The metabolic syndrome influences the risk of chronic complications in patients with type II diabetes

Aims/hypothesis: We examined features of the metabolic syndrome to see if they modified the risk of chronic diabetic complications in patients with Type II (non-insulin-dependent) diabetes mellitus. Methods: A total of 85 randomly selected patients with the metabolic syndrome (WHO definition) were compared with 85 Type II diabetic patients matched for age, sex, duration of diabetes, glycaemic control and without the syndrome to assess the microvascular and macrovascular complications. Results: The patients with the metabolic syndrome had a higher prevalence of cardiovascular disease (52 vs 21 %, p < 0.001), microalbuminuria or macroalbuminuria (23 vs 7 %, p = 0.003) and distal neuropathy (16 vs 6 %, p = 0.048) than patients without the syndrome. The patients with the metabolic syndrome had smaller LDL particle size (25.4 ± 1.4 vs 26.4 ± 1.1 nm; p < 0.001), which correlated with the ratio of serum triglycerides to HDL cholesterol (r = –0.64, p < 0.001). In a multiple logistic regression analysis the metabolic syndrome was associated with coronary heart disease (RR 3.84, p < 0.001) and microalbuminuria (RR 3.99, p = 0.01). Small LDL particle size was independently associated with neuropathy (RR 0.58; p = 0.04), whereas a high HbA_{1 c} was related to neuropathy (RR 1.69, p = 0.04), retinopathy (RR 1.53, p = 0.002) and microalbuminuria (RR 1.54, p = 0.01). Conclusion/interpretation: Although chronic hyperglycaemia is the main predictor of microvascular complications in patients with Type II diabetes, this risk is modified by some of the components of the metabolic syndrome. [Diabetologia (2001) 44: 1148–1154] Received: 9 February 2001 and in revised form: 17 May 2001     

Prospective Study of Autonomic Nerve Function in Type 1 and Type 2 Diabetic Patients: 24 Hour Heart Rate Variation and Plasma Motilin Levels Disturbed in Parasympathetic Neuropathy

To clarify the impact of autonomic neuropathy in diabetic patients, we have conducted a prospective study of 58 Type 1 and 51 Type 2 diabetic patients (investigated at baseline, after 4, and after 7 years). In Type 1 diabetic patients, the sympathetic nerve function (orthostatic acceleration and brake indices) and in Type 2 patients, parasympathetic nerve function (R-R interval variation; E/I ratio) deteriorated during 7 years of prospective observation. Symptoms of autonomic neuropathy were associated with signs of autonomic neuropathy (low brake indices) in Type 1 but not in Type 2 diabetic patients. In the latest assessment 24 h ECG recording was performed and blood samples assayed for neuropeptide Y (NPY) and motilin were obtained. Type 1 diabetic patients with parasympathetic neuropathy (abnormal E/I ratio) showed significantly lower SD value (less variation in the R-R intervals; 29 [17] vs 50 [16], [mean {interquartile range}]; p = 0.001) and higher postprandial plasma motilin values (70 [20] pmol I^?1 vs 50 [15] pmol I^?1; p< 0.01) than patients with normal parasympathetic nerve function. In Type 2 diabetic patients, sympathetic neuropathy (low brake indices) was associated with an increased frequency of ventricular extra systolic beats during 24 h ECG recording (r_s = 0.65; p<0.01). Postprandial plasma NPY levels were not associated with disturbed autonomic nerve function.     

Plasma adrenaline kinetics in Type 1 (insulin-dependent) diabetic patients with and without autonomie neuropathy

