A retroviral long terminal repeat adjacent to the HLA DQB1 gene (DQ-LTR13) modifies Type I diabetes susceptibility on high risk DQ haplotypes

Aims/hypothesis: HLA-DQ genes, located in the human leukocyte antigen region on chromosome 6 p, are the main inherited factors predisposing to Type I (insulin-dependent) diabetes mellitus. Endogenous retroviral long-terminal repeats are integrated at several sites within this region, one of which is known to enhance susceptibility for Type I diabetes. We examined another LTR within the HLA-region as an additional genetic risk marker. Methods: We investigated the segregation of one long-terminal repeat (DQ-LTR13), located 1.3 kb upstream of HLA DQB1 with different HLA-DQ haplotypes, and its transmission to patients. A total of 284 Caucasian families (203 German and 81 Belgian) with at least one diabetic offspring were genotyped for DQA1, DQB1 and DQ-LTR13. Results: DQ8/LTR13 ⁺ was preferentially transmitted (139 transmitted vs 28 not transmitted; P^TDT = 1.67 × 10^–14) whereas no deviation from expected transmission frequencies was observed for DQ8/LTR13 ^– (20 transmitted vs 17 not transmitted; P^TDT = 1.00). DQ8/LTR13 ⁺ alleles conferred a significantly higher risk for Type I diabetes than DQ8/LTR13 ^– alleles (pχ ² = 2.58 × 10^–14). This difference remained significant even after DRB1 subtyping (pχ ² = 0.02). Also, there was a significant difference when comparing the transmission of DQ2/LTR13 ⁺ and DQ2/LTR13 ^– alleles (pχ ² = 0.01), the latter conferring an increased risk. The transmission of DQ-LTR13 ⁺ haplotypes did not show any differences regarding paternal, maternal or gender-related stratification. However, DQ8/LTR13 ^– was significantly more often transmitted from mothers (pχ ² = 0.01) and to female patients (pχ ² = 0.04). Conclusion/interpretation: We conclude that DQ-LTR13 marks additional genetic risk for Type I diabetes on predisposing DRB1^*0401-DQ8 and DQ2 haplotypes and will help to further define susceptibility in this gene region. [Diabetologia (2002) 45: 443–447] Received: 2 August 2001 and in revised form: 29 October 2001     

Erythrocyte sodium-lithium countertransport is not different in Type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy

Summary We studied erythrocyte sodium-lithium countertransport in 33 patients with Type 1 (insulin-dependent) diabetes mellitus with diabetic nephropathy, 18 patients with Type 1 diabetes without diabetic nephropathy and in 42 nondiabetic patients with various other renal diseases. No significant differences were found in sodium-lithium countertransport between these three groups (median (range) 322 (162–676) vs 321 (189–627) vs 300 (142–655) mol·1 cells^–1·h^–1). We conclude, that sodium-lithium countertransport cannot be used as a marker for diabetic nephropathy.     

The impact of a family history of Type II (non-insulin-dependent) diabetes mellitus on the risk of diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus

Aims/hypothesis. There is substantial evidence for a role of genetic factors in the development of diabetic nephropathy. In Pima Indians, a link between susceptibility to diabetic nephropathy and Type II (non-insulin-dependent) diabetes mellitus has been proposed. In this study, our aim was to examine the association between a family history of Type II diabetes and diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus. Methods. In a cross-sectional case-control study, we assessed the prevalence of Type II diabetes in the parents of 137 Type I diabetic patients with diabetic nephropathy (albuminuria > 300 μg/min in two of three overnight urine collections) compared with the parents of 54 Type I diabetic patients without nephropathy (albuminuria < 20 μg/min). Results. Thirty-four (25 %) of the patients with nephropathy compared with five (9 %) of the patients without nephropathy had a parental history of Type II diabetes (p = 0.019). A parental history of Type II diabetes was associated with a three-fold risk [odds ratio 2.95 (95 % confidence interval: 1.03 to 8.40), p = 0.043] of diabetic nephropathy after adjustment for sex, glycaemic control and family history of hypertension. Furthermore, there was an excess of risk factors for development of Type II diabetes (higher fasting plasma glucose concentrations, higher prevalence of hypertension, higher waist-hip ratio and a tendency towards more glucose intolerance) among previously non-diabetic parents of patients with nephropathy. Conclusion/interpretation. Genetic or environmental factors or both related to familial Type II diabetes increase susceptibility to diabetic nephropathy in patients with Type I diabetes. [Diabetologia (1999) 42: 519–526] Received: 30 September 1998 and in final revised form: 28 December 1998     

