Body composition in young female adults with Type 1 diabetes mellitus. A prospective case-control study.

AIMS: Overweight is common during late puberty in female patients with Type 1 diabetes. The aim of this study was to examine the change in body composition from late puberty to early adulthood in such female patients in comparison with age-matched control subjects. METHODS: Eighteen females with Type 1 diabetes and 19 healthy female control subjects were recruited for a case-control study at the age of 16-19 years (baseline). Six years later, 16 of the diabetic females and 17 of the control subjects were re-examined (follow-up). Body composition was assessed by dual energy X-ray absorptiometry. RESULTS: Body mass index (BMI) and fat mass index (total fat mass/height2) were significantly higher at baseline in the diabetic patients than in the control subjects (26.4 +/- 2.6 vs. 23.9 +/- 3.7 kg/m2, P < 0.05, and 10.0 +/- 2.4 vs. 8.0 +/- 2.8 kg/m2, P = 0.04, respectively). At follow-up, these parameters still tended to be higher in the diabetic group (27.8 +/- 4.9 vs. 24.6 +/- 5.7 kg/m2, P = 0.09, and 11.8 +/- 5.6 vs. 8.7 +/- 4.9 kg/m2, P = 0.05, respectively). BMI at baseline was strongly correlated to BMI at follow-up in both diabetic patients (r = 0.60; P < 0.05) and control subjects (r = 0.83; P < 0.01). CONCLUSIONS: Increased fat mass in pubertal girls with Type 1 diabetes seems to persist in young adulthood. This study emphasizes the need for new strategies to prevent the development of overweight during puberty in diabetic girls.     

l-arginine infusion decreases plasma total homocysteine concentrations through increased nitric oxide production and decreased oxidative status in Type II diabetic patients

AIMS/HYPOTHESIS: Hyperhomocysteinaemia increases cardiovascular risk in Type II (non-insulin-dependent) diabetes mellitus by augmenting oxidative stress and reducing nitric oxide availability. In vitro, nitric oxide decreases homocysteine by its conversion to the vasodilative and antioxidant compound S-nitrosohomocysteine. We investigated whether or not changes in nitric oxide availability decrease homocysteine concentrations in vivo. METHODS: The study group consisted of 20 normotensive, normolipidaemic, non-atherosclerotic Type II diabetic patients in good metabolic control (16 men, 51.2+/-1.4 years) and 15 healthy subjects (12 men, 48.1+/-1.5 years). Circulating concentrations of homocysteine, nitrite+nitrate and sulphydryl groups, a marker of oxidative stress, were assessed at baseline and then 5', 10', 30' and 60' after the intravenous infusion of either L-arginine (3 g in 10 ml saline), the nitric oxide precursor, or vehicle according to a double-blind cross-over randomized protocol. RESULTS: At baseline diabetic patients showed lower plasma sulphydryl group concentrations (491.8+/-16.9 vs 551.3+/-21.0 micro mol/l, p<0.04) and nitrite+nitrate (21.4+/-0.8 vs 29.5+/-0.9 micro mol/l, p<0.0001) and higher total homocysteine concentrations (11.1+/-0.5 vs 8.3+/-0.6 micro mol/l, p<0.002) than the control subjects. After L-arginine infusion, blood pressure levels and total homocysteine concentrations ( p< or =0.05) decreased (peak at 5' and 30', respectively) whereas nitric oxide and sulphydryl group concentrations ( p< or =0.003) increased (peak at 10' and 30', respectively) in the patients and control subjects. CONCLUSION/INTERPRETATION: Acute L-arginine infusion in both Type II diabetic patients and healthy subjects decreases plasma total homocysteine concentrations, counteract oxidative stress and increases the availability of nitric oxide.     

Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients

AIMS/HYPOTHESIS: Glucagon-like-peptide-1 (GLP-1) is strongly insulinotropic in patients with Type II (non-insulin-dependent) diabetes mellitus, whereas glucose-dependent insulinotropic polypeptide (GIP) is less effective. Our investigation evaluated "early" (protocol 1) - and "late phase" (protocol 2) insulin and C-peptide responses to GLP-1 and GIP stimulation in patients with Type II diabetes. METHODS: Protocol 1: eight Type II diabetic patients and eight matched healthy subjects received i.v. bolus injections of GLP-1(2.5 nmol) or GIP(7.5 nmol) concomitant with an increase of plasma glucose to 15 mmol/l. Protocol 2: eight Type II diabetic patients underwent a hyperglycaemic clamp (15 mmol/l) with infusion (per kg body weight/min) of either: 1 pmol GLP-1 (7-36) amide (n=8), 4 pmol GIP (n=8), 16 pmol GIP (n=4) or no incretin hormone (n=5). For comparison, six matched healthy subjects were examined. RESULTS: Protocol 1: Type II diabetic patients were characterised by a decreased "early phase" response to both stimuli, but their relative response to GIP versus GLP-1 stimulation was exactly the same as in healthy subjects [insulin (C-peptide): patients 59+/-9% (74+/-6%) and healthy subjects 62+/-5% (71+/-9%)]. Protocol 2, "Early phase" (0-20 min) insulin response to glucose was delayed and reduced in the patients, but enhanced slightly and similarly by GIP and GLP-1. GLP-1 augmented the "late phase" (20-120 min) insulin secretion to levels similar to those observed in healthy subjects. In contrast, the "late phase" responses to both doses of GIP were not different from those obtained with glucose alone. Accordingly, glucose infusion rates required to maintain the hyperglycaemic clamp in the "late phase" period (20-120 min) were similar with glucose alone and glucose plus GIP, whereas a doubling of the infusion rate was required during GLP-1 stimulation. CONCLUSION/INTERPRETATION: Lack of GIP amplification of the late phase insulin response to glucose, which contrasts markedly to the normalising effect of GLP-1, could be a key defect in insulin secretion in Type II diabetic patients.     

Abnormal ventilatory responses to hypoxia in Type 2 diabetes.

AIMS: The incidence of Type 2 diabetes is increasing, along with its associated micro- and macrovascular disease manifestations. Previous studies indicate that patients with Type 2 diabetes exhibit abnormal cardiopulmonary reflex responses to various stimuli, although the impact of hypoxia, a common physiological stimulus, on ventilatory responses has not previously been studied in humans with Type 2 diabetes. METHODS: Minute ventilation (V(E)) breathing pattern responses (total breath time, T(TOT); expiratory time, T(E); inspiratory time, T(I); inspiratory duty cycle, T(I)/T(TOT)) were measured during 5 min each of normoxia and isocapnic hypoxia (arterial O2 saturation approximately 85%) in eight subjects with Type 2 diabetes and seven age- and body mass index-matched healthy subjects. RESULTS: During normoxia, V(E) was similar in control and diabetic subjects (6.4+/-1.2, 6.4+/-1.1 l/min, respectively). In response to hypoxia, V(E) significantly increased in both groups (to 17.0+/-5.0 and 9.5+/-2.0 l/min, respectively, P<0.05), but the magnitude of increase in V(E) was significantly less in diabetic than in control subjects (P<0.05). In addition, the breathing pattern response to hypoxia differed between groups in terms of T(I)/T(TOT) and T(TOT) (P<0.05), with control subjects significantly decreasing T(TOT) and T(E) (P<0.05) while diabetic subjects tended to increase both. CONCLUSIONS: Relative to matched control subjects, Type 2 diabetic subjects exhibit blunted V(E) responses to acute isocapnic hypoxia, suggesting that this group of diabetic subjects possesses a chemoreflex ill-equipped to respond homeostatically to hypoxic challenge.     

Physical activity and energy intake in adolescent girls with Type 1 diabetes.

