The Relationships between Cardiovascular Risk Factors and Socio-economic Status in People with Diabetes

The hypothesis that the prevalence of cardiovascular risk factors in people with diabetes is inversely related to socio-economic status was tested. Demographic and biochemical data were collected on 1246 patients, aged 20–69 years, attending a hospital diabetes clinic. This is estimated to represent between 71 % and 78 % of all people of this age with a diagnosis of diabetes in the health authority. In total, 296 people were classified as Type 1 (insulin-dependent) diabetic patients (age of onset <31, now on insulin). Using data from the 1991 census a deprivation score was ascribed to each individual according to their area (enumeration district) of residence. The total study population was ranked by deprivation score and divided into quintiles. The relationships between means and quintiles of deprivation were assessed by ANOVA for linear trend, and between proportions and quintiles of deprivation by the chi-squared test for trend. In Type 1 diabetes increasing quintiles of deprivation were significantly related to mean serum cholesterol (p < 0.01) and proportion smoking (p < 0.01), and in Type 2 (non-insulin-dependent) diabetes to mean body mass index (p < 0.001), proportion smoking (p < 0.001), and proportion with proteinuria (p < 0.05). The need for health measures to prevent cardiovascular disease in people with diabetes is greatest in deprived areas.     

Hospital Admissions and Social Deprivation of Patients with Diabetes Mellitus

This study examined the relationship between hospital admissions for patients with diabetes mellitus and residence in an area of social deprivation. Admissions of patients with diabetes mellitus were identified during a 5-year period between 1987 and 1992 using the district patient information service. All persons admitted were assigned to an electoral ward on the basis of their postcode. Age standardized admission rates were compared to the Townsend Deprivation Score for each electoral ward. A positive correlation was found between age standardized admission rate and Townsend Score (r = 0.76, p < 0.001). We believe this has significance for planning health care resources.     

Hospital Utilization as a Function of Social Deprivation: Diabetes vs Non-Diabetes

We tested the hypothesis that a relationship between ill health and deprivation exists for patients with diabetes, distinct from that experienced by the non-diabetic population. Age standardized admission and appointment rates and proportion of total activity for patients with and without diabetes were determined by electoral ward and correlated with the Townsend index of social deprivation for the health district of South Glamorgan (population 408000). Both diabetic (r = 0.78, p < 0.001) and non-diabetic (r = 0.74, p < 0.001) in-patient admissions were positively correlated with social deprivation. This relationship also existed for attended out-patient appointments (r = 0.67, p < 0.001 and r = 0.45, p < 0.01, respectively). The proportion of diabetic to non-diabetic admissions by ward also showed a positive correlation for in-patients (r = 0.47, p < 0.001). This remained true for IDDM (r = 0.23, not significant) and NIDDM (r = 0.62, p < 0.001) diabetes, for admissions for coronary heart disease (r = 0.50, p < 0.001) and cerebrovascular disease (r = 0.29, p < 0.05), elective admissions (r = 0.30, p > 0.05), and emergency admissions (0.46, p < 0.001). Our results suggest that secondary care utilization is positively correlated with social deprivation and that this relationship is stronger in the diabetic population. This may be due to different prevalence rates or increased complications requiring hospital treatment in different social circumstances. Further research is required to examine these factors more closely. © 1997 John Wiley & Sons, Ltd.     

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.     

Familial Risk of Type I diabetes in European Children

Summary The characteristics of familial Type I (insulin-dependent) diabetes mellitus – that is Type I diabetes in a first degree relative were investigated for children diagnosed before the age of 15 years using data from an international network of population-based registries (the Eurodiab Ace network) and from a case-control study (Eurodiab Ace Substudy 2) conducted by eight of the network's centres. Ecological analysis across the 18 centres showed a positive association between the population incidence rate of Type I diabetes and the prevalence of Type I diabetes in fathers of affected children (Spearman's rank correlation coefficient r _s = 0.70, p < 0.001). A similar association was observed with the prevalence in sibling (r _s = 0.71, p < 0.001), but the association with prevalence in mothers was weaker and not significant. Pooling results from all centres showed that a greater proportion of fathers (3.4 %) of affected children had Type I diabetes than mothers (1.8 %) giving a risk ratio of 1.8 (95 % CI 1.4 to 2.5). Affected girls were more likely to have a father with Type I diabetes than affected boys (odds ratio 1.56, 95 % CI 1.07 to 2.27), but there was no evidence of a similar finding for mothers or siblings. Children with disease onset in the 0–4 year age-range were more likely to have an affected father than were children who were older at onset, and similar although weaker associations were seen in mothers and siblings. This suggests that familial Type I diabetes patients have a younger age at onset than non-familial patients. In conclusion, a positive association between the prevalence of familial Type I diabetes and the population Type I diabetes incidence rate was shown and the characteristics of familial Type I diabetes (younger age at onset and preferential transmission of disease from tather to child and particularly from father to daughter) were described. [Diabetologia (1998) 41: 1151–1156] Received: 16 February 1998 and in revised form: 4 May 1998     

