The Regulation of Post-prandial Cellular Cholesterol Metabolism in Type 2 Diabetic and Non-diabetic Subjects

The purpose of the study was to determine the effect of diabetes on the regulation of postprandial cholesterol metabolism. Four groups of patients (n = 8 for each group) were examined: Type 2 diabetic patients with and without hypercholesterolemia and nondiabetic subjects with and without hypercholesterolaemia. Serum lipoproteins, lipoprotein composition, cellular cholesterol, and cellular cholesterol synthesis were measured before and 4 h after a high calorie meal. The BMI for the hypercholesterolaemic diabetic patients of 31.5 ± 0.95 (SEM) was significantly higher than that for the control group of 26.2 ± 1.0 (p < 0.01). Fasting triglyceride levels were significantly higher in the normocholesterolaemic and hypercholesterolaemic diabetic patients and in the hypercholesterolaemic non-diabetic subjects (1.45 ± 0.22, 2.27 ± 0.34, and 1.58 ± 0.18 mmol l^?1, respectively) compared with normocholesterolaemic non-diabetic subjects (0.75 ± 0.12 mmol l^?1: p < 0.01). The normocholesterolaemic and hypercholesterolaemic diabetic subjects had significantly lower fasting serum high density lipoprotein (HDL) (1.06 ± 0.08 and 1.04 ± 0.06 mmol l^?1) compared to the corresponding non-diabetic groups (1.29 ± 0.11 and 1.45 ± 0.17 mmol l^?1, p < 0.05). The esterified/free cholesterol ratio of very low density lipoprotein (including chylomicrons VLDL-C) decreased postprandially in all groups with an overall decrease of 1.33 to 0.83 (p < 0.01). Fasting cellular cholesterol in mononuclear leucocytes from normocholesterolaemic diabetic patients was similar to that for hypercholesterolaemic diabetic (36.8 ± 1.2 vs 40.6 ± 5.5 mg g^?1 protein) and non-diabetic subjects (36.7 ± 6.8 mg g^?1 protein) and significantly greater than cholesterol in cells from control subjects (29.7 ± 1.5 mg g^?1 protein, p < 0.05). In cells from control subjects only, there was a significant postprandial increase in cholesterol to 39.4 ± 5.2 mg g^?1 protein (p < 0.05) and a corresponding postprandial reduction in cholesterol synthesis from 149 ± 34 to 102 ± 33 nmol g^?1 cell protein (p < 0.05). These results demonstrate a lack of correlation between serum and cellular cholesterol in diabetic patients and an inability to suppress cellular cholesterol synthesis postprandially in these patients. The differences may, in part, explain the increased deposition of cholesterol in atheromatous plaques in normocholesterolaemic diabetic patients.     

Atrial natriuretic peptide in Type 2 diabetes mellitus: response to a physiological mixed meal and relationship to renal function

Relatively few data exist on atrial natriuretic peptide (ANP) characteristics in Type 2 diabetes mellitus (DM). Therefore, plasma immunoreactive ANP concentrations were measured before and for 4 h following the ingestion of a physiological mixed meal in 8 newly diagnosed, normotensive, normoalbuminuric, patients with Type 2 DM and 6 normotensive, non-diabetic controls. In patients with Type 2 DM, basal plasma ANP concentrations were 4.0 ± 2.0 and not significantly changed following ingestion of the meal, with peak levels of 4.9 ± 2.8 pmol l⁻¹. Non-diabetic controls had higher basal plasma ANP concentrations, 8.7 ± 3.4 pmol l⁻¹ (p < 0.05), significantly increasing to a peak of 11.9 ± 6.3 pmol l⁻¹ at 30 min post meal. Extracellular fluid volume (ECV) was not different between diabetic patients and controls (15877 ± 2679 vs 13668 ± 1792 ml³). Glomerular filtration rate (GFR) (isotopic clearance corrected for body surface area) was elevated in diabetic patients (mean ± SD) 130 ± 39 vs 98 ± 10 ml min⁻¹, p < 0.05). For the DM subjects, basal ANP levels were negatively correlated with GFR (r_s − 0.74, p < 0.05) and effective renal plasma flow (ERPF) (r_s − 0.8, p < 0.05). We conclude that patients with Type 2 DM demonstrate reduced basal plasma ANP concentrations which are inversely correlated to renal function. In contrast to non-diabetic controls, ANP in Type 2 DM does not rise in response to feeding. © 1998 John Wiley & Sons, Ltd.     

