, acutely uremic dogs have altered hepatic handling of glucose and its precursors, which only becomes evident during a glucose load.(ABSTRACT TRUNCATED AT 250 WORDS)     

Concordance of indirect methods for the detection of lactose malabsorption in diabetic and nondiabetic subjects

In order to collect data on (1) the prevalence of lactose malabsorption and (2) the value of indirect diagnostic methods for hypolactasia in diabetics, we compared lactose tolerance tests using serum glucose, serum galactose (after oral ethanol intake) and breath hydrogen excretion as diagnostic cutoff in 144 nondiabetic and 46 diabetic subjects. A good rate of concordance was found for the hydrogen breath test and galactose-dependent lactose tolerance test. The glucose-dependent lactose tolerance test was found to be of satisfactory diagnostic value in nondiabetic subjects and was useless for diagnostic purposes in diabetics. Lactose malabsorption was no more frequent in diabetics than in controls and lactose intolerance was found to be less frequent in the diabetic group. A distinction between hypolactasia and other gastrointestinal disorders in diabetics is possible by ambulatory indirect tests.     

Insulin-degrading activity in mononuclear and polymorphonuclear circulating leukocytes of nondiabetic and diabetic subjects

Insulin-degrading activity in mononuclear (MN) and polymorphonuclear (PMN) fractions of circulating leukocytes obtained from 7 nondiabetic and 13 insulin-dependent diabetic subjects was studied. Insulin-degrading activity in both MN and PMN fractions was activated by reduced glutathione and was inhibited completely by N-ethylmaleimide. Both fractions had Michaelis-Menten constant (Km) (insulin) values within the range of values reported for purified glutathione-insulin transhydrogenase (GIT). In double immunodiffusion tests with antibody to human liver GIT, the MN fraction showed immunoprecipitin bands continuous with those of purified liver enzyme, but the PMN fraction showed little or no reaction with the antibody. These data indicate that both leukocyte fractions contain thiol-dependent insulin-degrading activity; however, only in the MN fraction was the degrading activity immunologically similar to that of liver GIT. Kinetic studies showed that the insulin-degrading activity of MN and PMN cells from diabetic patients had a 3.6- and 14.5-fold, respectively, higher maximal capacity (Vmax) than the insulin-degrading activity of these cells from nondiabetic subjects, without any change in the half-saturation constant for the substrate (Km for insulin). These results demonstrate that diabetes and/or insulin therapy result in increased leukocyte glutathione-dependent insulin-degrading activity.     

Impaired stimulation of gluconeogenesis during prolonged hypoglycemia in intensively treated insulin-dependent diabetic subjects.

Defective glucose counterregulation commonly seen in intensively treated insulin-dependent diabetes (IDDM) is mediated in part by a failure of compensatory stimulation of hepatic glucose production. Since the response of the liver to insulin-induced hypoglycemia normally involves activation of gluconeogenesis, we measured [14C]alanine conversion to [14C]glucose (a qualitative index of gluconeogenesis) and glucose production (using [3-3H]glucose) in seven intensively treated type I diabetic subjects (hemoglobin-A1, 7.1 +/- 0.4%) during low dose infusion of insulin (0.3 mU/kg.min for 210 min). IDDM patients received insulin overnight to maintain euglycemia before study. Although insulin levels rose to a similar extent as those in normal control subjects (n = 6), the fall in plasma glucose was markedly greater in IDDM (2.5 +/- 0.2 vs. 3.64 +/- 0.2 mM in controls; P < 0.01). The glucagon response was totally lost in IDDM, and epinephrine release was delayed and slightly reduced compared to that in control subjects. In contrast to that in normal subjects, hepatic glucose production in the IDDM subjects remained persistently suppressed by about 60% throughout the study. The conversion of alanine and lactate to glucose remained virtually unchanged in the IDDM, whereas in controls it increased 2-fold above baseline during the last hour of the study. Our data suggest that the failure of gluconeogenesis to increase during hypoglycemia is an important factor contributing to the defective hepatic response observed in the intensively treated type I diabetic subjects.     

Inhibitory effect of enkephalin on insulin secretion in healthy subjects and in non insulin-dependent diabetic subjects

The administration of the long-acting met-enkephalin analogue (FK 33-824, Sandoz; Basel Switzerland) inhibits insulin secretion induced by glucose (oral and intravenous) and nonglucose (arginine and breakfast) secretagogues in both normal subjects and in patients with noninsulin-dependent diabetes mellitus. The plasma glucose rise triggered by oral glucose and breakfast is reduced by FK in both groups of subjects, suggesting for the opioid peptide an effect in delaying glucose absorption. The data suggest a negative role for enkephalin in the regulation of insulin secretion in both normal and noninsulin-dependent diabetic subjects.     