The relation of proinsulin and insulin to insulin sensitivity and acute insulin response in subjects with newly diagnosed Type II diabetes: the Insulin Resistance Atherosclerosis Study

Abstract Aims/hypothesis. Proinsulin concentrations are increased relative to insulin concentrations in subjects with Type II (non-insulin-dependent) diabetes mellitus. This could be secondary to hyperglycaemia or insulin resistance or due to a defect in insulin secretion. Methods. We investigated the association between fasting insulin, intact proinsulin and the intact proinsulin: insulin ratio with insulin sensitivity, estimated by a frequently sampled intravenous glucose tolerance test and the minimal model and with acute insulin response (AIR) in 182 newly diagnosed Type II diabetic subjects aged 40 to 69 years. None of the subjects was receiving hypoglycaemic medication. Results. Insulin sensitivity correlated inversely with fasting insulin (r _s = –0.42) and intact proinsulin (r _s = –0.32) (p < 0.001). The intact proinsulin:insulin ratio was not correlated with insulin sensitivity. AIR correlated positively with intact proinsulin (r _s = 0.23) and inversely with the intact proinsulin:insulin ratio (r _s = –0.29, p < 0.001). Fasting glucose correlated positively with intact proinsulin (r _s = 0.34) and the intact proinsulin:insulin ratio (r _s = 0.24, p < 0.001). The intact proinsulin:insulin ratio increased by decreasing AIR (quartiles of AIR from high to low: 7.8, 8.2, 9.7 and 12.1 %, p < 0.001). This association was independent of age, sex, ethnicity, body mass index, fasting glucose, and insulin sensitivity. Conclusion/interpretation. Insulin resistance (low insulin sensitivity) was not related to the intact proinsulin:insulin ratio in subjects with Type II diabetes. In contrast, both low AIR and high fasting glucose concentrations were associated with a disproportionate increase in proinsulin concentration. These results suggest that increased intact proinsulin:insulin ratio is a marker of a defect in insulin secretion in Type II diabetic subjects. [Diabetologia (1999) 42: 1060–1066] Received: 25 February 1999 and in revised form: 12 April 1999     

Socio-economic status, obesity and prevalence of Type 1 and Type 2 diabetes mellitus.

AIMS: The influence of socio-economic status on the prevalence of Type 1 and Type 2 diabetes mellitus, and on obesity, was explored using routinely collected healthcare data for the population of Tayside, Scotland. METHODS: Among 366,849 Tayside residents, 792 and 5,474 patients with Type 1 and Type 2 diabetes, respectively, were identified from a diabetes register. The Carstairs Score was used as a proxy for socio-economic status. This is a material deprivation measure derived from the UK census, using postcode data for four key variables. Odds ratios for diabetes prevalence, adjusted for age, were determined for each of six deprivation categories (1 - least deprived, 6/7 - most deprived). The mean body mass index (BMI) in each group was also determined, and the effect of deprivation category explored by analysis of covariance, adjusting for age and sex. RESULTS: The prevalence of Type 2 diabetes, but not Type 1 diabetes, varied by deprivation. People in deprivation category 6 and 7 were 1.6-times (95% confidence interval 1.4-1.8) more likely to have Type 2 diabetes than those least deprived. There was no relationship between deprivation and BMI in Type 1 diabetes (P = 0.36), but there was an increase in BMI with increasing deprivation in Type 2 diabetes (P < 0.001; test of linearity P < 0.001). CONCLUSIONS: The study confirms the relationship between deprivation and the prevalence of Type 2 diabetes. There are more obese, diabetic patients in deprived areas. They require more targeted resources and more primary prevention.     