AIMS: Girls with Type 1 diabetes often gain excessive weight during puberty. The aims of this study were to compare objectively assessed physical activity and energy intake in girls with Type 1 diabetes with those in healthy age-matched controls. METHODS: This prospective cohort study comprised 26 girls with Type 1 diabetes and 49 control girls. The mean age of the diabetic girls was 15.7 +/- 2.1 years and that of the control girls 15.8 +/- 2.1 years. In the diabetic group, mean haemoglobin A1c was 7.6 +/- 1.4% and daily insulin dosage was 1.1 +/- 0.3 U/kg. Physical activity was measured during 7 consecutive days with a uniaxial accelerometer, and energy intake was assessed concurrently with a 7-day food diary. RESULTS: There was a tendency towards lower total amount of physical activity in the diabetes group but the difference between the study groups did not reach statistical significance (Diabetes: 464 +/- 123 counts/min/day; Controls: 523 +/- 138 counts/min/day; P = 0.06). No difference was found between the groups regarding total energy intake (Diabetes: 8.5 +/- 1.8 MJ/day; Controls: 8.4 +/- 2.6 MJ/day). The carbohydrate intake was lower and the protein and fibre intakes were higher in girls with diabetes. No association was observed between physical activity, energy intake and HbA1c. CONCLUSIONS: In this prospective cohort study, we found a tendency towards lower physical activity but no differences in energy intake between girls with Type 1 diabetes and age-matched controls. Larger studies are needed to further explore the importance of the total amount of physical activity for excessive weight gain in adolescent girls with Type 1 diabetes.     

A mathematical model for pattern of change in beta-cell reserve and factors affecting residual reserve within the first 2 years of type 1 diabetes

The aim of this study was to investigate the effects of age, duration of diabetes, sex and ICA (Islet cell cytoplasmic antibody) on beta-cell reserves and to develop a model within the first 2 years of Type 1 diabetes. Beta-cell reserve is evaluated as fasting (FCp) and 1 mg i.v. glucagon stimulated C-peptide (SCp) levels in 58 Type 1 diabetics and in 12 normoglycemic subjects. Patients were divided into 3 groups according to duration of diabetes: Group I (2.5+/-0.3 weeks), Group II (13.4+/-1.2 months) and Group III (24.2+/-1.8 months). FCp/SCp level in nmol/l (mean+/-SE) were as follows. Group I: 0.21+/-0.02/0.38+/-0.04, Group II: 0.15+/-0.01/0.27+/-0.02, Group III: 0.07+/-0.01/0.11+/-0.02, Control group: 0.42+/-0.09/1.29+/-0.13. The scatter plots of C-peptide levels vs time in all the diabetic patients fitted in to a 4th-order polynomial regression (R: 0.96-0.98). Age was strongly correlated with FCp (rs: 0.46, p<0.05) and ICA positivity affected Cp-levels negatively (p>0.05). In conclusion, as the duration of diabetes increases, response time to glucagon prolongs and amplitude of it shortens. Duration of diabetes of less than 2 weeks, feminity, puberty and ICA positivity affect beta-cell reserve negatively, conversely, masculinity, post-puberty, older age and ICA negativity affect the reserve positively. The dynamics of C-peptide response to glucagon follow a mathematical model and Type 1 diabetes causes a decrease not only in the amplitude of the response but also in the duration of the response.     

Diastolic ventricular function in type 1 diabetic patients: a study using Doppler echocardiography.

The transmitral flow velocity pattern of 28 Type 1 diabetic patients and 39 age-matched healthy control subjects was studied for determination of left ventricular diastolic function. No patient had systemic hypertension, congestive heart failure, or ischaemic heart disease by clinical or electrocardiographic criteria. Echocardiographic measures of systolic ventricular function were within normal range in all subjects. The ratio of early to late transmitral peak flow velocity (ve/va) was significantly decreased in the diabetic patients (1.3 +/- 0.1 (+/- SE) vs 1.6 +/- 0.1, p less than 0.05), while other Doppler derived variables did not show any significant difference. No correlation of ve/va with duration of diabetes was found (r = -0.27), but it correlated with age in both groups (both r = -0.40, p less than 0.05). Furthermore, a significant correlation was found between ve/va and heart rate (r = -0.55 for diabetic patients, p less than 0.01; r = -0.58 for control subjects, p less than 0.01). After matching for heart rate (24 diabetic patients and 24 control subjects) no significant decrease of ve/va was observed in the diabetic group.     

Urinary concentration of transforming growth factor-beta-inducible gene-h3(beta ig-h3) in patients with Type 2 diabetes mellitus.