Physical properties of the aorta in normotensive insulin-dependent diabetic subjects. Study using Doppler echocardiography

We studied 16 normotensive insulin-dependent diabetic patients (D) (11 males + 5 females) aged of 25-51 years old (mean = 35 +/- 6) with a good glycemic control, without microangiopathy and previous heart disease and 16 healthy control of 25 subjects (C) matched for sex age and body area. We measured: Systolic blood pressure (SBP) with a mercury sphygmomanometer, aortic diameter (AD), end diastolic left ventricular radius (r) and wall thickness (Th) by Echocardiography TM with 2 D echo control, the pulse wave delay (PWD) by measurement of time between the feet of aortic velocity tracings, recorded in the isthmus and near the diaphragm, Sternal length (L). Parameters calculated were: the ratio th/r. The pulse wave velocity PWV = L/PWD and the ratio PWV/AD which represents an indirect index of aortic characteristic impedance. (table; see text) PWV and the radio Th/r are significantly increased in diabetic patients as compared to the control group. Th/r is not significantly correlated with PWV in the 2 groups. This lack of correlation could be explained in the control group by the small rang of values of PWV (5-7.3 ms-1) and Th/r (0.26-0.38). It is not the case in the diabetic group where values are widespread (PWD 5-10 ms-1 and Th/r 0.23-0.53). In conclusion: in normotensive young insulin-dependent diabetic patients studied by doppler echocardiography: aortic rigidity measured by the pulse wave velocity is increased. Th/r ratio is also increased but this change of left ventricular geometry is not related to aortic rigidity in this group of patients.     

Correlation between carotid artery distensibility and serum vascular endothelial growth factor concentrations in type 1 diabetic subjects and nondiabetic subjects.

The relationships between serum vascular endothelial growth factor (VEGF) concentrations and vessel wall ultrasonic characteristics in type 1 diabetic and nondiabetic subjects were assessed. Serum VEGF concentration was measured, and ultrasound imaging and blood pressure recordings were performed in 41 type 1 diabetic subjects (hemoglobin A(1c) [HbA(1c)], 7.63 [1.17%]; duration of diabetes, 12 (0 to 23) years), and 50 nondiabetic subjects. Change in carotid artery luminal diameter during the cardiac cycle was measured using M-mode ultrasound, from which percentage increase in carotid artery luminal diameter was calculated; the carotid artery distensibility index was calculated as the ratio of percentage increase in carotid artery luminal diameter and pulse pressure. Serum VEGF concentration was higher in the diabetic subjects (217 [135 to 336] v 137 [80 to 237] pg/mL; P =.009). The percentage increase in carotid luminal diameter during the cardiac cycle was not significantly different between the 2 groups (12.9 [10.2 to 15.7] v 13.0 [10.6 to 15.0%]; P =.270) despite significantly greater pulse pressure in the type 1 diabetic group (55 [45 to 71] v 46 [41 to 51] mm Hg; P =.0003). The distensibility index was therefore lower in the diabetic subjects (0.24 [0.10] v 0.28 [0.08%]/mm Hg; P =.031). There was a significant negative correlation between serum VEGF concentrations and mean percentage increase in carotid luminal diameter during the cardiac cycle in the diabetic group (r = -.36, P =.021) and in the nondiabetic group (r = -.28, P =.047). This negative correlation could be strengthened by relating mean percentage increase in luminal diameter to pulse pressure to give the distensibility index. Therefore, serum VEGF concentrations correlated strongly and inversely with the distensibility index in the diabetic group (r = -.49, P =.001), in the nondiabetic group (r = -.29, P =.041), and in both groups analyzed together (r = -.42, P <.0001). Vessel wall distensibility may be an important determinant of serum VEGF concentrations in both diabetic and nondiabetic populations and may underlie the previously observed association between blood pressure and serum VEGF concentrations. The pathophysiologic relevance of these findings remains to be elucidated.     