Impaired contraction and relaxation in aorta from streptozotocin-diabetic rats: Role of polyol pathway

Summary The effects of 3 months streptozotocin-induced diabetes mellitus on contraction and relaxation of aorta were examined in vitro. A further diabetic group was treated with a novel sulphonylnitromethane-based aldose reductase inhibitor for 3 months following diabetes induction. Diabetes resulted in reduced maximal tension production, particularly for responses to phenylephrine (p < 0.001) and serotonin (p < 0.001). However, with aldose reductase inhibitor treatment, responses were in the non-diabetic range. The ratio of maximum contractions to noradrenaline and phenylephrine were 28 % elevated by diabetes (p < 0.01), which may suggest increased ₂-adrenoreceptor-mediated responses. Endothelium-independent relaxation to glyceryl trinitrate was unaffected by diabetes or treatment. By contrast, there were 38 % deficits in endothelium-dependent relaxation to acetylcholine (p < 0.001) and Ca²⁺ ionophore A23187 (p < 0.001) with diabetes which were prevented by aldose reductase inhibitor treatment (p < 0.001). A 121 % shift in the concentration giving a 50% maximum effect for acetylcholine towards lower sensitivity with diabetes (p < 0.001) was also largely corrected by treatment (p < 0.001). A non-diabetic group treated with aldose reductase inhibitor showed a 30 % decrease in the 50 % effective concentration for acetylcholine (p < 0.05). A 15 % deficit in maximum relaxation to the ATP-sensitive K⁺ channel opener cromakalim for the diabetic group (p < 0.001) was prevented by aldose reductase inhibitor treatment (p < 0.01). We conclude that there are polyol pathway related abnormalities for contraction, some aspects of endothelium-independent relaxation, but particularly for endothelium-dependent relaxation in aorta from chronic streptozotocin-diabetic rats. If found in the appropriate circulatory beds, these could potentially contribute to the putative vascular basis of some of the complications of diabetes. Their amelioration could account for many of the beneficial effects of aldose reductase inhibitors.     

Erythrocyte Na/K ATPase activity and diabetes: relationship with C-peptide level

Summary Erythrocyte Na/K ATPase activity is decreased in Type I diabetic patients; for Type II diabetic patients, literature data are controversial. Therefore, we have compared this enzymatic activity in 81 patients with Type I diabetes mellitus, 87 with Type II diabetes mellitus and 75 control subjects. Mean erythrocyte Na/K ATPase activity was lower in the Type I diabetic patients (285 ± 8 nmol Pi · mg protein^–1· h^–1) than in the control subjects (395 ± 9 nmol Pi · mg protein^–1· h^–1) whereas that of the Type II diabetic patients did not differ from that of control subjects. Sex, age, body mass index, and HbA_{1 c} levels did not influence erythrocyte Na/K ATPase activity. The 25 Type II diabetic patients treated with insulin, however, had lower Na/K ATPase activity than the 62 on oral treatment (264 ± 18 vs 364 ± 16 nmol Pi · mg protein^–1· h^–1, p < 0.001) but similar to that of Type I diabetic patients. Among the Type II diabetic patients, stepwise regression analysis showed that fasting C-peptide level was the only factor independently correlated with Na/K ATPase activity; it explained 23 % of its variance. In fact, in the insulin-treated patients, those with almost total endogenous insulin deficiency (C-peptide < 0.2 nmol · l^–1) had the lower Na/K ATPase activity (181 ± 21 vs 334 ± 17 nmol Pi · mg protein^–1· h^–1, p < 0.0001). The biological effects of treatment with C-peptide have recently led to the suggestion that this peptide could have a physiological role through the same signalling pathway as insulin, involving G-protein and calcium phosphatase and thus restoring Na/K ATPase activity. The relationship we describe between endogenous C-peptide and this activity is a strong argument for this physiological role. [Diabetologia (1998) 41: 1080–1084] Received: 6 November 1997 and in final revised form: 10 April 1998     

Cerebral Glucose Metabolism in Type 1 Diabetic Patients

To evaluate whether cerebral glucose metabolism is impaired in diabetes the [¹⁸F]–2–deoxy–2–fluoro-d-glucose method and positron emission tomography were used to determine the regional cerebral metabolic rate of glucose in 12 healthy subjects, 8 newly diagnosed Type 1 diabetic patients, 6 Type 1 diabetic subjects without peripheral neuropathy, and 7 Type 1 diabetic patients with symptomatic peripheral neuropathy, all of whom were men. In addition, multimodal evoked potentials were assessed. Cerebral glucose consumption was significantly reduced in the group with neuropathy as compared with the newly diagnosed diabetic patients and the healthy subjects (26.9 ± 1.0 vs 33.9 ± 1.9 and 32.5 ± 1.1 ±mol 100 g^-1 min^-1; p<0.05), while in the patients without neuropathy it was 30.2 ± 2.5 ±mol 100 g^-1 min^-1 (NS vs the remaining groups). There were no significant differences between the groups regarding brainstem auditory and visual evoked potentials. No relationship was noted between cerebral glucose metabolism and P300 latency of event-related potentials as an index of cognitive function, but there was an inverse correlation with age (r = -0.42; p < 0.05) and duration of diabetes (r = -0.67; p < 0.05). These results suggest that cerebral glucose metabolism is normal at the time of diagnosis of Type 1 diabetes, but may become altered with both increasing duration of diabetes and age in the absence of central conduction deficits or cognitive dysfunction. Diabetic neuropathy may constitute a possible additional correlate of reduced cerebral glucose consumption.     