AIMS: The expression of TGF beta-inducible gene h3(beta ig-h3) has been used to assess the biological activity of TGF beta in the kidney. In this study, we investigated whether the urinary concentration of beta ig-h3 is associated with diabetic nephropathy in patients with Type 2 diabetes mellitus. We also evaluated the relationship between the urinary concentration of beta ig-3 and proteinuria and microalbuminuria (AER) in a normal healthy population and in Type 2 diabetes patients. METHODS: Four hundred and seventy-nine Type 2 diabetic patients without non-diabetic kidney diseases and 528 healthy control subjects were enrolled. The study subjects were divided into five groups: a non-diabetic healthy control group with normal ACR (n = 443), a non-diabetic healthy control group with microalbuminuria (n = 85), a normoalbuminuric diabetic group (n = 198), a microalbuminuric diabetic group (n = 155) and an overt proteinuria group (n = 126). Urinary levels of beta ig-h3 were measured by enzyme-linked immunosorbent assay. RESULTS: (i) Urinary excretion of beta ig-h3 was significantly higher in the diabetic groups than in the controls, even in the normoalbuminuric stage (25.02 +/- 8.84 vs. 18.67 +/- 6.56, P = 0.03). In diabetic patients, urinary beta ig-h3 levels increased significantly as diabetic nephropathy advanced (25.02 +/- 8.84 vs. 34.06 +/- 24.55 vs. 169.63 +/- 57.33, P < 0.001). (ii) Proteinuria was found to be significantly correlated with urinary beta ig-h3 (healthy control; r = 0.137, P = 0.019, diabetic patients; r = 0.604, P < 0.001). ACR was also found to be significantly related with urinary beta ig-h3 in diabetic patients (r = 0.383, P = 0.006). (iii) In diabetic patients, urinary beta ig-h3 was significantly related with systolic and diastolic blood pressure (systolic blood pressure: r = 0.436, P = 0.024; diastolic blood pressure, r = 0.365, P = 0.042), total cholesterol and HbA(1c) (cholesterol: r = 0.169, P = 0.03, HbA(1c); r = 0.387, P = 0.044). Logistic regression analyses showed that urinary beta ig-h3 was associated with a significant increase in the risk of microalbuminuria and proteinuria in diabetic patients. CONCLUSIONS: Longitudinal monitoring of urinary beta ig-h3 may improve the likelihood of detecting diabetic nephropathy at an earlier stage and beta ig-h3 could be a sensitive marker of diabetic kidney disease progression.     

Body composition in adolescent girls with type 1 diabetes.

AIMS: To compare body composition in adolescent girls with Type 1 diabetes with healthy controls. RESEARCH DESIGN AND METHODS: In this population-based study, body composition was examined, using dual-energy X-ray absorptiometry (DXA) and skinfold measurements, in 18 adolescent post-menarcheal females, 16-19 years of age, with Type 1 diabetes since childhood in comparison to age-matched healthy control subjects. RESULTS: Body mass index was 2.7 kg/m2 higher in diabetic patients (26.3 +/- 2.6 vs. 23.6 +/- 3.8; P < 0.05). The overweight consisted almost entirely of increased fat mass, as evaluated by both skinfold measurements and DXA. Bone mineral density did not differ between the two groups. In diabetic females, the distribution of the fat mass was increased in the upper part of the body. The fat distribution, expressed as the abdominal-to-leg ratio, was significantly correlated to glycated haemoglobin (HbA1c) (r = 0.69; P < 0.005), daily dosage of insulin expressed per kilogram body weight (r = 0.78; P < 0.0005) and total cholesterol (r = 0.60; P < 0.001). CONCLUSIONS: The observed overweight in adolescent females with Type 1 diabetes is explained by an increased fat mass. Abdominal fat accumulation was associated with poor glycaemic control, increased need for insulin and elevated blood lipids.     