Summary Plasma adrenaline kinetics (clearance, extraction across the forearm, initial plasma disappearance rate, mean sojourn time, volume of distribution) were studied in sixteen Type 1 (insulin-dependent) diabetic patients during constant i.v. infusion of tritium labelled adrenaline. In patients with (n=8) and without (n=8) neuropathy forearm venous plasma noradrenaline and adrenaline concentrations as well as plasma clearance of adrenaline based on arterial sampling (1.7 vs 2.1 l/min) were not significantly different. The initial disappearance time (T_1/2) after the infusion of the tritium labelled adrenaline had been stopped was significantly prolonged in Type 1 diabetic patients with neuropathy compared to those without (after 20 min infusion 2.7 vs 2.2 min, p<0.02, after 75 min infusion 3.7 vs 2.9 min, p<0.05). The corresponding values for the mean sojourn time of adrenaline in plasma were 6.5 vs 4.7 min (p<0.05) after 20 min infusion and 18 vs 10 min (p<0.05) after 75 min of infusion. The unchanged plasma clearance and the prolonged initial halftime and mean sojourn time of adrenaline in plasma suggest that adrenaline is distributed in a larger volume in Type 1 diabetic patients with neuropathy as compared to patients without neuropathy (estimated space of distribution 29 vs 201). Our results suggest that patients with diabetic neuropathy do not adjust the plasma adrenaline concentration to changes in adrenaline infusion rate as rapidly as those without neuropathy, i. e. the effect of an elevated adrenaline secretion rate may be prolonged in patients with diabetic autonomic neuropathy.     

Factors Related to the Electric Taste Threshold in Type 1 Diabetic Patients

To specify the factors related to taste function in Type 1 diabetes mellitus, 50 diabetic out-patients and 50 control subjects paired for age and sex were screened for taste disorders. None of them consumed significant amounts of alcohol, smoked, or had disease or took drugs capable of altering taste. Taste was studied with electrogustometry, retinopathy was detected by fluorescein angiography, nephropathy by measurement of albuminuria and microalbuminuria, peripheral neuropathy by electroneurography and electromyography, and autonomic neuropathy by cardiovascular function tests. The electrogustometric threshold was, on average, significantly higher in the diabetic group (133 ± 30 μA) than in the control group (29 ± 9 μA; p < 0.001). Electric hypogeusia (electrogustometric threshold > 100 μA) was found among 54% of the diabetic patients vs 2% of the control subjects (p < 0.001). In the diabetic group, the electrogustometric threshold was associated with complications of diabetes, especially with peripheral neuropathy (210 ± 24 vs 90 ± 22 μA; p < 0.001) and microalbuminuria (185 ± 25 vs 86 ± 21 μA; p < 0.01). It was correlated with age (r = 0.37; p < 0.01) and duration of diabetes (r = 0.52; p < 0.001) but not with HbA_1c (r = ?0.04). Using multivariate analysis, duration of diabetes and peripheral neuropathy had the strongest association with taste impairment. These results support previous findings, suggesting that taste impairment is a degenerative complication of diabetes mellitus.     

Evidence for specific autoimmunity against sympathetic and parasympathetic nervous tissues in Type 1 diabetes mellitus and the relation to cardiac autonomic dysfunction

There is growing evidence for the involvement of immunological factors in the pathogenesis of cardiac autonomic dysfunction in Type 1 diabetes mellitus (DM). To evaluate the presence of autoantibodies against autonomic nervous tissues and their relationship with tests of autonomic function, 64 newly diagnosed and 142 long duration Type 1 DM patients were investigated for sympathetic and parasympathetic ganglia (CF-SG and CF-PSG) autoantibodies with a complement-fixing indirect immunofluorescence technique. Five cardiac reflex tests were performed to assess autonomic function. Fifty-seven patients with neurological diseases other than diabetic neuropathy and 131 healthy control subjects were also tested for CF-SG and CF-PSG autoantibodies. CF-SG autoantibodies were observed in 47 (23 %) and CF-PSG autoantibodies in 21 (10 %) of 206 Type 1 DM patients (p < 0.001). In contrast, these autoantibodies were detected in 3 (5 %) and 1 (2 %) of patients with non-diabetic neurological diseases and 3 (2 %) and 4 (3 %) of control subjects (p < 0.01, p < 0.05, p < 0.0001, p < 0.05 vs Type 1 DM patients). All except two Type 1 DM patients with CF-PSG autoantibodies also presented with CF-SG autoantibodies. In diabetic patients with long duration, CF-SG autoantibodies were more frequent in patients with ECG-based cardiac autonomic neuropathy (CAN; ≥2 of 5 cardiac reflex tests abnormal) compared to patients without CAN although this did not reach statistical significance (29 % vs 17 %, p = 0.06). However, 4 (80 %) of 5 newly diagnosed and 23 (32 %) of 73 established Type 1 DM patients with abnormalities in heart rate variation during deep breathing and/or standing from lying presented with CF-SG autoantibodies compared to 12 (25 %) of 58 newly diagnosed (p < 0.05) and 7 (11 %) of 63 established Type 1 DM patients (p < 0.01), in whom both tests were normal. The results suggest that autoimmune factors contribute to the pathogenesis of cardiac autonomic dysfunction in Type 1 DM and that autoantibodies against sympathetic and parasympathetic nervous tissues are relatively specific for Type 1 DM. © 1998 John Wiley & Sons, Ltd.     