Relationship of Oxidative Stress and Fibrinolysis in Diabetes Mellitus

This study attempted to verify the existence of a relationship between oxidative stress documented by malondialdehyde (MDA) and superoxide dismutase (SOD) and fibrinolysis analysed by tissue plasminogen activator (tPA) and its inhibitor (PAI-1) in diabetes mellitus. Forty-seven patients with Type 1 (n = 27) and Type 2 (n = 20) diabetes were examined together with 20 non-diabetic controls. The following were analysed: plasma MDA concentration, SOD activity in erythrocytes, tPA activity and antigen, PAI-1 activity and antigen, fasting blood glucose, fructosamine, glycated haemoglobin (HbA_lc), and urine albumin. SOD activity was decreased in patients with diabetes. This contrasted with an increased plasma MDA concentration especially in Type 2 diabetes as compared with Type 1 or healthy persons (p < 0.001). tPA activity was increased in both groups of patients with diabetes as compared to healthy persons (p < 0.001), PAI-1 activity was higher in Type 2 diabetes with vascular changes than in the remaining subgroups (p < 0.001). Multivariate analysis revealed a significant positive relationship between plasma MDA concentrations and PAI-1 antigen (r = 0.53, p < 0.001) and a negative relationship between SOD and tPA activities (r = −0.53, p < 0.01). We conclude that oxidative stress may modulate fibrinolytic properties in diabetes mellitus.     

Increased Red Cell Sodium Lithium Countertransport Activity,Total Exchangeable Sodium,and Hormonal Control of Sodium Balance in Normoalbuminuric Type 1 Diabetes

The relationship between erythrocyte sodium lithium countertransport activity (SLC), total exchangeable sodium (NaE), and hormonal control of renal function was examined in 40 normotensive, normoalbuminuric, non-neuropathic Type 1 diabetic subjects, of whom 8 had elevated SLC (> 0.40 mmol Li h^?1l^?1 rbc). Eleven health controls with normal SLC, who were of comparable age, body mass, and blood pressure were also studied. By contrast with healthy controls, SLC in Type 1 diabetes was not associated with plasma renin activity (PRA), aldosterone, systolic blood pressure or lean body mass. SLC was also unrelated to atrial natriuretic peptide (ANP) (Type 1 diabetes only) and NaE. NaE was not correlated with any other variables. The relationships between PRA and aldosterone in healthy controls were retained in Type 1 diabetes (R² 0.37 supine, p = 0.00001, and 0.27 ambulant, p = 0.0005), as were respective direct and inverse relations between vasopressin and ANP and both PRA (r_s 0.54 to 0.57, r_s ?0.43 to ?0.53), and aldosterone (r_s 0.78 to 0.80, r_s ?0.71 to ?0.80). Fasting free serum insulin and vasopressin were both inversely related to ANP (r_s ?0.91 and ?0.71, respectively). In the absence of autonomic dysfunction, hypertension or early nephropathy in Type 1 diabetes, increased SLC or exchangeable sodium were unrelated to each other or with hormonal control of sodium balance, but the homeostatic factors controlling hormonal interaction appear to be maintained. The interaction between insulin and hormonal control of sodium and water balance may be modified by circulating free insulin concentrations.     

Insulin Therapy Increases Low Plasma Growth Hormone Binding Protein in Children with New-onset Type 1 Diabetes

This study was undertaken (1) to evaluate growth hormone binding protein (GHBP) levels in newly diagnosed patients with Type 1 diabetes before and after insulin therapy and (2) to determine the relationship of GHBP to glycaemic control, C-peptide level and blood pH. GHBP, expressed as a percentage of (¹²⁵I)GH bound, was determined in 33 patients with Type 1 diabetes (M/F = 19/14, 12.3 ± 0.4 years) before (day 0), after 5 days (day 5) and after 3 months (month 3) of insulin therapy. At day 0, GHBP was lower in Type 1 diabetes compared with 38 matched healthy control subjects (3.9 ± 0.4 vs 8.2 ± 0.4 %, p < 0.001). There was no significant improvement in GHBP at day 5 (4.4 ± 0.3 %). At month 3, GHBP increased to (6.0 ± 0.4 %, p < 0.001 vs day 0), but was still lower than controls, p < 0.001. At day 0 GHBP correlated with BMI (r = 0.50, p = 0.001), blood glucose (r = ?0.43 p = 0.006) and pH (r = 0.48, p = 0.004), but not HbA₁. GHBP at month 3 correlated with day 0 C-peptide (r = 0.41, p = 0.02). Thus, (1) circulating GHBP is low in newly diagnosed patients with Type 1 diabetes, and increases after 3 months of insulin therapy but does not normalize and (2) the severity of biochemical derangement and residual β-cell function at diagnosis may determine GHBP status and its recovery. We conclude that insulin is an important modulator of GH binding protein in newly diagnosed children with Type 1 diabetes.     