Altered Regulation of Cholesterol Metabolism in Type I Diabetic Women During the Menstrual Cycle

This study examines the relationship of cellular cholesterol metabolism to oestrogen and progesterone during the menstrual cycle in diabetic and non-diabetic subjects. Nine premenopausal diabetic women were compared to nine non-diabetic women of the same age. Oestrogen, progesterone, lipoproteins, including lipoprotein (a) (Lp(a)) and cholesteryl ester transfer protein (CETP) were determined in serum. Cellular cholesterol content and cellular cholesterol synthesis were measured in mononuclear leucocytes. There was no significant change in serum lipoproteins including Lp(a) during the cycle in either group. CETP activity was significantly higher over the 4 weeks in the diabetic patients compared with non-diabetic subjects (mean 463 ± μmol I***^?1 h^?1 vs 405 ± 28 μmol ***I^?1 h^?1, p<0.01). Serum high density lipoprotein (HDL) cholesterol was significantly lower during the 4 weeks in the diabetic patients (1.7 ± 0.1 mmol I^?1 vs 1.8 ± 0.1 mmol^?1, p<0.05). Cellular cholesterol synthesis decreased steadily up to the third week in cells from the control subjects whereas there was no significant change in cells from diabetic patients whose cellular cholesterol synthesis was higher at week 3 compared with non-diabetic subjects (663 ± 54 nmol mg^?1 cell protein vs 432 ± 43 nmol mg^?1 cell protein, two-way interaction p<0.05). There was a significant negative correlation between cellular cholesterol synthesis and serum oestrogen in the non-diabetic subjects (p<0.05) but not in the diabetic patients. These results show that cellular cholesterol synthesis is not downregulated during the menstrual cycle in diabetic patients, a finding which may help to explain the increased incidence of atherosclerosis in the diabetic, pre-menopausal woman.     

Reduced Plasma Aldosterone Concentrations in Randomly Selected Patients with Insulin-dependent Diabetes Mellitus

Abnormalities of the renin-angiotensin system have been reported in patients with diabetes mellitus and with diabetic complications. In this study, plasma concentrations of prorenin, renin, and aldosterone were measured in a stratified random sample of 110 insulin-dependent (Type 1) diabetic patients attending our outpatient clinic. Fifty-four age- and sex-matched control subjects were also examined. Plasma prorenin concentration was higher in patients without complications than in control subjects when upright (geometric mean (95 % confidence intervals (CI): 75.9 (55.0–105.6) vs 45.1 (31.6–64.3) mU I^-1, p < 0.05). There was no difference in plasma prorenin concentration between patients without and with microalbuminuria and between patients without and with background retinopathy. Plasma renin concentration, both when supine and upright, was similar in control subjects, in patients without complications, and in patients with varying degrees of diabetic microangiopathy. Plasma aldosterone was suppressed in patients without complications in comparison to control subjects (74 (58–95) vs 167 (140–199) ng I^-1, p < 0.001) and was also suppressed in patients with microvascular disease. Plasma potassium was significantly higher in patients than in control subjects (mean ± standard deviation: 4.10±0.36 vs 3.89±0.26 mmol I^-1; p < 0.001) and plasma sodium was significantly lower (138 ± 4 vs 140 ± 2 mmol I^-1; p < 0.001). We conclude that plasma prorenin is not a useful early marker for diabetic microvascular disease. Despite apparently normal plasma renin concentrations, plasma aldosterone is suppressed in insulin-dependent diabetic patients.     

Increased Proximal Tubular Sodium Reabsorption in Hypertensive Patients with Type 2 Diabetes