Serum Immunoglobulin Concentrations in Diabetic Patients

The relationship between glycated haemoglobin (an index of long-term diabetic control), fructosamine (an index of intermediate-term diabetic control), and serum IgA, IgG, and IgM was studied in 110 diabetic patients (41 Type 1 and 69 Type 2) and compared with 111 healthy non-diabetic subjects. Significant increases in serum IgA (by 82.7%, p < 0.001) and IgG (by 35.2%, p< 0.001) concentrations were observed whereas the concentration of IgM was significantly decreased (by 46.7%, p < 0.001) in diabetic patients compared with non-diabetic subjects. Using Spearman's rank correlations, IgA correlated with fructosamine (r = 0.77, p < 0.001), HbA₁ (r = 0.76, p < 0.001), and albumin (r = ?0.58, p < 0.001) for the entire population sample but only fructosamine (r = 0.19, p < 0.05) and HbA₁ (r = 0.28, p < 0.001) correlated with IgA in diabetic patients, respectively. It is concluded that abnormal levels of IgA, IgG, and IgM are very common in diabetic patients in whom serum IgA concentrations are influenced by the degree of glycaemic control. Whether changes in IgA and other immunoglobulins are implicated in the pathogenesis of diabetic complications (such as susceptibility to infection) deserve further study.     

The Prevalence of Autonomic and Peripheral Neuropathy in Insulin-treated Diabetic Sbjects

The prevalence of autonomic and peripheral neuropathy was examined in 506 diabetic sbjects treated with insulin, mean age 43 years, diabetes duration 15 (range 1–54) years. Autonomic neuropathy was present if two or more (of four) cardiovascular autonomic function tests were abnormal using age-related ranges derived from 310 normal control sbjects. Peripheral neuropathy was defined as a vibration threshold >95th centile for age combined with absent/impaired ankle reflexes. Eighty-four (16.6%) of diabetic sbjects had abnormal autonomic function and 119 (23.5%) peripheral neuropathy, concordant in 44/506 (8.7%). Of the diabetic sbjects with autonomic neuropathy 40/84 (47.6%) did not have peripheral neuropathy and only 44/119 (37.0%) with peripheral neuropathy had abnormal autonomic function (p<0.001). The prevalence of both neuropathies increased in relation to diabetes duration (both p<0.001). Autonomic neuropathy was more common in sbjects diagnosed <20 years of age (18.2%) vs age >40 years (11.1%) (p<0.05). In contrast peripheral neuropathy was more common with older age at diagnosis (<20 years 13.5% vs 36.8% >40 years, p<0.001). The age-related prevalence of autonomic neuropathy peaked at age 40–49 years while peripheral neuropathy increased progressively with age (p<0.001). The prevalence of peripheral exceeded autonomic neuropathy 20 years after diagnosis (40.2% vs 30.7%, p<0.001).     

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.     