Frequency and Symptoms of Hypoglycaemia Experienced by Patients with Type 2 Diabetes Treated with Insulin

This study ascertained the prevalence of severe hypoglycaemia and loss of awareness of hypoglycaemia in patients with Type 2 diabetes treated with insulin. One hundred and four sequentially selected Type 2 diabetic patients were compared with 104 patients with Type 1 diabetes who were matched for duration of insulin therapy. The patients were interviewed using a standardized questionnaire. During treatment with insulin, 18 Type 2 patients had experienced fewer than two episodes of hypoglycaemia, while 86 had experienced two or more episodes; 80 (93%) reported normal awareness, six (7%) reported partial awareness, and none had absent awareness of hypoglycaemia. All 86 Type 1 diabetic patients matched to the 86 Type 2 patients had experienced multiple episodes of hypoglycaemia; 71 (83%) had normal awareness, 14 (16%) had partial awareness and one patient (1%) reported absent awareness of hypoglycaemia. The Type 1 patients who had altered awareness of hypoglycaemia had longer duration of diabetes and insulin therapy (normal awareness: 5 (1–17) years (median (range)) vs partial awareness: 9 (3–18) years, p < 0.01). Similarly, Type 2 patients with altered awareness had longer duration of diabetes (normal awareness: 11 (2–25) years vs partial awareness: 19 (8–24) years, p < 0.02) and had received insulin for longer (normal awareness: 3 (1–18) years vs partial awareness: 12 (6–17) years, p < 0.001). Severe hypoglycaemia in the preceding year had occurred with a similar prevalence in the Type 2 patients (9 (10%)) and Type 1 patients (14 (16%)), but was more frequent in those patients with partial awareness both in Type 1 patients (normal awareness: 3 (4%) vs partial awareness: 11 (73%), p < 0.001) and in Type 2 patients (normal awareness: 3 (4%) vs partial awareness: 6 (100%), p < 0.001). Although the symptoms of hypoglycaemia were idiosyncratic in individual Type 2 patients, the range and prevalence of specific symptoms were similar to those described by the patients with Type 1 diabetes.     

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.     

Oxidative stress could precede endothelial dysfunction and insulin resistance in Indian Mauritians with impaired glucose metabolism

Aims/hypothesis. To measure oxidative stress, endothelial dysfunction and insulin resistance in Indian Mauritians at different stages of development of Type II (non-insulin-dependent) diabetes mellitus. Methods. Plasma total 8-epi-PGF₂α, an indicator of oxidative stress, was determined in age-matched subjects with normal glucose metabolism (n = 39), impaired glucose tolerance (n = 14), newly diagnosed diabetes (n = 8) and established diabetes (n = 14). Plasma glucose and insulin were measured at baseline and 2 h following an oral glucose tolerance test. Endothelial function was assessed by non-invasive digital pulse wave photoplethysmography. Results. Plasma 8-epi-PGF₂α increased in subjects with impaired glucose tolerance (p < 0.05) compared with control subjects, and was even higher in newly diagnosed diabetic patients (p < 0.01) and established (p < 0.01) diabetic patients. A tendency towards reduced endothelial function in subjects with impaired glucose tolerance became significant in patients with newly diagnosed and established diabetes (p < 0.01), and was correlated with 8-epi-PGF₂α (r = 0.36, p < 0.01). Insulin resistance (homeostasis model assessment) did not change in subjects with impaired glucose tolerance compared with control subjects, but increased in newly diagnosed (p < 0.01) and established (p < 0.001) diabetic subjects. The 8-epi-PGF₂α was correlated with fasting glucose (r = 0.50, p < 0.001), triglycerides (r = 0.40, p < 0.001) and insulin resistance (r = 0.35, p < 0.001). Conclusion/interpretation. Oxidant stress is an early event in the evolution of Type II diabetes and could precede the development of endothelial dysfunction and insulin resistance. [Diabetologia (2001) 44: 706–712 Received: 1 November 2001 and in revised form: 14 February 2001     