Exercise in Type 1 (insulin-dependent) diabetic patients treated with continuous subcutaneous insulin infusion

Summary The study was performed to investigate the effects of mild to moderate exercise on blood glucose levels, metabolite concentrations and responses of counterregulatory hormones in tightly controlled Type 1 (insulin-dependent) diabetic patients treated by continuous subcutaneous insulin infusion, and to quantify the measures necessary to prevent acute and late exercise-induced hypoglycaemia. Seven male patients started a 60 min exercise period 90 min after an insulin bolus and a standard breakfast; they were monitored during a post-exercise resting period of 5 h 30 min. Different basal and premeal insulin infusion rates were applied. (Near)normoglycaemia prevailed throughout the study during the control protocol when the subjects did not exercise and received their usual insulin dose. When they exercised without changing the insulin dose, four patients were forced to stop due to hypoglycaemia. This effect of exercise could be attenuated but not completely avoided if the basal infusion rate of insulin was discontinued during the exercise period. The pronounced increase in catecholamine and growth hormone concentrations during exercise were not sufficient to prevent hypoglycaemic reactions. Hypoglycaemia during exercise could only be prevented when the premeal insulin bolus was reduced by 50% in addition to the discontinuation of the basal insulin infusion during exercise. In order to reduce late hypoglycaemic reactions after exercise the best measure proved to be a reduction of the basal insulin infusion rate by 25% during post-exercise hours. Administration of only 50% of the basal insulin infusion rate during this time was associated with blood glucose levels being raised up to 8 mmol/l. In conclusion, Type 1 diabetic patients treated with continuous subcutaneous insulin infusion at (near)normoglycaemia need to reduce their insulin dosage before, during, and after mild to moderate endurance exercise in order to minimize the risk of acute and late hypoglycaemia.     

Nocturnal electroencephalogram registrations in Type 1 (insulin-dependent) diabetic patients with hypoglycaemia

Summary Eight Type 1 (insulin-dependent) diabetic patients with no diabetic complications were studied overnight for two consecutive and one subsequent night with continuous monitoring of electroencephalogram and serial hormone measurements. The aims were: 1) to evaluate the influence of spontaneous and insulin-induced hypoglycaemia on nocturnal electroencephalogram sleep-patterns and, 2) to evaluate counter-regulatory hormone responses. Spontaneous hypoglycaemia occurred on six nights (38%) with blood glucose concentrations <3.0 mmol/l and on four nights <2.0 mmol/l. All the patients experienced insulin-induced hypoglycaemia with a blood glucose nadir of 1.6 (range 1.4–1.9) mmol/l. The electroencephalogram was analysed by a new method developed for this purpose in contrast to the traditional definition of delta-, theta-, alpha- and beta-activity. The blood glucose concentration could be correlated to the rank of individual electroencephalogram-patterns during the whole night, and specific hypoglycaemic amplitude-frequency patterns could be assigned. Three of the eight patients showed electroencephalogram changes at blood glucose levels below 2.0 (1.6–2.0) mmol/l. The electroencephalogram classes representing hypoglycaemic activity had peak frequencies at 4 and 6 Hz, respectively, clearly different from the patients' delta- and theta-activity. The changes were not identical in each patient, however, they were reproducible in each patient. The changes were found equally in all regions of the brain. The three patients with electroencephalogram changes during nocturnal hypoglycaemia could only be separated from the other five patients by their impaired glucagon responses. Against this background the possibility of protection by glucagon, against neurophysiologic changes in the brain during hypoglycaemia may be considered.     

