Long-term risk of IDDM in first-degree relatives of patients with IDDM

Summary Due to a short observation period previous studies may have underestimated prevalence and recurrence risk of IDDM in relatives of IDDM patients. To obtain a more exact life-time risk estimate we identified 310 probands, representative of Danish IDDM patients, characterized by current age more than 50 years, age at onset 40 years or less and diabetes duration of more than 30 years. Family data were obtained from 291 probands. Mean observation times (age) (± SD) for siblings (n = 553) and offspring (n=359) were 59.4 ± 16.1 years and 33.8 ± 8.8 years, respectively. Of the probands 73 (25.1%) had at least one first-degree relative with IDDM. Seventeen percent had at least one affected sibling. An increase from 10.4% to 22.4% of having first-degree relatives with IDDM among probands with age at onset below 20 years was observed during the period from proband at age 21 years up to 1 September 1992. Among affected siblings 48% of the second cases were affected more than 10 years after the first affected sibling. Using the life-table method cumulative recurrence risks from time of birth were calculated for siblings up to age 30 years of 6.4% and up to age 60 years of 9.6%. For offspring the risk up to age 34 years was 6.3%. In addition, we present a life-table method evaluating the cumulative recurrence risk from time of onset in the proband, as this is the most relevant when giving genetic counselling. In conclusion, the long-term risks of IDDM in siblings and offspring are high compared to that shown in previous reports.Abbreviations IDDM insulin-dependent diabetes mellitus - SE standard error     

Evidence for importance of gender and birth cohort for risk of IDDM in offspring of IDDM parents

Summary The risk of developing diabetes is higher in offspring of fathers than of mothers with insulin-dependent diabetes mellitus (IDDM). The reasons for this sex differential are unclear, as early studies were often selected and relatively small. We conducted a prospective study on the risk of IDDM in a cohort of 9,453 offspring from 5,255 Finnish parents with diabetes diagnosed before age 30 years. Age of first admission to the hospital was considered to be the age of diagnosis of IDDM in the offspring; IDDM occurred in 248 offspring. The risk of IDDM tended to be lower in the offspring of the same gender as the diabetic parent (adjusted risk ratio (RR) 0.78; p=0.50). When offspring were of same gender as the diabetic parent, male offspring had a higher risk of IDDM than female offspring (RR 2.28; 95% confidence interval 1.53–3.38), whereas if the gender of the diabetic parent and the offspring were different, the risk in male offspring was lower (RR 0.43; 95% confidence interval 0.31–0.62). For the offspring of diabetic fathers, the cumulative risk by the age of 20 was higher (7.6%) than for those with diabetic mothers (3.5%) (p<0.0001). In a multivariate analysis statistically significant predictors of IDDM in the offspring were the sex of the parent, the year of birth and the birth order of the offspring. The risk of IDDM in the offspring increased by 9% per year of birth cohort. By age 20, the cumulative risk of developing IDDM in the offspring of diabetic parents was 5.3%, 10 times higher than in the background population. It is likely that genetic factors seem to have played a major role in the continuous increase of IDDM incidence in Finnish children.Abbreviations IDDM Insulin-dependent diabetes mellitus - CI confidence interval - RR risk ratio     