Hyperinsulinaemia and sodium retention have been studied in 22 Type 2 diabetic patients (10 normotensive, 12 hypertensive) and 10 normal control subjects matched for age, sex, and body mass index. Exchangeable sodium was similar in the three groups. Plasma renin activity and plasma angiotensin II were lower in both groups of diabetic patients than in the normal control subjects (p<0.01). Plasma atrial natriuretic peptide was increased in the hypertensive patients (7.3 ± 1.1 vs normotensive 4.7 ± 1.1 pmol I^?1 and control 4.0 ± 0.2 pmol I^?1, p<0.01). Fractional lithium clearance, a measure of sodium clearance from the proximal tubule, was decreased (18.5 ± 1.4, p<0.01) and fractional excretion of sodium in the distal tubule was increased (6.66 ± 0.66, p<0.01) in untreated hypertensive diabetic patients compared with both normotensive diabetic patients (25.3 ± 1.6 and 3.96 ± 0.52 respectively) and normal control subjects (25.2 ± 2.9 and 3.31 ± 0.38, respectively). Fasting serum insulin was higher in hypertensive than in normotensive diabetic patients (18.5 ± 3.0 vs 10.7 ± 1.1 mU I^?1, p<0.01) and higher in both groups than in normal control subjects (5.6 ± 0.1 mU I^?1, both p<0.01). Creatinine clearance was higher in both groups of diabetic patients than in normal control subjects (p<0.05). Thus there appears to be increased proximal renal tubular sodium reabsorption in these hypertensive Type 2 diabetic patients, matched by a reduction in distal sodium reabsorption so that net sodium excretion was maintained. This was associated with fasting hyperinsulinaemia.     

Changes in Glucose Disposal and Cellular Insulin Binding in Obese Black Southern African Patients with Type 2 Diabetes Mellitus Before and After Sulphonylurea Therapy

Peripheral insulin action and cellular insulin binding were studied in 10 newly detected, obese, black, Southern African women with Type 2 diabetes mellitus before and after midterm oral sulphonylurea therapy and in five obese, non-diabetic controls. Glucose disposal (assessed by the euglycaemic insulin clamp technique) was significantly reduced in diabetic patients compared to control subjects (4.4 ± 0.5 vs 6.4 ± 0.5 mg kg^-1 min^-1, p < 0.05), and increased after 1 and 3 months of sulphonylurea therapy to 6.8 ± 0.6 mg kg^-1 min^-1 (p = 0.01) and 6.3 ± 0.7 mg kg^-1 min^-1 (p = 0.04), respectively. The major change in the binding kinetics of insulin to peripheral monocytes was an increase in the mean receptor concentration in the diabetic patients which was significant after 3 months of therapy (0.2 ± 0.08 to 0.6 ± 0.01 nM, p = 0.05). The basal plasma C-peptide concentration was significantly lower in the diabetic patients than in the controls and remained so following sulphonylurea therapy, despite significant reductions in fasting glucose and HbA_-1 concentrations. We conclude that newly diagnosed, obese, black Southern Africans with Type 2 diabetes showed diminished peripheral glucose disposal which increased following sulphonylurea therapy. This was accompanied by an increase in insulin receptor concentration but not with changes in basal insulin secretion.     

Relationships Between Diabetes Duration,Metabolic Control and β-cell Function in a Representative Population of Type 2 Diabetic Patients in Sweden

To clarify whether metabolic control and β-cell function deteriorate with increasing duration of diabetes, we investigated in a cross-sectional study Type 2 diabetic patients in an area-based population. Type 2 diabetic patients (n = 231: 112 males, 119 females) were identified by age at onset > 35 years, fasting levels of C-peptide > 0.04 nmol l^?1, and absence of islet cell antibodies. Body weight was slightly elevated (BMI 26.8 ± 0.3 kg m^?2), however 76/210 (36%), had normal weight (BMI < 25 kg m^?2). Fasting blood glucose rose significantly during the first 10 years of known diabetes from 8.2 ± 0.3 mmol l^?1 in patients with 0–5 years of duration to 9.9 ± 0.7 mmol l^?1 in those with 5–10 years of duration, p < 0.01 and HbA_1c from 6.4 ± 0.2 to 7.4 ± 0.4%, p < 0.05. Fasting C-peptide levels decreased after 10 years duration from 0.90 ± 0.06 nmol l^?1 during 5–10 to 0.69 ± 0.08 nmol l^?1 during 10–15 years of diabetes, p < 0.05. The proportion of insulin treated patients increased from 13% (12/94) with 0–5 years of duration to 33% (13/39) with 10–15 years and 60% (18/30) with more than 15 years of duration. In conclusion in Type 2 diabetic patients without signs of autoimmunity, metabolic control, and β-cell function deteriorate with increasing duration of diabetes, leading to common but not inevitable occurrence of ‘secondary failure’.     