Sibutramine in the treatment of obesity in type 2 diabetic patients and in nondiabetic subjects

Abstract Obesity is considered a chronic disease requiring treatment. The effect of sibutramine combined with hypocaloric diet and exercise on body weight, body fat mass, lipids, glycemic control, insulin secretion and insulin resistance was evaluated in a randomized, controlled, open-label study. A total of 44 obese type 2 diabetic patients (aged 45.2±5.2 years, BMI 33.62±2.2 kg/m²) and 49 obese nondiabetic subjects (aged 41.9±5.7 years, BMI 34.3±2.6 kg/m²) were treated with sibutramine for 3 months. Moreover, 39 age-matched obese type 2 diabetic patients and 41 obese nondiabetic subjects only on hypocaloric diet and exercise served as control groups. Insulin secretion was estimated during intravenous glucose tolerance test; insulin resistance was assessed by the HOMA index. There was a significant reduction in body weight in both sibutramine-treated diabetic patients (7.1%) and nondiabetic subjects (9.1%), accompanied by a significant reduction in body fat mass. HbA1c decreased significantly in the diabetic patients after sibutramine treatment. There was a significant improvement of lipid parameters in the two groups. Insulin resistance decreased by 21.9% in the sibutramine-treated diabetic patients and by 38.5% in the nondiabetic group. Weight loss was accompanied by an increase of 43.8% in first phase insulin secretion in the sibutramine-treated diabetic group; in the treated nondiabetic subjects there was a decrease in first and second phase insulin secretion and the area under the curve for total insulin secretion. In conclusion, sibutramine leads to a significant reduction in body weight, body fat mass and waist and hip circumferences; it improves insulin sensitivity, insulin secretion, glycaemic control and lipid parameters in both diabetic and nondiabetic obese subjects.     

The variability of overnight urinary albumin excretion in insulin-dependent diabetic and normal subjects

The variability of overnight urinary albumin excretion rate (AER) and albumin to creatinine ratio was assessed in eight normal subjects and two groups of insulin-dependent diabetic patients divided on the basis of an initial overnight urinary albumin excretion rate below (n = 15) or above (n = 12) 30 micrograms/min. The latter group is known to be at risk of developing clinical diabetic nephropathy. An albumin to creatinine ratio of 2.6 and above identified all patients with an initial albumin excretion rate greater than 30 micrograms/min. The mean of the coefficients of variation, calculated from five successive overnight urine collections, for all subjects was 38% for albumin excretion rate and 37% for albumin to creatinine ratio. There was no significant difference in the variation of albumin excretion rate and albumin to creatinine ratio within or between the groups. Subsequent AERs from diabetics with an initial rate greater than 30 micrograms/min changed category more often (chi 2 = 11.9, p less than 0.001) than those from diabetics with lower initial rates and normal subjects. This was due to four subjects with initial values close to the cut-off level, whose subsequent values varied around it. Albumin excretion rates in normal subjects never exceeded 11 micrograms/min. Whether a patient's risk status is influenced by the degree of variation of albumin excretion rate around a risk level, or whether the classification of risk is improved by multiple collections, awaits testing in prospective subjects.     

Absorption of soluble and isophane semi-synthetic human and porcine insulin in insulin-dependent diabetic subjects

A double-blind cross-over study of the sc absorption of radiolabelled semi-synthetic human (SHI) and purified porcine (PPI) insulin was made. Absorption of both isophane (n = 10) and soluble insulin (n = 8) was studied. There was no significant difference between the disappearance from the injection site, the plasma free insulin concentrations, or blood glucose levels after sc injection of the isophane preparations. A faster disappearance of the soluble SHI (as judged from T/50 and AUC) was found (both P-values less than 0.01). However, no difference was observed between the plasma insulin concentrations at any time point (P less than 0.05). Blood glucose levels showed no statistical differences between the two soluble preparations. The data indicate minor differences between the pharmacokinetics of SHI and PPI, but these seem of no clinical importance.     

The role of central fat distribution in coronary artery disease in obesity: comparison of nondiabetic obese, diabetic obese, and normal weight subjects