Autoimmunity to CD38 and GAD in Type I and Type II diabetes: CD38 and HLA genotypes and clinical phenotypes

AIMS/HYPOTHESIS: Autoantibodies against CD 38 have been found in some patients with Type II (non-insulin-dependent) diabetes mellitus and have been shown to stimulate insulin secretion by cultured human islets. We tested whether this new form of autoimmunity, (i). overlaps with anti-GAD autoimmunity, (ii). identifies an insulin-deficient phenotype, (iii). is under the influence of genetic factors. METHODS: We screened 496 adults by immuno-blot analysis in the Botnia Study (298 with Type II and 98 with Type I (insulin-dependent) diabetes mellitus, 100 non-diabetic control subjects). RESULTS: CD 38-autoantibodies were found in 8.4% of Type II diabetic patients ( p<0.003 vs 0% of control subjects), particularly in anti-GAD positive (14% vs 6% of anti-GAD negative, p=0.0004). CD 38 ab were also found in 4% of Type I diabetic patients; in the whole study group, 59% of anti- CD 38 positive had DQB1*02 compared with 38% of anti-CD 38 negative ( p=0.04).On the OGTT, beta-cell function (as the ratio of insulin-to-glucose areas) was impaired ( p=0.02) only in association with anti-GAD positivity (3.2+/-3.1 U/mol, mean +/- SD) but not in anti- CD 38 positive patients (5.6+/-2.9) as compared with patients free of autoimmunity (4.5+/-4.6, p=NS). In 44 Type II diabetic patients (22 negative and 22 positive for anti- CD 38), no mutations were detected in any of the 8 exons, 5' end of intron 1 or the 5' and 3' untranslated regions of the CD 38 gene. The previously described missense mutation (Arg140Trp) in exon 3 was not found in this cohort. There was no association between the PvUII polymorphism and clinical phenotype. CONCLUSION: Anti-CD 38 autoimmunity identifies a clinical phenotype similar to non-autoimmune Type II diabetes, with relative preserved beta-cell function and weak genetic influence.     

The epidemiology of foot lesions in diabetic patients aged 15-50 years

All diabetic patients aged 15–50 years (n = 395) in the county of Umeå (population 118 500) were invited to have a standardized foot examination and 380 (96%) attended. Three-quarters (78%) had Type 1 diabetes, 20% Type 2 diabetes, and 1% secondary diabetes. They were compared with 100 healthy control subjects. Both Type 1 and Type 2 diabetic patients had slight or moderate loss of forefoot arches more often than control subjects (57% and 60% vs 31%, p < 0.001). Callosities were not significantly more common in diabetic patients than in control subjects. Lesions observed on the lower legs and feet of the Type 1 and Type 2 diabetic patients were Melin's shin spots (33% and 39%), dry feet (33% and 29%), yellow toenails (27% and 31%), purpura (9% and 5%), ulcers (3% and 0%), necrobiosis (3% and 0%), and diabetic osteopathy (2% and 0%). Intermittent claudication was present in 1% and 3%, respectively. Three Type 1 diabetic patients had undergone below-knee amputation. Two of the control subjects had Melin's shin spots. With the exception of necrobiosis which was only found in women with Type 1 diabetes and Melin's shin spots which were twice as common in diabetic men as women, whether Type 1 or Type 2, lesions were equally distributed between the sexes. Sensory thresholds for vibration, perception, and pain were significantly elevated in Type 1 diabetic patients with dry feet, fallen forefoot arches or hammer toes compared with those without. They were not increased in Type 2 diabetic patients or control subjects with these lesions. In conclusion, foot deformity and lesions of skin and nails are common in the feet of diabetic patients in this age group while macroangiopathy appears to be uncommon.     

Risk factors for non-ischaemic foot ulceration in diabetic nephropathy.