Effect of insulin on blood rheology in non-diabetic subjects and in patients with type 2 diabetes mellitus

We evaluated the effect of insulin on platelet function, blood viscosity, and filterability in healthy subjects and in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Fifteen diabetic patients were free from cardiovascular complications (group A), while the other 15 patients had both clinical and measured evidence of coronary or peripheral vascular disease (group B); 15 non-diabetic subjects served as controls. On blood samples taken without stasis, maximal platelet aggregation to 1.25 μmol l⁻¹ ADP, blood and plasma viscosity, and blood filterability were measured in basal conditions, and after incubation of blood, plasma or platelet-rich plasma with insulin at two physiological concentrations (120 and 480 pmol l⁻¹). Compared with healthy subjects, the diabetic patients of group B had higher values of blood (p < 0.01) and plasma (p < 0.05) viscosity, and platelet aggregation response to ADP (p < 0.01), as well as lower values of blood filterability (p < 0.01). The diabetic patients of group A had values intermediate between normal subjects and the patients of group B. In non-diabetic subjects, insulin significantly decreased platelet aggregation and blood viscosity at low shear rates (22.5 s⁻¹) (p < 0.01 for both), and had no significant effects on other parameters. In the diabetic patients of group A, insulin decreased blood viscosity at high (225 s⁻¹) rates of shear (p < 0.01) and increased blood filterability (p < 0.01). The effects of insulin were not dose-related. In the diabetic patients of group B, none of the parameters evaluated was significantly influenced by insulin. Type 2 diabetic patients present many abnormalities of the rheologic properties of blood. The beneficial effects of insulin on platelet aggregation and blood viscosity are not evident in Type 2 diabetic patients, especially those with vascular complications and this may be relevant to the development of those complications. © 1997 John Wiley & Sons, Ltd.     

The Role of Plasma Non-esterified Fatty Acids During Exercise in Type 2 Diabetes Mellitus

Elevated fasting plasma non-esterified fatty acid (NEFA) levels have been reported in Type 2 diabetes. We examined whether such changes persist during low-grade exercise and influence carbohydrate metabolism. Eight Type 2 diabetic patients with moderate glycaemic control and eight healthy controls received the anti-lipolytic agent, acipimox, or placebo on separate occasions before exercising for 45 min at 35 % pre-determined V_o2max. Fasting plasma NEFA levels were similar (0.40 ± 0.06 (SEM) and 0.45 ± 0.05 mmol l^?1; healthy and Type 2 diabetic subjects) following placebo, and increased to comparable levels with exercise (0.73 ± 0.07 and 0.73 ± 0.10 mmol l^?1). Acipimox lowered basal NEFA levels (0.14 ± 0.03 and 0.28 ± 0.04 mmol I^?1; both p < 0.05 vs placebo), and prevented the rise with exercise. Blood glucose (p < 0.001) and serum insulin (p < 0.01) levels were higher in the Type 2 diabetic patients (vs controls) for both treatments. Whole body lipid oxidation increased from baseline to a comparable degree with exercise following placebo (3.2 ± 0.3 and 2.8 ± 0.3 mg kg^?1 min^?1; healthy and Type 2 diabetic subjects, both p < 0.02). Although less marked, the same was also observed following acipimox (2.0 ± 0.4 and 2.1 ± 0.5 mg kg^?1 min^?1; both p < 0.05). Carbohydrate oxidation increased with exercise in both subject groups, but with no significant difference between the treatments. Thus, the metabolic response to low-grade exercise was normal in Type 2 diabetic patients with moderate glycaemic control, but occurred against a background of hyperinsulinaemia. Plasma NEFA do not exert a major regulatory effect on carbohydrate metabolism during low-grade exercise.     

Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial

To test the efficacy of surgical treatment of non-infected neuropathic foot ulcers compared to conventional non-surgical management, a group of diabetic outpatients attending our diabetic foot clinic were studied. All patients who came to the clinic for the first time from January to December 1995 inclusive with an uncomplicated neuropathic ulcer were randomized into two groups. Group A received conservative treatment, consisting of relief of weight-bearing, regular dressings; group B underwent surgical excision, eventual debridement or removal of bone segments underlying the lesion and surgical closure. Healing rate, healing time, prevalence of infection, relapse during a 6-month period following intervention and subjective discomfort were assessed. Twenty-four ulcers in 21 patients were treated in group A (17 Type 2 DM/3 Type 1 DM, age 63.24 ± 13.46 yr, duration of diabetes 18.2 ± 8.41 yr, HbA_1c 9.5 ± 3.8%) and 22 ulcers in 21 patients in group B (19 Type 2 DM/2 Type 1 DM, age 65.53 ± 9.87 yr, duration of diabetes 16.84 ± 10.61 yr; HbA_1c 8.9 ± 2.2%). Healing rate was lower (79.2% = 19/24 ulcers) in group A than in group B (95.5% = 21/22 ulcers; p < 0.05), and healing time was longer (128.9 ± 86.60 days vs 46.73 ± 38.94 days; p < 0.001). Infective complications occurred significantly more often in group A patients (3/24, 12.5% vs 1/22, 4.5%; p < 0.05), as did relapses of ulcerations (8 vs 3; p < 0.01). There were only two minor perioperative complications in group B patients. Patients reported a higher degree of satisfaction in group B (p < 0.01) as well as lower discomfort (p < 0.05) and restrictions (p < 0.05). Thus surgical treatment of neuropathic foot ulcers in diabetic patients proved to be an effective approach compared to conventional treatment in terms of healing time, complications, and relapses, and can be safely performed in an outpatient setting. © 1998 John Wiley & Sons, Ltd.     