Insulin Therapy in Type 2 Diabetic Subjects Suppresses Plasminogen Activator Inhibitor (PAI-1) Activity and Proinsulin-like Molecules Independently of Glycaemic Control

Eleven Type 2 diabetic subjects (10 male 1 female: age 56.2 ± 9.7 (SD) yr) were treated in random order either with insulin or with sulphonylureas for 8 weeks each, without attempting to alter glycaemic control between the two treatment periods. Insulin treatment was associated with suppression of endogenous insulin secretion (fasting C-peptide levels -35.0 ± 24.2%; p = 0.006), and of intact proinsulin (-43.1 ± 36.8%; p = 0.03) and 32,33 split proinsulin -20.1 ± 27.0%; p = 0.03). Activity of plasminogen activator inhibitor (PAI-1), a fast acting inhibitor of fibrinolysis, decreased significantly (-14.3% ± 27.5 %; p = 0.02) but no changes occurred in concentration of lipoproteins or apoproteins between therapies. Changes in concentrations of 32,33 split and intact proinsulin were closely and significantly related (r_s = 0.83; p < 0.001) to each other but not with changes in concentrations of C-peptide (intact proinsulin r_s = -0.41; p = 0.11) and 32,33 split proinsulin r_s = -0.27; (p = 0.21). Percentage changes in intact proinsulin concentrations were positively correlated with those in PAI-1 (r_s = 0.51; p = 0.05). There was, however a paradoxical negative relationship between changes in C-peptide concentrations and those of PAI-1 (r_s = -0.73; p = 0.006). These preliminary observations suggest that insulin treatment in Type 2 diabetic subjects without any changes in glycaemic control is associated with a reduced activity of PAI-1, but is without effect on any other cardiovascular risk factors. Concentrations of insulin precursor molecules may play a role in determining fibrinolytic activity.     

The Relationship Between Plasminogen Activator Inhibitor-1 and Insulin Resistance in Newly Diagnosed Type 2 Diabetes Mellitus

It is not clear whether elevated levels of the fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1) in Type 2 diabetes mellitus are the result of obesity or coexistent atherosclerosis. Therefore the relationship between PAI-1 and insulin resistance, determined by the homeostasis model assessment (HOMA) was investigated in a group of 26 insulin-resistant, normotensive newly diagnosed Type 2 diabetic patients with a low probability of atherosclerosis. Compared with a normal control group, closely matched for body mass index (BMI), fibrinolytic activity was depressed in the diabetic patients due to elevated levels of the inhibitor PAI-1, 17.6 (11.1–28) vs 8.4 (4.9–14.1) IU ml^?1, p < 0.001. PAI-1 was related to BMI, r = 0.59, p < 0.001 plasma insulin, r=0.66, p < 0.001; insulin resistance, r = 0.54, p< 0.005 and urinary albumin excretion, r=0.48, p < 0.01, but not HbA_1c or fasting glucose. PAI-1 was not related to blood pressure or plasma triglyceride levels. This study suggests that at the time of diagnosis of Type 2 diabetes mellitus, elevated PAI-1 levels are already linked to other risk factors for vascular disease including hyperinsulinaemia, insulin resistance, and urinary albumin excretion, and this is not the result of obesity or coexistent atherosclerosis.     

Plasma concentration of C-reactive protein is increased in Type I diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic inflammation