Relationship of progressively increasing albuminuria to apoprotein(a) and blood pressure in Type 2 (non-insulin-dependent) and Type 1 (insulin-dependent) diabetic patients

Summary This study has explored the temporal relationship between apoprotein(a), blood pressure and albuminuria over a mean interval of 11 years in a cohort of 107 diabetic patients of whom 26 (14 Type 2 (non-insulin-dependent), 12 Type 1 (insulin-dependent) had progressively increasing albuminuria (‘progressors’). In Type 2 diabetic patients, no significant differences were noted for HbA₁, blood pressure, creatinine clearance or serum lipids between progressors and non-progressors. In Type 1 diabetic patients, final systolic and diastolic blood pressures were higher in progressors compared with non-progressors and progressors showed impairment of renal function in association with a rise in blood pressure at the macroalbuminuric stage. Initial apoprotein(a) levels were similar in progressors and non-progressors of either diabetes type. Apoprotein(a) levels increased exponentially with time in 12 of 14 Type 2 progressors but only in 5 of 12 Type 1 progressors (p<0.01). In Type 2 diabetic patients, the annual increase in apoprotein(a) levels was 9.1±2.4%, which was significantly greater than in non-progressors, 2.0±1.2% (p<0.01) and also exceeded the rates of increase of apoprotein(a) in progressors with Type 1 diabetes, 4.0±1.4%, (p<0.05). Apoprotein(a) levels correlated significantly with albuminuria in 8 of 14 Type 2 progressors but only in 3 of 12 Type 1 progressors (p<0.05). The rate of increase of apoprotein(a) levels was not related to mean HbA₁, creatinine or creatinine clearance levels, or to albuminuria. The rate of rise of apoprotein(a) was not influenced by initial apoprotein(a) levels, suggesting that specific apoprotein(a) isoforms do not influence albuminuria-related increases in apoprotein(a). The data are consistent with the hypothesis that apoprotein(a) levels increase in response to albuminuria and may be part of a self-perpetuating process. This study also suggests that increases in apoprotein(a) levels commence during the microalbuminuria stage in diabetic patients, which is earlier than has been documented in non-diabetic proteinuria.     

Subclinical diabetic neuropathy: similarities between electrophysiological results of patients with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus

Summary Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients share many clinical and biochemical characteristics. However, sural nerve biopsies from patients with advanced and chronic neuropathy show ultrastructural differences between these two groups. We investigated whether at a subclinical stage of the illness, when Type 1 and Type 2 diabetic patients are clinically uniform and the histopathological nerve alterations are not advanced, comparison between the two diabetes groups might show differences in nerve fibre involvement related to the different pathogeneses of the neuropathies. A total of 88 diabetic patients (52 Type 1 and 36 Type 2), with a subclinical form of polyneuropathy were selected. The clinical neurophysiological examination consisted of motor and sensory nerve conduction studies, Hoffmann (H)-reflex, single fibre electromyography and static as well as dynamic pupillometry. With regard to clinical neurophysiological abnormalities, the severity of the polyneuropathy appeared to be equal in both groups. Despite the absence of clinical symptoms the neurophysiological abnormalities were pronounced and it was impossible to differentiate Type 1 diabetic patients from Type 2 diabetic patients on a clinical neurophysiology basis when correcting for differences in age, height, and duration of illness. In the Type 1 diabetic group as well as in the Type 2 diabetic group the autonomic nerve fibres and nerves in the legs were more frequently affected than the thick myelinated nerves in the arms. These findings do not support the assumption that there is a difference in the manifestation of polyneuropathy between Type 1 and Type 2 diabetic patients.     

Type 1 (insulin-dependent) diabetes in Japanese children is not a uniform disease

Summary The initial course of Type 1 (insulin-dependent) diabetes mellitus was studied in two groups of Japanese children, i. e. 21 patients with abrupt onset (Group A) and 19 patients detected by urine glucose screening at school with minimal or no symptoms (Group B). There was no statistical difference in mean age at diagnosis between Group A and B (11±3 years vs 11±3 years). Group A patients revealed a rapid deterioration of pancreatic B-cell function, but there was evident recovery of the B-cell function from 3 to 9 months following initial treatment. The B-cell capacity in Group B was self maintained until 24 months after diagnosis. There-after, even these patients exhibited a progressive decline in the B-cell function. The two groups had a similar incidence of islet cell antibodies at diagnosis (58% vs 69%). However, human leukocyte antigen studies revealed that patients in Group A had a significantly higher prevalence of DR4 and DRW9 than those in Group B (p<0.01). These results suggest that in Japanese children there are two forms of diabetes, an abrupt and a slow onset form, which are clinically different and which also seemed to be genetically independent types, or possibly the same disease diagnosed at different stages.     