Decreased Plasminogen Activator Inhibitor-1 Activity in Newly Diagnosed Type 2 Diabetic Patients Following Dietary Modification

Increased plasminogen activator inhibitor-1 (PAI-1) activity has been reported in Type 2 (non-insulin-dependent) diabetes and is a recognized risk factor for coronary artery disease. Fourteen newly diagnosed Type 2 diabetic patients were studied before and 3 months after standard clinical dietary modification. To assess the effect of improved metabolic control on PAI-1 activity, nine Type 2 diabetic patients established on diet therapy and with previous stable glycaemic control served as controls. In the newly diagnosed patients diet therapy resulted in a significant decrease in HbA_1c levels (8.3 ± 0.5 vs 5.2 ± 0.3 % (mean ± SEM); p < 0.001), and this was accompanied by a fall in fibrinogen (4.3 ± 0.3 vs 3.0 ± 0.2 g.1^?1; p < 0.01) concentration, and PAI-1 (18.7 ± 2.3 vs 12.2 ± 0.9 arbitrary units ml^?1; p < 0.02) and factor VIII (147 ± 17 vs 115 ± 13 %; p < 0.01) activities. PAI-1 activity was correlated with triglyceride levels at the first assessment in the newly diagnosed patients (r = 0.66; p < 0.01), and this was the only independent association by multiple regression analysis when all patients (n = 23) were considered (r = 0.62; p < 0.002). However, there was no association between the changes in PAI-1 activity and the changes in HbA_1c BMI, and serum triglyceride levels following treatment in the newly diagnosed patients. Serum triglyceride concentrations, HBA_1c, PAI-1 activity, and the coagulation factors remained unchanged in the control group over the same treatment period. In conclusion, the introduction of conventional diet therapy in newly diagnosed Type 2 diabetic patients was accompanied by a significant improvement in circulating PAI-1 activity, but this could not be related to changes in the common indices of metabolic control.     

Relationships between dyspeptic symptoms and gastrointestinal motility in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary Reports on motor abnormalities in Type 1 (insulin-dependent) diabetes mellitus are inconsistent. In 20 Type 1 diabetic patients and in 11 control subjects antroduodenojejunal manometry was performed under euglycaemic conditions in order to examine the prevalence of gastric and small intestinal motor abnormalities in relation to dyspeptic symptoms and the degree of cardiac autonomic neuropathy. In diabetic patients compared to control subjects phase III (regular, high-amplitude contractile activity at maximal frequency) involved the gastric antrum less often (12 vs 35%,p<0.05), the duration of phase I (motor quiescence) was shorter (6±1 vs 21±4 min,p<0.002) and in phase II (irregular motor activity) the frequency of duodenal and jejunal contractions was higher. After a meal the duration of the fed state was shorter in diabetic patients with symptoms during the study than in diabetic patients without symptoms and than in control subjects (57±27 vs 157±11 and 140±13 min,p<0.02). Postprandial antral hypomotility was seen in diabetic patients with symptoms only in the first 30 min after the meal. One hour after the meal the frequency of duodenal and jejunal contractions was again higher in diabetic patients. In diabetic patients compared to control subjects more burst activity (clusters of non-propagated high-amplitude contractile activity at maximal frequency) was seen (7.9±1.6 vs 0.8±0.5% of the total time of study,p<0.002). No correlation was found between manometric parameters and the degree of cardiac autonomic neuropathy. In conclusion, in Type 1 diabetic patients with cardiac autonomic neuropathy a variety of gastric and small intestinal motor abnormalities can be found. The most important of these is hyperactivity in the interdigestive state. These abnormalities correlate with symptoms, but are not related to the severity of cardiac autonomic neuropathy.     

Normalization of fasting glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in Type 2 diabetic patients