OBJECTIVE: To investigate the degree of coronary artery disease (CAD) in relation to obesity and fat distribution in obese patients with normal glucose tolerance, in comparison with CAD of diabetic obese patients and of normal weight subjects with CAD. DESIGN: Patients listed for coronary angiography with different body mass index (BMI) with or without diabetes: study of the correlation between severity of coronary damage and fat distribution. SUBJECTS: 92 patients subdivided into: 30 normal glucose tolerant obese (BMI 31.7+/-0.5, aged 53+/-1.7 y), 28 type 2 diabetic obese (BMI 30.7+/-0. 3, aged 57+/-1.2 y), and 34 normal weight patients (BMI 23.1+/-0.3, aged 54+/-1.7 y). MEASUREMENTS: CAD assessed by angiography and evaluated according to the method of Gensini. Fat mass and fat distribution assessed by bioelectrical impedance and anthropometry. Clinical, biochemical and hormonal variables, as well as smoking habits and alcohol intake. RESULTS: The angiographic coronary scores were similar in nondiabetic obese and in diabetic obese patients, and were significantly higher than those of normal weight subjects. In the entire population coronary score correlated with indices of abdominal fat distribution. In the stepwise analysis of each group separately, waist hip ratio (WHR) correlated with coronary score only in normal weight nondiabetic patients. CAD was inversely associated with BMI only in nondiabetic obese patients. CONCLUSION: CAD of obese patients: 1) is similar to that of diabetic obese patients; 2) is more severe than that of normal weight individuals; and 3) is inversely correlated with BMI. CAD appears to be associated with WHR, not with BMI, only in nondiabetic patients with normal body weight. On the contrary, CAD of diabetic obese patients is unrelated to BMI and parameters of fat distribution, but is associated with smoking habits.     

Insulin resistance is accompanied by increased von Willebrand factor levels in nondiabetic women: a study of offspring of type 2 diabetic subjects compared to offspring of nondiabetic subjects

OBJECTIVES: To examine whether levels of von Willebrand factor (vWF), fibrinogen and fibronectin are related to a parental history of type 2 diabetes and to determine possible explanatory factors for high versus low vWF and fibrinogen. DESIGN: Cross-sectional study. SUBJECTS, MAIN OUTCOME MEASURES: We compared vWF, fibrinogen and fibronectin in 88 nondiabetic offspring of type 2 diabetic subjects (relatives) and 103 offspring of nondiabetic subjects (controls). Other measurements included urinary albumin excretion rate, blood pressure, lipid profile and insulin resistance using homeostasis model assessment (HOMAIR). RESULTS: There were no significant differences in vWF (1.12 vs. 1.06 IU x mL(-1), P = 0.296), fibrinogen (3.2 vs. 3.1 g x L(-1); P = 0.263) or fibronectin (0.39 vs. 0.40 g x L(-1), P = 0.448) between relatives and controls. With multiple logistic regression we determined explanatory factors for high versus low vWF and fibrinogen. Age (P < 0.01), urinary albumin excretion rate (P < 0.05), ischaemic heart disease (IHD) (P < 0.05) were found to be significant explanatory factors for vWF above the median (1.10 IU x mL(-1)). Interaction between insulin resistance and sex was found. Odds ratio for high versus low insulin resistance was 18.39 (P < 0.001) for women and 1.92 (P = 0.32) for men. Body mass index (BMI) (P < 0.05), sex (P < 0.01), smoking status (P < 0.05) and IHD (P < 0.01) were significant explanatory factors for fibrinogen above the median (3.1 g x L(-1)). CONCLUSIONS: Levels of vWF, fibrinogen and fibronectin were not influenced by a parental history of type 2 diabetes. Insulin resistance was found to be a significant risk indicator for high vWF only in women. This may indicate that insulin resistance is a higher risk factor for women than for men, when the outcome is endothelial dysfunction possibly resulting in overt cardiovascular disease.     

Transport of gamma-glutamyl amino acids: role of glutathione and gamma-glutamyl transpeptidase.

This work relates to the hypothesis that one of the mechanisms that mediates amino acid translocation across cell membranes involves the action of membrane-bound gamma-glutamyl transpeptidase on intracellular glutathione and extracellular amino acids to form gamma-glutamyl amino acids. According to this idea, the latter are translocated into the cell where the gamma-glutamyl moiety is removed to yield free amino acids. Previous studies in this laboratory showed that intracellular glutathione is translocated out of many cells. We have now directly examined the transport of gamma-glutamyl amino acids into tissues in the mouse by use of the model substrate L-gamma-glutamyl-L-[14C]methionine sulfone. Of 11 tissues examined, only the kidney showed strong and preferential uptake of the substrate. A substantial amount of the administered L-gamma-glutamyl-L-[14C]methionine sulfone was found intact in the kidney; the total uptake of this compound was greater (by about 2-fold) than that of free L-methionine sulfone. Studies with a number of other gamma-glutamyl amino acids and gamma-glutamyl compounds indicate that the kidney has a relatively specific transport system for gamma-glutamyl amino acids. Small but significant amounts of gamma-glutamylmethionine sulfone were found in the liver and pancreas, suggesting that other tissues may also have this system. Transport of gamma-glutamylmethionine sulfone into the kidney was inhibited by inhibitors of glutathione synthesis and of gamma-glutamyl transpeptidase. The results suggest that both the transpeptidase and glutathione may be involved in transport of gamma-glutamyl amino acids.     