Intramuscular triglyceride content is increased in IDDM

Summary Increased lipid oxidation is related to insulin resistance. Some of the enhanced lipid utilization may be derived from intramuscular sources. We studied muscle triglyceride (mTG) concentration and its relationship to insulin sensitivity in 10 healthy men (age 29 ± 2 years, BMI 23.3 ± 0.6 kg/m²) and 17 men with insulin-dependent diabetes mellitus (IDDM) (age 30 ± 2 years, BMI 22.8 ± 0.5 kg/m², diabetes duration 14 ± 2 years, HbA_{1 c} 7.7 ± 0.3 %, insulin dose 48 ± 3 U/day). Insulin sensitivity was measured with a 4 h euglycaemic (5 mmol/l) hyperinsulinaemic (1.5 mU or 9 pmol · kg^–1· min^–1) clamp accompanied by indirect calorimetry before and at the end of the insulin infusion. A percutaneous biopsy was performed from m. vastus lateralis for the determination of mTG. At baseline the IDDM patients had higher glucose (10.2 ± 0.9 vs 5.6 ± 0.1 mmol/l, p < 0.001), insulin (40.3 ± 3.2 vs 23.2 ± 4.2 pmol/l, p < 0.01), HDL cholesterol (1.28 ± 0.06 vs 1.04 ± 0.03 mmol/l, p < 0.01) and mTG (32.9 ± 4.6 vs 13.6 ± 2.7 mmol/kg dry weight, p < 0.01) concentrations than the healthy men, respectively. The IDDM patients had lower insulin stimulated whole body total (–25 %, p < 0.001), oxidative (–18 %, p < 0.01) and non-oxidative glucose disposal rates (–43 %, p < 0.001), whereas lipid oxidation rate was higher in the basal state ( + 44 %, p < 0.01) and during hyperinsulinaemia ( + 283 %, p < 0.05). mTG concentrations did not change significantly during the clamp or correlate with insulin stimulated glucose disposal. In healthy men mTG correlated positively with lipid oxidation rate at the end of hyperinsulinaemia (r = 0.75, p < 0.05). In conclusion: 1) IDDM is associated with increased intramuscular TG content. 2) mTG content does not correlate with insulin sensitivity in healthy subjects or patients with IDDM. [Diabetologia (1998) 41: 111–115] Received: 12 June 1997 and in revised form: 8 September 1997     

The prevalence of IDDM in the first degree relatives of children newly diagnosed with IDDM in Austria--a population-based study. Austrian Diabetes Incidence Study Group.

Insulin dependent diabetes mellitus shows a strong familial predisposition and an unexplained geographical variation in incidence. It is not known whether the risk of IDDM in first degree relatives depends on the risk in the background population. The aim of the study was to assess the prevalence of IDDM in parents and siblings of newly diagnosed children with IDDM in Austria, a known area of low risk for IDDM. The family history data of all diabetic children (< 15 years) diagnosed between 1988-1994 in Austria were analysed. The cumulative incidence of IDDM in siblings of newly diagnosed diabetic children was 0.0026772 cases/year, this means 29.7 times increased risk compared to the background population. Of the diabetic children 5.8% had at least one parent with IDDM and the prevalence of IDDM in fathers (3.9%) was higher (p = 0.015) compared to mothers (1.9%).The risk of IDDM tended to be higher for offsprings of diabetic fathers (OR 3.8, p < 0.003) in families with 2 or more children than in single child families, where the prevalence was 4.2% both in fathers and mothers. In conclusion the prevalence of IDDM in parents of diabetic children in Austria was lower than reported in populations with high IDDM incidence. This may reflect a lesser degree of genetic predisposition of the Austrian population. The prevalence of IDDM in siblings was similar to that in high risk populations. We saw an interaction of gender of the diabetic parent and diabetic offspring and the family size.     

Glucose tolerance and insulin secretion in children of mothers with pregestational IDDM or gestational diabetes