It is recognized that diabetic patients with nephropathy frequently have macrovascular disease leaving them at risk of ischaemic foot lesions. In order to assess non-vascular risk factors for foot ulceration 64 patients were stratified into four groups: microalbuminuria, albuminuria with creatinine clearance greater than 40 ml min-1, chronic renal failure (clearance less than 40 ml min-1), and a non-nephropathic diabetic control group. Vibration perception threshold was measured by biothesiometry, peroneal nerve conduction velocity by conventional methods, and dynamic foot pressure by pedobarography. Vibration perception threshold was elevated in all three groups when compared with age-matched normal and diabetic control groups. Mean vibration perception threshold was 20.8 +/- 8.6 (+/- SD) in the microalbuminuria group (p less than 0.001 compared with age-matched normal control group), 28.1 +/- 5.6 (p less than 0.001) in the albuminuria group, 38.9 +/- 9.4 (p less than 0.001) in the renal failure group, 14.8 +/- 5.2 in the diabetic control group and 12.3 +/- 2.9 in the normal control group. Peroneal motor conduction velocity was reduced in all three groups when compared with normal control subjects, microalbuminuria 38.6 +/- 4.2 m s-1 (p less than 0.001), albuminuria 38.0 +/- 6.1 m s-1 (p less than 0.01), renal failure 35.5 +/- 1.2 m s-1 (p less than 0.001), diabetic control 40.6 +/- 1.8 m s-1, and normal 43.1 +/- 2.3 m s-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

The production of immunoreactive alpha- and gamma-interferon by circulating mononuclear cells in type 1 diabetes

Using a specific immunoradiometric assay method the in vitro alpha interferon response to polyinosinic:polycytidylic acid (poly-I:C) and the gamma interferon response to concanavalin A were measured in peripheral blood mononuclear cells from 11 healthy matched pairs of Type 1 diabetic patients and normal subjects. The alpha-interferon response to poly-I:C was significantly higher in the diabetic group (median 3.7 (range less than 1-25.7) u ml-1) than in the normal group (1.1 (less than 1-15.4) u ml-1, p less than 0.01). The mean gamma-interferon response to concanavalin A was 64.3 +/- 46.9 (+/- SD) u ml-1 in the diabetic patients and 49.4 +/- 18.5 u ml-1 in the normal group (NS). The higher alpha-interferon response to poly-I:C in the diabetic patients was not related to blood glucose concentration, HbA1, age of onset of diabetes, duration of diabetes, or islet cell antibody positivity, and may therefore indicate intrinsic hyper-responsiveness of circulating mononuclear cells in Type 1 diabetes.     

The relationship between passive range of motion and range of motion during gait and plantar pressure measurements.

AIMS: To investigate the relationship between limited joint mobility (LJM; measured both passively and during gait) and plantar pressure measurements. METHODS: A cross-sectional study involving 28 diabetic patients with peripheral neuropathy but no plantar ulceration (DN), 25 diabetic patients with ulceration (DU), 25 diabetic control patients with no ulceration or peripheral neuropathy (DC), and 25 non-diabetic reference subjects (NDR). Movements of the ankle joint complex (AJC) and 1st metatarsophalangeal (MTP) joint were recorded, together with plantar pressures. RESULTS: The passive range of motion at the AJC was significantly reduced in all the diabetes groups, but the gait range of motion was comparable with non-diabetic subjects. At the AJC, no correlation was found between the passive and gait range of motion (ROM) and these were not correlated with plantar pressure variables. At the 1st MTP, a correlation was found between the passive and gait dorsiflexion ROM and a significant correlation existed between gait dorsiflexion ROM at the 1st MTP joint and peak forefoot pressures in the DU group. CONCLUSIONS: Despite a significant reduction in the passive ROM at the AJC in the diabetic groups, the gait ROM was indistinguishable from reference subjects and was not correlated with plantar pressure variables. At the 1st MTP joint, a correlation was found between the passive and gait ROM and furthermore the gait ROM was correlated with peak forefoot pressures, suggesting ROM measures at the 1st MTP joint may be preferable to ROM measures at the AJC.     

Hypovolemia contributes to the pathogenesis of orthostatic hypotension in patients with diabetes mellitus.