C-peptide prevents and improves chronic Type I diabetic polyneuropathy in the BB/Wor rat

Aims/hypothesis. Insulin and C-peptide exert neuroprotective effects and are deficient in Type I (insulin-dependent) diabetes mellitus but not in Type II (non-insulin-dependent) diabetes mellitus. These studies were designed to test the preventive and interventional effects of C-peptide replacement on diabetic polyneuropathy in the Type I diabetic BB/Wor rat. Methods. Diabetic BB/Wor rats were replaced with rat C-peptide from onset of diabetes and between 5 and 8 months of diabetes. They were examined at 2 and 8 months and compared to non-C-peptide replaced BB/Wor rats, Type II diabetic (non-C-peptide deficient) BB/Z rats and non-diabetic control rats. Animals were monitored as to hyperglycaemia and nerve conduction velocity (NCV). Acute changes such as neural Na⁺/K⁺-ATPase and paranodal swelling were examined at 2 months, morphometric and teased fiber analyses were done at 8 months. Results. C-peptide replacement for 2 months in Type I diabetic rats prevented the acute NCV defect by 59 % (p < 0.005), the neural Na⁺/K⁺-ATPase defect by 55 % (p < 0.001) and acute paranodal swelling by 61 % (p < 0.001). Eight months of C-peptide replacement prevented the chronic nerve conduction defect by 71 % (p < 0.001) and totally prevented axoglial dysjunction (p < 0.001) and paranodal demyelination (p < 0.001). C-peptide treatment from 5 to 8 months showed a 13 % (p < 0.05) improvement in NCV, a 33 % (p < 0.05) improvement in axoglial dysjunction, normalization (p < 0.001) of paranodal demyelination, repair of axonal degeneration (p < 0.01), and a fourfold (p < 0.001) increase in nerve fibre regeneration. Conclusion/interpretation. C-peptide replacement of Type I BB/Wor-rats partially prevents acute and chronic metabolic, functional and structural changes that separate Type I diabetic polyneuropathy from its Type II counterpart suggesting that C-peptide deficiency plays a pathogenetic role in Type I diabetic polyneuropathy. [Diabetologia (2001) 44: 889–897]     

Serum 7S domain of type IV collagen levels in essential hypertension and hypertensive type 2 diabetic patients

Metabolic alteration of Type IV collagen occurs in micro- or macrovascular basement membrane of diabetic patients. Hypertension, a risk factor for clinical progression of diabetic vascular disease, may influence this metabolic alteration. The object of this study was to evaluate the serum 7S domain of type IV collagen (7S-collagen) levels in patients with essential hypertension and in Type 2 diabetic patients with or without hypertension and to investigate the relationship between the type IV collagen metabolism and the arterial blood pressure. Serum 7S-collagen levels in 18 patients with essential hypertension were significantly higher than in 24 normal subjects (4.2 ± 0.5 vs 3.6 ± 0.4 ng ml⁻¹ p < 0.01). Serum 7S-collagen levels in 28 normotensive diabetic patients (4.2 ± 0.5 ng ml⁻¹) were significantly higher than in normal subjects (p < 0.01). The serum 7S-collagen levels were significantly higher in 22 diabetic patients with hypertension (4.8 ± 0.6 ng ml⁻¹) than in the other groups. There was a significant correlation between the serum 7S-collagen levels and the systolic blood pressure in cases with essential hypertension (r = 0.59, p < 0.001) and in all diabetic patients (r = 0.52, p < 0.001), suggesting that elevation of the systolic blood pressure may influence the type IV collagen metabolism of vascular basement membrane. We conclude that the metabolic alteration of basement membrane occurring in patients with diabetes mellitus may worsen in the presence of high systolic blood pressure. © 1997 by John Wiley & Sons, Ltd.     

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.     

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.     