Leucocyte Na+/H+ antiport activity in Type 1 (insulin-dependent) diabetic patients with nephropathy

Summary The development of proteinuria in Type 1 (insulin-dependent) diabetic patients may depend on predisposition to essential hypertension in addition to poor glycaemic control. Previous work has shown increased leucocyte Na^–/H⁺ antiport activity in essential hypertension and increased erythrocyte Li⁺/Na⁺ exchange in Type 1 diabetic patients with proteinuria. To test whether susceptibility to nephropathy in Type 1 diabetes was linked to abnormalities of leucocyte Na⁺/H⁺ antiport activity, we measured the intracellular pH and kinetics of the Na⁺/H⁺ antiport in 19 Type 1 diabetic subjects with, and 15 diabetic subjects without albuminuria and compared them to 25 matched normal control subjects. Intracellular pH (mean ±SD 7.59 ± 0.14) and maximal transport capacity of the antiport (V_max 87.7 ±24.9 mmol· 1^–1·min^–1) were higher in diabetic subjects with albuminuria compared to normotensive control subjects (pH 7.44±0.09; V_max 55.6±10.3 mmol·1^–1min^–1; p <0.001 for both), similar to the defect described in essential hypertension. These differences were not seen in diabetic subjects with normal urinary albumin/creatinine ratios (pH 7.46 ±0.09; V_max 61.0 ±13.6mmol·1^–1min^–1). Buffering characteristics of the leucocytes at different pH in the Type 1 diabetic subjects with albuminuria differed from normal control subjects and diabetic subjects with normal urinary albumin/creatinine ratios. We conclude that increased leucocyte Na⁺/H⁺ antiport activity, a known marker of essential hypertension, is usually associated with nephropathy in Type 1 diabetes.     

Glucose-induced insulin response and insulin sensitivity is not related to HLA-type but to age in young siblings of Type 1 (insulin-dependent) diabetic patients

Summary Glucose-induced insulin response and insulin sensitivity were studied in 32 HLA-identical, 38 haplo-identical and 24 non-identical, islet-cell-antibody-negative, healthy siblings of young Type 1 (insulin-dependent) diabetic patients (age range 10–28 years). No significant differences were obtained between HLA-identical, HLA-haplo-identical siblings and HLA-non-identical siblings in insulin response using an i.v. glucose infusion test even when the insulin sensitivity as estimated by the somatostatin-insulin-glucose infusion test was taken into account. A significant inverse correlation to age was found for both insulin response (r=-0.24, p=0.02) and insulin sensitivity (r=-0.36, p<0.01) in the young siblings studied.     

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.     

Plasma apolipoprotein (a) is increased in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria

Summary Patients with Type 2 (non-insulin-dependent) diabetes mellitus complicated by microalbuminuria or albuminuria, have an increased risk of developing macrovascular disease and of early mortality. Because lipoprotein abnormalities have been associated with diabetic nephropathy, this study tested the hypothesis that levels of apolipoprotein (a) are elevated in patients with Type 2 diabetes and increased levels of urinary albumin loss. Levels of apolipoprotein (a) in diabetic patients with microalbuminuria (n = 26, geometric mean 195 U/1, 95 % confidence interval 117–324) and albuminuria (n = 19, 281 U/1,165–479) were higher than in non-diabetic control subjects (n = 140,107 U/1, 85–134,p < 0.05), and in the albuminuric group than diabetic patients without urinary albumin loss (n = 58, 114 U/1, 76–169,p < 0.05). Patients with microalbuminuria and albuminuria had levels comparable with patients undergoing elective coronary artery graft surgery (n = 40,193 U/1,126–298). Apolipoprotein (a) levels were higher in diabetic patients with macrovascular disease than in those without (n = 49, 209 U/1, 143–306 vsn = 54, 116 U/1, 78–173,p < 0.05). These preliminary results suggest that raised apolipoprotein (a) levels of Type 2 diabetic patients with microalbuminuria and albuminuria may contribute to their propensity to macrovascular disease and early mortality.     