PURPOSE: To investigate whether body sodium content and blood volume contribute to the pathogenesis of orthostatic hypotension in patients with diabetes mellitus. SUBJECTS AND METHODS: Exchangeable sodium, plasma and blood volumes, and catecholamine, renin, and aldosterone levels were assessed in 10 patients with Type II diabetes mellitus who had orthostatic hypotension and control groups of 40 diabetic patients without orthostatic hypotension and 40 normal subjects of similar age and sex. In subgroups, clinical tests of autonomic function and cardiovascular reactivity to norepinephrine and angiotensin II infusions were performed. RESULTS: In diabetic patients with orthostatic hypotension, mean (+/- SD) supine blood pressure was 165/98 +/- 27/12 mm Hg (P <0.05 compared with other groups) and mean upright blood pressure was 90/60 +/- 38/18 mm Hg. Compared with controls, diabetic patients with orthostatic hypotension had a 10% lower blood volume. They also had less exchangeable sodium than patients with diabetes who did not have orthostatic hypotension (P <0.01). Compared with both groups of controls, diabetic patients with orthostatic hypotension had decreased 24-hour urinary norepinephrine excretion and a reduced diastolic blood pressure response to handgrip (P <0.05). Moreover, they displayed reduced products of exchangeable sodium or blood volume and sympathetic function indexes. Cardiovascular pressor reactivity to norepinephrine was enhanced (P <0.01) and beat-to-beat variation decreased (P <0.01) in both groups of diabetic patients. Microvascular complications were more prevalent in the diabetic patients with orthostatic hypotension (90% vs 35%). CONCLUSIONS: Patients who have Type II diabetes mellitus and orthostatic hypotension are hypovolemic and have sympathoadrenal insufficiency; both factors contribute to the pathogenesis of orthostatic hypotension.     

Tissue factor pathway inhibitor (TFPI) release after heparin stimulation is increased in Type 1 diabetic patients with albuminuria.

AIMS: To study heparin-stimulated TFPI release in relation to complications in Type 1 diabetic patients. SUBJECTS AND METHODS: Nineteen uncomplicated Type 1 diabetic patients (group I) were compared with 18 patients with retinopathy (group II), and nine patients with retinopathy and albuminuria (group III). Blood samples were taken before (basal) and till 30 min after 5000 IU of heparin i.v. (post-heparin). TFPI activity was measured chromogenically. Von Willebrand factor, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and thrombomodulin were also measured. RESULTS: Basal TFPI activity was higher in group III (121 +/- 10%) compared with group II (111 +/- 8%) or group I (110 +/- 13%) (P < 0.05), and strongly correlated with albuminuria (r = 0.66, P < 0.05). At all time points after heparin administration, TFPI activity in group III was significantly higher than in group I. TFPI activity was also higher in group III than in group II 5-30 min post-heparin. The increase in post-heparin TFPI activity, measured as the incremental area under the curve, was higher in group III compared with group I (65 +/- 7 vs. 59 +/- 4; P < 0.05). Of the other parameters, only thrombomodulin was higher in group III (44 +/- 24 vs. 26 +/- 7 (group II) and 28 +/- 9 ng/ml (group I); P < 0.01). CONCLUSIONS: We conclude that basal and post-heparin TFPI activity is increased in albuminuric patients. The increase in heparin-stimulated TFPI release in patients with albuminuria is higher than in patients with retinopathy or without complications. This could be the result of altered endothelial glycosaminoglycan characteristics.     

Insulin binding of human and porcine monocomponent insulin to monocytes in Type 1 (insulin-dependent) diabetic patients and control subjects

In the present study insulin binding properties of human semi-synthetic and porcine insulin were compared in Type 1 (insulin-dependent) diabetic patients treated from the onset of their disease either with human semi-synthetic insulin (n = 12) or porcine insulin (n = 12) and control subjects (n = 12). In all three groups, insulin binding to circulating monocytes revealed no difference between human semi-synthetic and porcine insulin (specific insulin binding at tracer concentration: 5.7 +/- 0.5% versus 5.4 +/- 0.5% in control subjects, 5.5 +/- 0.4% versus 5.4 +/- 0.4% in Type 1 diabetic patients on porcine insulin, 5.3 +/- 0.4% versus 5.6 +/- 0.4% in Type 1 diabetic patients on human insulin). Treatment with human or porcine insulin did not have any significant influence on receptor binding properties of the two diabetic groups investigated. Absolute receptor number and affinity of both diabetic groups were within the range of healthy control subjects irrespective of treatment with human or porcine insulin.     

Biochemical markers of type III and I collagen: association with retinopathy and neuropathy in type 1 diabetic subjects.