Intravenous GLP-1 [7-36 amide] can normalize fasting hyperglycaemia in Type 2 diabetic patients. Whether GLP-1 [7-37] has similar effects and how quickly plasma glucose concentrations revert to hyperglycaemia after stopping GLP-1 is not known. Therefore, 8 patients with Type 2 diabetes (5 female, 3 male; 65 ± 6 years; BMI 34.3 ± 7.9 kg m⁻²; HbA_1c 9.6 ± 1.2 %; treatment with diet alone (n = 2), sulphonylurea (n = 5), metformin (n = 1)) were examined twice in randomized order. GLP-1 [7-36 amide] or [7-37] (1 pmol kg⁻¹min⁻¹) were infused intravenously over 4 h in fasted subjects. Plasma glucose (glucose-oxidase), insulin and C-peptide (ELISA) was measured during infusion and for 4 h thereafter. Indirect calorimetry was performed. Fasting hyperglycaemia was 11.7 ± 0.9 [7-36 amide] and 11.3 ± 0.9 mmol l⁻¹ [7-37]. GLP-1 infusions stimulated insulin secretion approximately 3-fold (insulin peak 168 ± 32 and 156 ± 47 pmol l⁻¹, p < 0.0001 vs basal; C-peptide peak 2.32 ± 0.28 and 2.34 ± 0.43 nmol l⁻¹, p < 0.0001, respectively, with GLP-1 [7-36 amide] and [7-37]). Four hours of GLP-1 infusion reduced plasma glucose (4.8 ± 0.4 and 4.6 ± 0.3 mmol l⁻¹, p < 0.0001 vs basal values), and it remained in the non-diabetic fasting range after a further 4 h (5.1 ± 0.4 and 5.3 ± 0.4 mmol l⁻¹, for GLP [7-36 amide] and [7-37], respectively). There were no significant differences between GLP-1 [7-36 amide] and [7-37] (glucose, p = 0.99; insulin, p = 0.99; C-peptide, p = 0.99). Neither glucose oxidation nor lipid oxidation (or any other parameters determined by indirect calorimetry) changed during or after the administration of exogenous GLP-1. In conclusion, GLP-1 [7-36 amide] and [7-37] normalize fasting hyperglycaemia in Type 2 diabetic patients. Diabetes therapy (diet, sulphonyl ureas or metformin) does not appear to influence this effect. In fasting and resting patients, the effect persists during administration of GLP-1 and for at least 4 h thereafter, without rebound. Significant changes in circulating substrate concentrations (e.g. glucose) are not accompanied by changes in intracellular substrate metabolism. © 1998 John Wiley & Sons, Ltd.     

Improved Blood Glucose Control by Insulin Therapy in Type 2 Diabetic Patients Has No Effect on Lipoprotein(a) Levels

The effects of improved blood glucose control by insulin therapy on lipoprotein(a) and other lipoproteins were studied in 54 patients with Type 2 diabetes (mean ± SD: age 67 ± 9 years, body mass index 26.1 ± 4.4 kg m^?2, median duration of diabetes 10 (range 1–37) years, 23 males, 31 females), who were poorly controlled despite diet and maximal doses of oral hypoglycaemic agents. After 6 months of insulin treatment, mean fasting blood glucose concentrations had decreased from 14.1 ± 2.2 mmol l^?1 to 8.4 ± 1.8 mmol l^?1 (p < 0.001), and HbA^1c had fallen from 11.1 ± 1.4 % to 8.2 ± 1.1 % (p < 0.001). Significant decreases of total and LDL cholesterol, triglycerides, apolipoprotein B, and free fatty acids were observed, while HDL-cholesterol and apoA1 increased by 10 %. Baseline serum Lp(a) levels were elevated compared to non-diabetic subjects of similar age (median 283, range 8–3050 mg I^?1, vs 101, range 8–1747 mg I^?1, p < 0.05), but did not change with insulin, and there was no correlation with the degree of metabolic improvement and changes in Lp(a) levels. It is concluded that improved blood glucose control by insulin therapy does not alter elevated Lp(a) levels in Type 2 diabetic patients, but has favourable effects on the other lipoproteins.     

Neutrophil Bactericidal Function in Diabetes Mellitus: Evidence for Association with Blood Glucose Control

Neutrophil bactericidal activity was assessed in patients with type 1 (n=45) and Type 2 diabetes mellitus (n=68) and non-diabetic control subjects (n=40) by measurement of whole blood chemiluminescence. Though chemiluminescence values tended to be highest in the non-diabetic subjects these differences were not statistically significant (mean ± SD) (2.73 ± 1.65 mV (controls), 2.33 ± 1.41 mV (Type 1 diabetes) and 2.38 ± 1.12 mV (Type 2 diabetes), F=1.12, p=0.33). Significant negative correlations were evident, however, in patients with both Type 1 and Type 2 diabetes between chemiluminescence and glycated haemoglobin (r_s=-0.35, p=0.005 (Type 1), r_s=-0.45, p=0.002 (Type 2), fructosamine (r_s=-0.36, p=0.003 (Type 1), r_s=-0.42, p=0.004 (Type 2)), and random blood glucose (r_s=-0.25, p=0.04 (Type 1), r_s=-0.48, p=0.001 (Type 2)). Changes in whole blood chemiluminescence in a further group of 10 patients with Type 2 diabetes mellitus commenced on insulin therapy were followed for 21 days. Serum fructosamine concentrations fell significantly over this time (524 ± 58 μmol l^?1 to 405 ± 47 μmol l^?1, p<0.001), however, although chemiluminescence values tended to rise these changes were not statistically significant (1.01 ± 0.38 mV to 1.60 ± 0.91 mV, S=4.24, df=5, p=0.52). These results suggest that impaired neutrophil bactericidal function is associated with poor blood glucose control. While it is likely that neutrophil bactericidal function will improve as blood glucose control improves, further studies are required both to confirm this and to demonstrate a reduction in the incidence of clinical bacterial infection.     