Alterations in serum lipids and apolipoproteins in male Type 1 (insulin-dependent) diabetic patients with microalbuminuria

Summary The relationships between serum lipid, apolipoprotein levels and urinary albumin excretion were investigated in 20 male Type 1 (insulin-dependent) diabetic patients with microalbuminuria (overnight urinary albumin excretion between 10 and 200 g/min), in 18 male Type 1 diabetic patients without microalbuminuria and in 18 male control subjects. In the microalbuminuric patients low density lipoprotein cholesterol was higher than in the control subjects (p<0.05); the high density lipoprotein/low density lipoprotein cholesterol ratio was lower than in the normoalbuminuric diabetic patients (p<0.05), and in the control subjects (p<0.01); apolipoprotein B was higher than in the normoalbuminuric patients (p<0.05); the apolipoprotein A₁/B ratio was lower than in the normoalbuminuric diabetic patients (p<0.05). Serum triglyceride was higher in the microalbuminuric diabetic patients and in the control subjects than in the normoalbuminuric diabetic patients (p<0.05, for both), but was not different between the microalbuminuric diabetic patients and the control subjects. No significant differences between the 3 groups were present with respect to serum cholesterol, high density lipoprotein cholesterol and apolipoprotein A₁. In the 2 combined Type 1 diabetic groups there were significant correlations between urinary albumin excretion and the high density lipoprotein/low density lipoprotein cholesterol ratio (R -0.40, p<0.02), apolipoprotein B (R0.35, p<0.05) and the apolipoprotein A₁/B ratio (R -0.44, p<0.01). These results indicate microalbuminuria related differences in lipid and apolipoprotein levels in male Type 1 diabetic patients, which may contribute to an increased risk of cardiovascular disease.     

Lack of familial predisposition to cardiovascular disease in Type 1 (insulin-dependent) diabetic patients with nephropathy

Summary A familial predisposition has been proposed as a major determinant of the increased morbidity and mortality from cardiovascular disease demonstrated in Type 1 (insulin-dependent) diabetic patients with nephropathy. We assessed this concept by studying 91 parents of Type 1 diabetic patients with nephropathy and 94 parents of aged-matched Type 1 diabetic patients with normoalbuminuria. The two groups of parents were of a similar age (58±8 vs 58±7 years). The prevalence (%) of death and cardiovascular diseases (World Health Organisation questionnaire) was 10 (4–18)% and 12 (6–21)% in parents of nephropathic patients compared to 8 (3–16)% and 13 (6–23)% in parents of normoalbuminuric Type 1 diabetic patients. The frequency of risk factors for cardiovascular disease were about the same in both groups of parents. Microalbuminuria was found in 5% and 11%, hypercholesterolaemia (> 6.5 mmol/l) in 25% and 26% and smokers constituted 40% and 34% of parents of patients with and without proteinuria, respectively. A familial predisposition to cardiovascular disease cannot explain the increased morbidity and mortality from cardiovascular disease in young patients with diabetic nephropathy.     

Autoantibodies to 64,000-Mr islet cell protein in long-term Type 1 (insulin-dependent) diabetic patients

Summary Autoantibodies to the 64,000-M_r (64K) islet cell protein, identified as glutamic acid decarboxylase, were assayed in 46 Type 1 (insulin-dependent) diabetic patients with a disease duration of more than 5 years. Of 46 Type 1 diabetic patients, 18 (39.1 %) were found to be positive for 64K antibodies and 12 of these patients had been diagnosed with autoimmune thyroid disease. Serum C-peptide levels were not detectable in 15 of 18 patients positive for 64K antibodies. The samples were also tested for titres of islet cell antibodies. Islet cell antibodies were detected in 15 (32.6%) of the 46 patients and all the islet cell antibody positive patients were also found to be positive for 64K antibodies. Furthermore, of these 15 patients 12 had previously been diagnosed with autoimmune thyroid disease. A correlation between levels of 64K antibodies and islet cell antibody titre revealed that higher levels of 64K antibodies were observed in patients who had higher islet cell antibody titre. These results demonstrate that most long-term Type 1 diabetic patients with 64K antibodies were also positive for islet cell antibodies complicated by autoimmune thyroid disease.     