Enhancement of soluble CD23 serum levels and cell-surface CD23-expression in subjects at increased risk of Type 1 diabetes mellitus and in diabetic patients

The low affinity receptor for IgE, CD23, is expressed on lymphocytes among other cell types. The purpose of the present study was to assess serum sCD23 levels and CD23 expression on peripheral blood mononuclear cells (PBMC) in people at increased risk of developing Type 1 diabetes mellitus and in diabetic patients. Serum sCD23 levels were significantly higher in first-degree relatives of Type 1 patients (median: 3.2 U ml⁻¹) (p < 0.001) and in newly diagnosed (median: 3.3 U ml⁻¹) (p < 0.001) and long-standing (median: 2.5 U ml⁻¹) (p = 0.01) Type 1 diabetic patients than in controls (median: 1.2 U ml⁻¹). Newly diagnosed patients showed higher levels than those with long-standing disease (p = 0.026). Moreover the percentage of B cells expressing CD23 were significantly higher in first-degree relatives (median: 48.6 %) (p < 0.001) and in newly diagnosed (median: 58 %) (p < 0.001) and long-standing (median: 44.8 %) (p = 0.03) Type 1 diabetic patients than in controls (median: 28.5 %). The increased sCD23 levels and the increased number of cells expressing CD23 observed in subjects at increased risk of Type 1 diabetes and diabetic patients may be indicators of Th2 activity in Type 1 diabetes. © 1998 John Wiley & Sons, Ltd.     

Coagulation Activation in Type 2 Diabetes Mellitus: the Higher Coronary Risk of Female Diabetic Patients

Thrombophilia in diabetic patients is a well-recognized phenomenon which constitutes an additional risk of coronary heart disease. This study included 1980 ethnic Chinese people (835 male, 1145 female); age range: 45 to 69 years, including 280 Type 2 diabetic patients (male 125, female 155). Haemostatic parameters measured were fibrinogen, prothrombin time, activated partial thromboplastin time (APTT), factor VIIc, factor VIIIc, antithrombin III, and plasminogen. Compared with a control group, male diabetic patients showed significantly shorter APTT (25.6 ± 3.7 vs 27.5 ± 3.6 s, p<0.001), and elevated factor VIIIc (171.1 ± 77.48 vs 131.16 ± 52.23%, p<0.0001), whereas female diabetic patients showed significantly shorter APTT (24.9 ± 4.2 vs 26.5 ± 3.9 s, p<0.001) and elevated fibrinogen (10.6 ± 3.3 vs 9.8 ± 2.6 μmol 1^?1, p<0.05), factor VIIc (150.4 ± 68.7 vs 135.3 ± 32.3%, p<0.001), factor VIIIc (190.1 ± 92.6 vs 141.1 ± 62.4%, p<0.0001), and plasminogen (140.3 ± 41.9 vs 128.4 ± 38.7%, p<0.01). This study showed that Chinese diabetic patients had coagulation activation, and that female diabetic patients seemed to constitute a higher risk group for coronary heart disease than males.     

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.     

Prevalence of left ventricular hypertrophy in Type I diabetic patients with diabetic nephropathy

Summary The increased mortality of patients with diabetic nephropathy is mainly due to cardiovascular disease and end stage renal failure. Left ventricular hypertrophy is an independent risk factor for myocardial ischaemia and sudden death. The aim of our cross-sectional study was to evaluate left ventricular structure and function in Type I (insulin-dependent) diabetic patients with diabetic nephropathy. M-mode and Doppler echocardiography were done on 105 Type I diabetic patients with diabetic nephropathy [61 men, age (means ± SD) 44 ± 9 years, and albuminuria [median(range)] 567(10–8188) mg/24 h, serum creatinine 109 (53–558) μmol/l], and 140 Type I diabetic patients with persistent normoalbuminuria [79 men, 47 ± 10 years, urinary albumin excretion rate 8 (0–30) mg/24 h, and serum creatinine 81 (55–121) μmol/l]. Patients with and without nephropathy were comparable with respect to sex, body mass index, and duration of diabetes. Arterial blood pressure was slightly higher in patients with nephropathy: 140/79 ± 17/9 mm Hg vs 134/78 ± 15/8 mm Hg, p < 0.01, and the majority of proteinuric patients received antihypertensive drugs, 84 vs 17 %, respectively, p < 0.001. Left ventricular mass index was increased in the nephropathic group (means ± SD) 100.6 ± 23.9 g/m² compared with the normoalbuminuric group 91.4 ± 21.9 g/m², p = 0.002. Left ventricular hypertrophy was found more often in patients with nephropathy 23 (14–31)% compared with patients with normoalbuminuria 9 (5–14)%, p < 0.005. Diastolic function, assessed by the ratio between the peak diastolic velocity and the peak atrial systolic velocity (E/A ratio) and isovolumic relaxation time, was reduced in patients with vs without nephropathy: 1.17 ± 0.29 vs 1.34 ± 0.32, and 81.7 ± 16.5 vs 74.6 ± 14.5, p < 0.001 and p = 0.002, respectively. Systolic function was about the same and normal in both groups. Our study suggests that an increase in left ventricular mass index and a decrease in diastolic function occurs early in the course of diabetic nephropathy. [Diabetologia (1999) 42: 76–80] Received: 16 April 1998 and in final revised form: 5 August 1998     

Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4

Summary To test the hypothesis that interaction between genetic, immunological, clinical and metabolic risk factors influences the outcome of Type II (non-insulin-dependent) diabetes mellitus, we examined which of the above factors present at baseline were associated with mortality in 134 Type II diabetic patients followed for 9 years. Thirty-eight patients (29 %) died during the follow-up period; the majority of whom (68 %) died from cardiovascular disease. At baseline, the deceased patients had higher HbA_{1 c} values (p = 0.002), higher LDL-triglycerides (p = 0.007), lower HDL-cholesterol (p = 0.007), higher non-esterified fatty acid (NEFA) concentrations (p = 0.014), and higher albumin excretion rate (p < 0.0001) than the patients who survived. In addition, the frequency of HLA-DR4 (21 vs 39 %, p = 0.048) and of parietal cell antibodies (5 vs 14 %, p = 0.016) were decreased in the deceased as compared to the living patients. Patients who died during follow-up also had more retinopathy (42 vs 16 %, p = 0.002), neuropathy (57 vs 23 %, p < 0.001), microalbuminuria (45 vs 6 %, p < 0.0001), coronary heart disease (50 vs 13 %, p < 0.0001), and peripheral vascular disease (27 vs 9 %, p = 0.005) at baseline than patients who survived. In a multiple logistic regression analysis macroangiopathy (p = 0.004), neuropathy (p = 0.007), HbA_{1 c} (p = 0.018) and albumin excretion rate (p = 0.016) were independent risk factors for death. In patients free of cardiovascular disease at baseline, conventional risk factors such as LDL-cholesterol (p = 0.005) and age (p = 0.003) were associated with subsequent development of cardiovascular disease. In conclusion, in addition to coexisting macroangiopathy, increased albumin excretion rate, poor glycaemic control and neuropathy are risk factors for cardiovascular mortality in patients with Type II diabetes. The presence of HLA-DR4 and signs of autoimmunity may be associated with decreased risk of cardiovascular disease. [Diabetologia (1998) 41: 1253–1262] Received: 29 December 1997 and in revised form: 27 April 1998     

Insulin-like Growth Factor-I and IGF-I Receptors in Diabetic Patients with Neuropathy

Since a number of animal studies have shown that Insulin-like growth I (IGF-I) stimulates nerve regeneration, the aim of our study was to evaluate the possible relationship between IGF-I and IGF-I receptors in diabetic patients with peripheral neuropathy. One hundred and four patients with Type 2 diabetes (57 with peripheral neuropathy and 47 non-neuropathic) were studied. Controls were 17 non-diabetic persons. After an overnight fast, blood was taken for IGF-I, IGF-I receptors, glucose, HbA₁, C-peptide, and insulin. The neuropathy study group had significantly lower levels of IGF-I:144.5 ng mI^-1 (57.5–363.0, 95% confidence limits) compared to controls: 186.2 ng mI^-1 (93.3–371.5), p<0.01, and to diabetic patients without neuropathy: 173.7 ng mI^-1 (83.1–363.0), p<0.01. The study group also had a lower number of IGF-I receptors per red cell: 22.9 times 10³ (13.08–38.01) vs control subjects: 28.1 times 10³ (18.62–42.65), p<0.01, and non-neuropathic diabetic patients: 26.3 times 10³ (16.59–41.68), p<0.01. In diabetic subjects there was a positive correlation (r = 0.20, p<0.05) between IGF-I and HbA₁, while in the neuropathy group there was a negative correlation between the score for nerve dysfunction with the IGF-I (r = -0.39, p<0.01) and with IGF-I receptors (r = -0.34, p<0.01). We conclude that in diabetic patients with peripheral neuropathy there are abnormalities of IGF-I and IGF-I receptors which may contribute to impaired neuronal regeneration.     