Summary Moderately increased plasma concentrations of C-reactive protein are associated with an increased risk of cardiovascular disease. C-reactive protein, its relation to a low degree of inflammatory activation and its association with activation of the endothelium have not been systematically investigated in Type I (insulin-dependent) diabetes mellitus. C-reactive protein concentrations were measured in 40 non-smoking patients with Type I diabetes without symptoms of macrovascular disease and in healthy control subjects, and in a second group of Type I diabetic patients (n = 60) with normo- (n = 20), micro- (n = 20) or macroalbuminuria (n = 20). Differences in glycosylation of α₁-acid glycoprotein were assayed by crossed affinity immunoelectrophoresis. Activation of the endothelium was measured with plasma concentrations of endothelial cell markers. The median plasma concentration of C-reactive protein was higher in Type I diabetic patients compared with healthy control subjects [1.20 (0.06–21.64) vs 0.51 (0.04–9.44) mg/l; p < 0.02]. The Type I diabetic subjects had a significantly increased relative amount of fucosylated α₁-acid glycoprotein (79 ± 12 % vs 69 ± 14 % in the healthy control subjects; p < 0.005), indicating a chronic hepatic inflammatory response. In the Type I diabetic group, log(C-reactive protein) correlated significantly with von Willebrand factor (r = 0.439, p < 0.005) and vascular cell adhesion molecule-1 (r = 0.384, p < 0.02), but not with sE-selectin (r = 0.008, p = 0.96). In the second group of Type I diabetic patients, increased urinary albumin excretion was associated with a significant increase of von Willebrand factor (p < 0.0005) and C-reactive protein (p = 0.003), which were strongly correlated (r = 0.53, p < 0.0005). Plasma concentrations of C-reactive protein were higher in Type I diabetic patients without (clinical) macroangiopathy than in control subjects, probably due to a chronic hepatic inflammatory response. The correlation of C-reactive protein with markers of endothelial dysfunction suggests a relation between activation of the endothelium and chronic inflammation. [Diabetologia (1999) 42: 351–357] Received: 4 September 1998 and in final revised form: 24 November 1998     

High amniotic fluid erythropoietin levels are associated with an increased frequency of fetal and neonatal morbidity in Type 1 diabetic pregnancies

Aims/hypothesis In this study we investigated whether chronic fetal hypoxia, as indicated by amniotic fluid erythropoietin levels, is associated with perinatal morbidity in Type 1 diabetic pregnancies.Methods A total of 331 women with Type 1 diabetes had at least one childbirth between 1995 and 2000. The amniotic fluid erythropoietin concentration was measured in 156 diabetic singleton pregnancies at a median time of 1 day before Caesarean section without labour contractions and in 19 healthy control subjects at Caesarean section.Results The median amniotic fluid erythropoietin level was 14.0 mU/ml (range 2.0–1975.0) in diabetic pregnancies and 6.3 mU/ml (range 1.7–13.7) in controls (p<0.0001). Of the 156 diabetic patients, 21 (13.5%) had amniotic fluid erythropoietin levels higher than 63.0 mU/ml. Amniotic fluid erythropoietin levels correlated negatively with umbilical artery pH (r=–0.49, p<0.0001) and pO₂ (r=–0.62, p<0.0001) at birth and neonatal lowest blood glucose level (r=–0.47, p<0.0001). Positive correlations were found between amniotic fluid erythropoietin levels and umbilical artery pCO₂ (r=0.49, p<0.0001) and last maternal HbA₁c (r=0.43, p<0.0001). Furthermore, a U-shaped correlation was demonstrated between amniotic fluid erythropoietin levels and birthweight z score (z score below –0.6 SD units: r=–0.63, p=0.0007; z score above +1.0 SD units: r=0.32, p=0.0014). Neonatal hypoglycaemia, hypertrophic cardiomyopathy and admission to the neonatal intensive care unit occurred significantly more often in cases with high amniotic fluid erythropoietin levels (>63.0 mU/ml) than in those with normal levels. Multivariate logistic regression analysis revealed that amniotic fluid erythropoietin was the only variable independently related to low umbilical artery pH (<7.21; p<0.0001) and neonatal hypoglycaemia (p=0.002). Low umbilical artery pO₂ (<15.0 mm Hg) was explained by amniotic fluid erythropoietin (p<0.0001) and birthweight z score (p=0.004).Conclusions/interpretation Antenatal high amniotic fluid erythropoietin levels can identify Type 1 diabetic pregnancies at increased risk of severe perinatal complications.     