Increased reduction in fasting C-peptide is associated with islet cell antibodies in Type 1 (insulin-dependent) diabetic patients

Summary A cohort of 82 patients with Type 1 (insulin-dependent) diabetes was followed prospectively for 24 months, and 54 of them for 30 months, to study the relationship between fasting levels of immunoreactive C-peptide and titres of islet cell antibodies. After diagnosis, fasting C-peptide rose temporarily for 1–6 months of insulin therapy and declined continuously thereafter. While islet cell antibodies were present among 55% of the newly diagnosed patients, only 31% remained positive at 30 months. Their antibody titres decreased from 181 at diagnosis to 13. Only 3 patients (4%) who were islet cell antibody negative at diagnosis became positive later. The median C-peptide values among the persistently islet cell antibody positive patients decreased from 0.11 pmol/ml at 18 months, to 0.09 pmol/ml at 24 months, to 0.06 pmol/ml at 30 months compared to 0.18 (p=0.04), 0.15 (p=0.05) and 0.16 (p< 0.003) pmol/ml, respectively, for the islet cell antibody negative patients. The median slope for the latter was –0.09 compared to –0.19 for the islet cell antibody positive patients (p=0.01). These differences were reflected in increasing dosages of insulin, since patients remaining antibody-positive for 30 months were given 1.3–1.4 times more insulin (p=0.01–0.004) than the antibody negative patients. This study demonstrates that islet cell antibodies may be a useful marker for predicting an increased rate by which endogenous B cell function is lost in Type 1 diabetes.     

Increased transcapillary escape rate of albumin in Type 1 (insulin-dependent) diabetic patients with microalbuminuria

Summary The transcapillary escape rate, intravascular mass and outflux of albumin were measured in 75 Type 1 (insulin-dependent) diabetic patients. The groups were defined as: group 1: normal urinary albumin excretion, <30 mg/24 h (n=21); group 2: microalbuminuria, 30–300 mg/24 h (n=36); group 3: diabeticnephropathy, <300 mg/24 h (n=18). Fifteen sex- and age-matched non-diabetic persons served as control subjects. The diabetes duration was: group 1: 20±9 years, group 2: 17±5 years, group 3: 19±7 years. The transcapillary escape rate of albumin was similar in controls and group 1 (5.0±1.8 versus 5.2±1.5%) and was significantly higher in the microalbuminuric group 2 and group 3 (8.1±2.2 versus 8.1±2.3 %). The differences were not explained by differences in metabolic control or blood pressure at the time of investigation. The outflux of albumin was also higher in group 2 than in group 1 and controls (7.1 ± 2.0 versus 5.3±1.5 and 5.1±2.0 g/h × 1.73 m²). It was indistinguishable from controls in group 3 (5.8±1.5 g/h × 1.73 m²) because of a reduced intravascular mass of albumin (p<0.01) in group 3. In conclusion, a universal vascular leakage of albumin is an early event in the development of diabetic nephropathy, with the leakage of albumin being fully developed in the microalbuminuric patient. In contrast, long-term diabetic patients with normal urinary albumin excretion have a normal transcapillary escape rate of albumin.     

Coronary heart disease in young Type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors

Summary Fifty-nine Type 1 (insulin-dependent) diabetic patients with (group I) and 59 patients without nephropathy (group II) pair-matched according to sex (30 males and 29 females), age (33 years, range 15–48) and diabetes duration (19 years, range 6–42) were followed for a period of 10 years from about 5 years before to 5 years after onset of proteinuria. The cumulative incidence of coronary heart disease was estimated, and blood pressure and serum cholesterol were followed. Within six years after onset of proteinuria the cumulative incidence of coronary heart disease was increased eight-fold in group I (40%) compared with group II (5%), (p<0.001). Blood pressure was higher in group I compared with group II from before onset of proteinuria (135/86±17/9 mmHg vs 129/80±15/8 mmHg, p<0.001), and serum cholesterol elevated from onset of proteinuria in group I (6.3±1.2 mmol/l) vs. group II (5.5±1.0 mmol/l), (p<0.005). Patients in group I who developed coronary heart disease had similar age (36 years, range 21–51, vs 38 years, range 21–53), sex (50% males vs. 52% males), smoking frequency (50% vs 49%), diabetes duration (22 years, range 9–39, vs 24 years, range 10–42) and serum creatinine (110 mol/l, range 69–284, vs 108 mol, range 72–1024) compared with patients not developing coronary heart disease. However, the patients with coronary heart disease had higher blood pressure (135/87mmHg±16/9 vs 128/82±15/7, p<0.05) and serum cholesterol (7.3 mmol/l+ 1.2 vs 6.4 mmol/l±0.9, p<0.05) than patients without coronary heart disease. Thus, patients developing clinical nephropathy have a highly increased incidence of coronary heart disease compared with patients not developing nephropathy. Patients who developed coronary heart disease were characterized by higher blood pressure and serum cholesterol.     