Prothrombotic and Antithrombotic Factors are Elevated in Patients with Type 1 Diabetes Complicated by Microalbuminuria

Increased urinary albumin loss in patients with Type 1 diabetes is associated with accelerated atherosclerosis. Prothrombotic factors known to be associated with cerebrovascular and coronary artery disease in the general population, and antithrombotic factors, were studied in 52 patients with Type 1 diabetes and varying urinary albumin loss and 24 non-diabetic control subjects. Fibrinogen increased from 2.5 g I_-1 (95 % confidence interval 2.3–2.8) in control subjects and 2.8 g I_-1 (2.6–3.0) in diabetic patients without microalbuminuria to 3.1 g I_-1 (2.7–3.5) with microalbuminuria (p < 0.005 vs control; p < 0.001 vs without microalbuminuria). Factor VIIc increased from 81 % (75–86 % in non-diabetic control subjects and 84 % (78–90 %) in diabetic patients without microalbuminuria to 103 % (89–117 %) with microalbuminuria (p < 0.005 vs control; p < 0.05 vs without microalbuminuria) and 118% (86–150%) with albuminuria (p < 0.005 vs control and p < 0.001 vs without microalbuminuria). Levels of the antithrombotic factors protein C, protein S, and antithrombin III also rose in the diabetic patients with evidence of renal damage. Elevation of prothrombotic factors has been associated with increased risk of microvascular disease, whereas elevation of antithrombotic factors has no known protective effect. Therefore, this pattern of alteration of haemostatic factors in diabetic renal disease may contribute to the increased risk of vascular disease associated with both microalbuminuria and albuminuria.     

Advanced glycation endproducts in peripheral nerve in type 2 diabetes with neuropathy

Abstract Advanced glycation endproducts (AGE) accumulate over proteins as a consequence of diabetic hyperglycemia, and thus contribute to the pathogenesis of diabetic complications. To improve the understanding of the pathology of diabetic neuropathy, AGE accumulation was analyzed in sural and/or femoral nerves obtained under spinal anesthesia from 8 type 2 diabetic patients with both distal symmetrical polyneuropathy and proximal neuropathy. Pronounced AGE immunoreactivity was detected on axons and myelin sheaths in 90% of diabetic peripheral nerves but not in the control specimen. The intensity of axonal AGE immunopositivity significantly correlated with the severity of morphological alterations (p<0.005). AGE localization, demonstrated by immunohistochemical methods, was also present in the endoneurium, perineurium and microvessels. Morphometric analysis of the diabetic peripheral nerve showed perineurial thickening (diabetic vs. control, 15.5±4.9 vs. 6.6±2.1 µm, p<0.001), narrowing of the microvessel lumina (66.6±50.5 vs. 579.5±38.4 x10³ µm², p<0.001) and significant reduction in the number of preserved axons (3.6±3 vs. 8.9±2.3 per 10⁵ µm² per area, p<0.037). The sera of diabetic patients contained epitope(s) of AGE structure and soluble immune complexes containing AGE moiety. In conclusion, to the best of our knowledge, this is the first study providing evidence for excessive AGE formation on peripheral nerve components, primarily axons, and a significantly higher level of circulating AGE-immune complexes in patients with both distal diabetic polyneuropathy and proximal neuropathy. Humoral immune mechanisms, including the production of anti-AGE autoantibody, may potentially be involved in the development of structural abnormalities described in this report.