Incidence of cardiovascular disease in Type 1 (insulin-dependent) diabetic subjects with and without diabetic nephropathy in Finland

Summary This study evaluates the impact of diabetic nephropathy on the incidence of coronary heart disease, stroke and any cardiovascular disease in the Finnish population, which has a high risk of Type 1 (insulin-dependent) diabetes mellitus and cardiovascular disease. We performed a prospective analysis of the incidence of coronary heart disease, stroke and cardiovascular disease in all Type 1 subjects in the Finnish Type I diabetes mellitus register diagnosed before the age of 18 years between 1 January 1965 and 31 December 1979 nationwide. The effect of age at onset of diabetes, attained age at the end of follow-up, sex, diabetes duration and of the presence of diabetic nephropathy on the risk for cardiovascular disease was evaluated. Cases of nephropathy, coronary heart disease, stroke and all cardiovascular diseases were ascertained from the nationwide Finnish Hospital Discharge Register and National Death Register using computer linkage with the Type I diabetes mellitus register. Of the 5148 Type 1 diabetic patients followed up, 159 had a cardiovascular event of which 58 were coronary heart diseases, 57 stroke events and 44 other heart diseases. There were virtually no cases of cardiovascular disease before 12 years diabetes duration. The cumulative incidence of cardiovascular disease by the age of 40 years was 43 % in Type 1 diabetic patients with diabetic nephropathy, compared with 7 % in patients without diabetic nephropathy, similarly in men and women. The relative risk for Type 1 diabetic patients with diabetic nephropathy compared with patients without diabetic nephropathy was 10.3 for coronary heart disease, 10.9 for stroke and 10.0 for any cardiovascular disease, similarly in men and women. The presence of nephropathy in Type I diabetic subjects increases not only the risk of coronary heart disease, but also of stroke by tenfold. [Diabetologia (1998) 41: 784–790] Received: 14 August 1997 and in final revised form: 2 March 1998     

Porcine and human insulin absorption from subcutaneous tissues in normal and insulin-dependent diabetic subjects: a deconvolution-based approach

The mechanisms of sc insulin absorption are not understood, and models for interpreting in vivo data cannot be developed without gross simplification. To overcome this difficulty we developed a new approach which makes use of deconvolution analysis and does not require any model of the sc tissue. In five normal subjects and seven insulin-dependent diabetic (IDDM) patients endogenous insulin secretion was suppressed by means of a hypoglycemic glucose clamp procedure (approximately 2.8 mmol/L) sustained by a continuous insulin infusion (approximately 4 pmol/min.kg). A bolus injection of insulin (5.4 nmol) was administered iv, and plasma insulin concentrations were measured frequently for 2 h to assess iv insulin kinetics. Insulin then was injected sc in the abdominal region, and plasma insulin concentrations were measured for 8 h. Each subject was studied twice, with porcine and semisynthetic human insulin (Actrapid, Novo). The rate of insulin absorption was reconstructed by deconvolution from the plasma concentrations and iv insulin kinetic data. Linearity of the iv insulin kinetics, essential for deconvolution analysis, was confirmed by a dose-response study in the range of the measured concentrations (150-1800 pmol/L). In most instances, a two-compartment model was adequate to describe the iv response. The mean plasma insulin clearance rates were 15.5 +/- 1.9 (+/- SD) mL/min.kg (porcine) and 17.2 +/- 6.0 (human) in normal subjects and 20.7 +/- 8.8 (porcine) and 20.9 +/- 9.1 (human) in the IDDM patients. The rate of appearance of human insulin from sc tissue was faster than that of porcine insulin in both normal and IDDM subjects, but no significant differences were found in bioavailability, which was 55 +/- 12% (+/- SD; porcine) and 61 +/- 34% (human) in the normal subjects, and 84 +/- 28% (porcine) and 86 +/- 23% (human) in the IDDM patients. The rate of absorption and bioavailability were higher in the IDDM patients than in the normal subjects, a difference possibly related to increased sc blood flow in the IDDM patients. No differences were found with regard to glucose requirement values, normalized to plasma insulin concentrations, in agreement with the finding that the bioavailability of the two insulin species was similar.