Relationship Between Blood Pressure and Urinary Albumin Excretion Rate in Young Danish Type 1 Diabetic Patients: Comparison to Non-diabetic Children

In 1989 a nation-wide investigation of blood pressure and urinary albumin excretion rate (AER) was carried out in 506 boys and 441 girls with Type 1 diabetes (approximately 80 % of total) treated at 22 paediatric departments. In addition a reference population from 1979 consisting of 663 healthy non-diabetic children (334 boys, 329 girls) served as a control group with respect to blood pressure and body mass index. Microalbuminuria was defined as AER of 20–150 μg min^-1 in at least two out of three timed overnight urine collections and was diagnosed in 30 adolescents (16 boys, 14 girls). Five patients (3 boys, 2 girls) had overt proteinuria (AER: > 150μg min^-1). Age-related percentile charts based on one blood pressure reading were provided for normoalbuminuric diabetic patients and the healthy control group. The study revealed an increase in arterial blood pressure during the period of the pubertal growth spurt for the diabetic and non-diabetic group. The changes were most pronounced for systolic blood pressure. No statistically significant difference was observed in systolic and diastolic blood pressure between normoalbuminuric diabetic children and healthy control children. However, diabetic females aged 15–18 years had significantly higher diastolic blood pressure (75 ± 1 mmHg, n = 139, mean ± SE) than healthy control females (72± 1 mmHg, n = 155, p ± 0.01), and significantly (p ± 0.001) higher body mass index (diabetic females: 22.3± 0.2 kg m^-2 vs healthy females: 20.9± 0.2 kg m^-2, mean± SE). Boys aged from 15 to 18 years with Type 1 diabetes had significantly higher systolic blood pressure (123± 1 mmHg, n = 164) than girls (117± 1 mmHg, n = 139, p± 0.0001), while girls aged from 15 to 18 years had significantly higher diastolic blood pressure (75± 1 mmHg, n = 139) than boys (72± 1 mmHg, n = 72, p ± 0.01). Among the 30 adolescents with persistent microalbuminuria, 18 (10 boys, 8 girls) had diastolic blood pressure above the upper quartile for normoalbuminuric patients, while 2 out of 5 with macroalbuminuria had diastolic blood pressure above this limit. By multiple logistic regression the only risk determinants for elevated urinary albumin levels were age and diastolic blood pressure. These findings suggest that elevated arterial blood pressure is related to the increased prevalance of microalbuminuria observed in adolescents with Type 1 diabetes.     

Fibrinolytic measurements in Type 2 diabetic patients with acute cerebral infarction

The aim of this study was to investigate disturbances in fibrinolytic components in Type 2 diabetes patients with acute ischaemic stroke. Levels of plasminogen activator inhibitor-1 (PAI-1) activity and tissue PA (t-PA) antigen were measured in Type 2 diabetes subjects with (n=40) and without (n=80) acute stroke compared to non-diabetic subjects with (n=80) and without (n=80) acute ischaemic stroke. Diabetes was defined by WHO criteria and absence of diabetes by blood glucose <7.8 mmol⁻¹ and HbA_IC <6 % (reference range for assay 4.5–6.5 %). Levels of t-PA antigen were lower in healthy controls (9.2 ng ml⁻¹) than in either stroke group (non-diabetic stroke patient: 12.6 ng ml⁻¹; diabetic patient with stroke: 13.5 ng ml⁻¹ (each at p<0.05)) and intermediate in diabetic patients without stroke (11.1 ng ml⁻¹, ns). In a regression model levels of t-PA were related to stroke, BMI and age but not to diabetes or sex. Diabetic subjects without stroke had higher PAI-1 activity levels than either non-diabetic group (17.7 Uml⁻¹ vs 12.1 U ml⁻¹ and 9.2 U ml⁻¹ (each at p<0.05)). Levels were intermediate in diabetic subjects with stroke (12.8 U ml⁻¹, ns). In a regression model levels of PAI-1 were related to Type 2 diabetes, female sex, and body mass index but not stroke or age. These data suggest that further suppression of fibrinolysis does not occur with ischaemic stroke in Type 2 diabetes. The findings contrast with the importance of impaired fibrinolysis in coronary artery disease previously reported in both Type 2 diabetic patients and non-diabetic subjects. © 1998 John Wiley & Sons, Ltd.