AIMS: Connective tissue alterations may contribute to the development of diabetic long-term complications in eyes, kidneys and peripheral nerves. Collagen deposition may be increased in micro- and macrovascular disease in diabetic subjects. We tested whether biochemical markers of type III and I collagen metabolism are associated with retinopathy and neuropathy in Type 1 diabetes. METHODS: A total of 28 patients, mean age 43.4 +/- 9.5 (sd) and duration of diabetes 25.2 +/- 9.7 years, were studied. Stereoscopic colour fundus photographs were taken for assessment of retinopathy which was classified as no, background or proliferative. Concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in serum and urinary excretion of cross-linked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) into urine were measured. RESULTS: Average serum PIIINP was higher in subjects with proliferative (3.2 +/- 1.1 microg/l) than without proliferative retinopathy (2.5 +/- 0.6 microg/l) (P = 0.03). Average serum PICP was higher in subjects without retinopathy (181.7 +/- 19.5 microg/l) than in subjects with background retinopathy (132.1 +/- 42.7 microg/l) (P = 0.02). Concentrations of other collagen markers were not different in subjects with or without retinopathy. No association between collagen markers and neuropathy was found. CONCLUSIONS: The increased synthesis of type III collagen, reflecting deposition of matrix and basement membrane connective tissue, may be involved in the pathogenesis of proliferative retinopathy in Type 1 diabetic subjects. On the other hand, we observed decreased synthesis of Type I collagen, which can result in weakened vascular integrity in subjects with retinopathy.     

The effects of smoking and its cessation on 8-epi-PGF2alpha and transforming growth factor-beta 1 in Type 1 diabetes mellitus.

BACKGROUND: Oxidative stress and transforming growth factor-beta 1 (TGF-beta1) are associated with diabetic complications, and smoking is a risk factor. AIMS: This study aimed (i) to compare urinary 8-epi-PGF2alpha and plasma and urinary TGF-beta1 levels obtained in heavy smokers with Type 1 diabetes with those observed in age-matched non-smoker patients with Type 1 diabetes and controls, and (ii) to investigate the effects of smoking cessation (SC) on the above-mentioned parameters in patients with Type 1 diabetes. METHODS AND RESULTS: Compared with control subjects (n = 12), non-smoker diabetic patients (n = 12) presented higher values of urinary 8-epi-PGF2alpha (74.2 +/- 29.6 vs. 29.6 +/- 11.1 pg/mg urinary creatinine, P = 0.01), plasma TGF-beta1 (7.7 +/- 4.7 vs. 3.6 +/- 1.7 ng/ml, P = 0.001) and urinary TGF-beta1 (15.3 +/- 6.3 vs. 8.1 +/- 4.4 ng/mg urinary creatinine, P = 0.02). Compared with non-smoker diabetic patients, smoker diabetic patients (n = 16) showed higher levels of urinary 8-epi-PGF2alpha (107.8 +/- 40.2 vs. 74.2 +/- 29.6 pg/mg urinary creatinine, P = 0.0001), plasma TGF-beta1 (12.6 +/- 4.9 vs. 7.7 +/- 4.7 ng/ml, P = 0.001) and urinary TGF-beta1 (27.5 +/- 16.0 vs. 15.3 +/- 6.3 ng/mg urinary creatinine, P = 0.01). Smoker patients were included in a smoking cessation programme. In the 10 patients that gave up smoking there was a reduction of urinary 8-epi-PGF2alpha (basal: 110.47 +/- 47.0 vs. week 12: 73.2 +/- 25.6; P < 0.001), plasma TGF-beta1 (basal: 11.2 +/- 5.9 vs. week 12: 4.89 +/- 2.25; P < 0.01) and urinary TGF-beta1 (basal: 18.12 +/- 9.27 vs. week 12: 10.32 +/- 2.0; P < 0.01) levels. CONCLUSIONS: In patients with Type 1 diabetes, smoking increased oxidative stress, evaluated by lipid peroxidation, and TGF-beta1 production. Smoking cessation decreased these parameters, providing additional support to encourage diabetic patients to give up smoking.