Glomerular Charge Selectivity in Type 1 (Insulin-dependent) Diabetes Mellitus

Glomerular charge selectivity was assessed using the ratio of the clearance of pancreatic isoamylase to the clearance of the more anionic salivary isoamylase (C_PAm/C_SAm) in 12 normal subjects and 50 patients with Type 1 diabetes: 13 with normal albumin excretion and short duration of diabetes (<5 years), 15 with normal albumin excretion and long duration of diabetes (>15 years), 13 with microalbuminuria, and 9 with clinical nephropathy. None had serum creatinine >200 μmol I^?1. There were no significant differences in C_PAm/C_SAm between the normal subjects and the two groups of normoalbuminuric patients with Type 1 diabetes. C_PAm/C_SAm was significantly lower in diabetic patients with microalbuminuria or clinical nephropathy than in normoalbuminuric patients with Type 1 diabetes. When the 37 patients with normoalbuminuria and long-standing diabetes, microalbuminuria, and nephropathy were considered together, there was a significant negative correlation between C_PAm/C_SAm and albumin excretion rate (r_s = 0.71, p < 0.001). Progressive impairment of glomerular charge selectivity at the molecular size of amylase (molecular mass 56 kDa) accompanies increasing albuminuria in Type 1 diabetes.     

Relation between glycaemic control,hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type II diabetes

Aims/hypothesis: Increased plasma concentrations of circulating adhesion molecules in patients with Type II (non-insulin-dependent) diabetes mellitus could be associated with the increased cardiovascular risk in these patients. However, it is controversial whether increased adhesion molecule plasma concentrations are primarily related to hyperglycaemia or to hyperinsulinaemia. Methods: We evaluated the plasma concentrations of soluble E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) at baseline and during euglycaemic hyperinsulinaemic clamp in three different groups without additional cardiovascular risk factors: group A (control group), 28 healthy volunteers with normal glucose tolerance; group B, 24 subjects with fasting hyperinsulinaemia, normal fasting glucose but impaired glucose tolerance; group C, 32 patients with Type II diabetes, fasting hyperinsulinaemia and chronic hyperglycaemia. Results: Plasma soluble E-selectin, ICAM-1, and VCAM-1 concentrations were higher (p < 0.05) in patients with Type II diabetes (group C) compared with the other groups. The adhesion molecule concentrations correlate with the fasting plasma glucose (r = 0.59, p < 0.001), the 2-h OGTT plasma glucose (r = 0.70, p < 0.01), and the HbA_{1 c} value (r = 0.61, p < 0.05). The E-selectin but not the ICAM-1 and VCAM-1 plasma concentrations correlated with the fasting insulin concentrations (r = 0.62, p < 0.05) or the whole body glucose uptake (r = 0.59, p < 0.05) in the clamp. The hyperinsulinaemia during the euglycaemic hyperinsulinaemic clamp had no significant effect on the plasma concentrations of E-selectin, ICAM-1, and VCAM-1 in all three groups. Conclusion/interpretation: Our results suggest that increased E-selectin concentrations are related to hyperglycaemia, hyperinsulinaemia and insulin resistance, whereas increased ICAM-1 and VCAM-1 plasma concentrations in patients with Type II diabetes are rather related to hyperglycaemia than to hyperinsulinaemia or insulin resistance. [Diabetologia (2002) 45: 210–216] Received: 13 August 2001 and in revised form: 1 October 2001     

Serum Lipids and Apolipoproteins and Their Relationship with Macrovascular Disease in Type 1 Diabetes

In order to examine the relationship between serum lipids and apolipoproteins and macrovascular disease in patients with Type 1 diabetes mellitus, 50 patients with Type 1 diabetes mellitus attending the diabetic clinics at St Mary's and St Charles' Hospitals, London were recruited into a cross-sectional study. B-mode ultrasound was used to measure intima-media thickness and define an arterial ultrasound score for each patient as a non-invasive indicator of atherosclerotic change. Intima-medial (i-m) thickness was significantly higher in those subjects with clinical evidence of macrovascular disease compared to those without macrovascular disease (0.865 ± 0.191 vs 0.695 ± 0.162 mm, p = 0.0038). In the study group there were significant correlations between i-m thickness and age (r = 0.65, p < 0.01), total serum cholesterol (r = 0.32, p < 0.01), and serum fibrinogen (r = 0.43, p < 0.01) but no other lipid or apolipoprotein variable. When i-m thickness was corrected for age there were significant correlations with total cholesterol (r = 0.43, p < 0.01) and LDL-cholesterol (r = 0.42, p < 0.01). Whereas total and LDL-cholesterol and serum fibrinogen concentrations were related to the extent of atherosclerotic disease by ultrasound techniques, there was no relationship with high density lipoprotein (HDL) or subfraction cholesterol concentrations. HDL-cholesterol may not be a useful marker for cardiovascular disease in Type 1 diabetes.