Enhanced hepatic insulin sensitivity,but peripheral insulin resistance in patients with Type 1 (insulin-dependent) diabetes

Summary Sensitivity to insulin in vivo was studied in 8 normal weight C-peptide negative Type 1 (insulin-dependent) diabetic patients (age 23±1 years, diabetes duration 6±2 years), and in 8 age, weight and sex matched healthy subjects, using the euglycaemic clamp and 3-³H-glucose tracer technique. Prior to the study diabetic patients were maintained normoglycaemic overnight by a glucose controlled insulin infusion. Sequential infusions of insulin in 3 periods of 2 h resulted in mean steady state insulin levels of 12±2 versus 11±1, 18±2 versus 18±2 and 28±3 versus 24±2 U/ml in diabetic patients and control subjects. Corresponding glucose utilization rates were 2.4±0.2 versus 2.4±0.1, 2.4±0.2 versus 3.0±0.3 and 2.9±0.3 versus 4.6±O.6 mg·kg^–1·min^–1, p<0.02. Portal insulin values in the three periods were calculated to 12±2 versus 25±3, 18±2 versus 32±3 and 28±3 versus 37±3 U/ml in the diabetic patients and control subjects using peripheral insulin and C-peptide concentrations and assuming a portal to peripheral insulin concentration gradient of 1 in diabetic patients and of 2.4 in control subjects. Corresponding glucose production rates were 2.5±0.2 versus 2.4±0.1, 1.6±0.1 versus 0.9±0.2 and 0.7±0.1 versus 0.4±0.2 mg·kg^–1·min^–1. Using this approach the insulin dose-response curve for the peripheral glucose utilization was right-ward shifted, while the dose-response curve for the hepatic glucose production as a function of portal insulin levels was left-ward shifted. We conclude that in vivo insulin action is increased in the liver but decreased in peripheral tissues in insulin treated Type 1 diabetic patients. Presumably these oppositely directed changes in insulin action are acquired defects, secondary to the present mode of peripheral insulin treatment.     

Social status and the quality of care for adult people with Type I (insulin-dependent) diabetes mellitus – a population-based study

Summary The objective of this study was to assess the degree of diabetes care and education achieved for Type I (insulin-dependent) diabetes mellitus at the community level in relation to social status and to elucidate potential pathways that mediate any social class gradient. A population-based sample of 684 adults with Type I diabetes (41 % women, mean ± SD age 36 ± 11, diabetes duration 18 ± 11 years) in the district of North-Rhine (9.5 million inhabitants), Germany, were examined in their homes using a mobile ambulance. Results: HbA_1c (normal 4.3–6.1 %) 8.0 ± 1.5 %, incidence of severe hypoglycaemia (injection of glucose or glucagon) 0.21 cases per patient-year; 62 % of patients had participated in a structured group treatment and teaching programme for intensification of insulin therapy; 70 % used 3 or more insulin injections per day, 9 % were on continuous subcutaneous insulin infusion; 91 % reported to have had measurements of HbA_1c during the preceding year, and 80 % to have had an examination of the retina by an ophthalmologist. Care was insufficient with respect to the quality of blood pressure control (70 % of patients on antihypertensive drugs had blood pressure values ≥ 160/95 mmHg), patient awareness of proteinuria/albuminuria (27 % of patients had not heard about it) and prevention of foot complications (only 42 % with a diabetes duration over 10 years had remembered to have a foot examination during the preceding 12 months). There was a pronounced social gradient with respect to micro- and macrovascular complications (prevalence of overt nephropathy 7 vs 20 % for highest vs lowest quintiles of social class [OR 3.5, 95 % CI 1.6–7.5, p = 0.002]) and diabetes-specific quality of life. HbA_1c, blood pressure and smoking accounted for part of the association between social class and microvascular complications. The social class gradient was not due to inequality to access to health services, but to lower acceptance among low social class patients of preventive and health maintaining behaviour. In conclusion, achieved standards of care are high with respect to the implementation of intensified treatment regimens, the level of patient education achieved, treatment control and eye care, whereas areas for improvement are blood pressure control and preventive measures for foot care. A substantial social gradient in diabetes care persists despite equal access of patients to health services. [Diabetologia (1998) 41: 1139–1150] Received: 29 September 1997 and in revised form: 8 April 1998