Summary The offspring of mothers with diabetes mellitus during pregnancy are presumed to develop altered glucose homeostasis. We analysed metabolic parameters at birth and glucose tolerance and insulin secretion during oral glucose tolerance tests at 1–9 years of age in 129 children born to mothers with pregestational insulin-dependent diabetes (IDDM) and 69 infants of gestational diabetic mothers. Newborns of IDDM mothers displayed higher insulin (p < 0.001), glucose (p < 0.05), and insulin/glucose ratios (p < 0.002) than newborns of gestational diabetic mothers. During childhood, frequencies of impaired glucose tolerance (IGT) rose in infants of IDDM mothers from 9.4 % at 1–4 years to 17.4 % at 5–9 years of age, while in children of gestational diabetic mothers an increase from 11.1 % up to 20.0 % was observed. Offspring of gestational diabetic mothers displayed higher stimulated blood glucose (p < 0.025) than infants of IDDM mothers, while children of IDDM mothers showed higher stimulated insulin (p < 0.025), accompanied by increased fasting and stimulated insulin/glucose ratios (p < 0.05 and p < 0.02, respectively). Stimulated insulin in childhood was positively correlated to insulin at birth (p < 0.05). Furthermore, insulin/glucose ratio in childhood showed a positive correlation to insulin (p < 0.01) and insulin/glucose ratio at birth (p < 0.005). In conclusion, a pathogenetic role of fetal and neonatal hyperinsulinism for the development of IGT in both groups of infants of diabetic mothers is suggested, in particular for early induction of insulin resistance in the offspring of mothers with pregestational IDDM. [Diabetologia (1997) 40: 1097–1100] Received: 24 February 1997 and in revised form: 7 May 1997     

Enhanced G protein activation in IDDM patients with diabetic nephropathy

Summary Genetic susceptibility contributes significantly to the risk of developing nephropathy in insulin-dependent diabetes mellitus (IDDM). The cellular substrate for this has remained enigmatic. We investigated whether afflicted IDDM patients display an enhanced activation of pertussis toxin (PTX)-sensitive G proteins, a phenomenon which has been demonstrated in patients with essential hypertension. We established immortalised B lymphoblast cell lines from 10 IDDM patients without nephropathy (DC) and 15 IDDM patients with nephropathy (DN). Nephropathy was defined as a persistent albumin excretion rate of more than 20 μg/min (DC 3.9 ± 5.8, DN 562.3 ± 539.0 μg/min, respectively). Subjects were matched with regard to age (DC 28.9 ± 6.5, DN 35.9 ± 9.9 years), diabetes duration (DC 19.3 ± 6.9, DN 22.7 ± 5.8 years) and HbA_{1 c} values (DC 8.5 ± 1.4, DN 8.8 ± 1.6 %). Reactivity of PTX-sensitive G proteins was quantified by measuring platelet-activating factor (PAF)-induced Ca^{2 +} mobilisation (fura 2 method) and by mastoparan-stimulated [³⁵S]GTPγS binding. Expression of Gα_i proteins was quantified by Western blot analysis. PAF-evoked Ca^{2 +} increases above baseline averaged 77.0 ± 52.5 nmol/l in DC and 150.7 ± 61.5 nmol/l in DN (p = 0.005). PAF-evoked Ca^{2 +} increases correlated with stimulated [³⁵S]GTPγS binding (r ² = 0.42, p = 0.012). From Western blot analysis an overexpression of Gα_i proteins could be excluded in DN. A consequence of the altered metabolic milieu in diabetes is the increased release of vasoactive and proliferative agonists which promote glomerular hyperfiltration, hypertrophy, enhanced matrix deposition, and, finally, glomerulosclerosis. Many of these auto- and paracrine agonists bind to G protein-coupled receptors. Therefore, their cellular effects are reinforced by the enhanced G protein reactivity and increase the propensity to nephropathy in IDDM. [Diabetologia (1998) 41: 94–100] Received: 9 May 1997 and in revised form: 3 September 1997     

IDDM2/insulin VNTR modifies risk conferred by IDDM1/HLA for development of Type 1 diabetes and associated autoimmunity

AIM/HYPOTHESIS: Type 1 diabetes (T1D) is an autoimmune disease with multiple susceptibility genes. The aim of this study was to determine whether combining IDDM1/HLA and IDDM2/ insulin( INS) 5' variable number of tandem repeat locus (VNTR) genotypes improves T1D risk assessment. METHODS: Patients with T1D (n=488), control subjects (n=846), and offspring of parents with T1D (n=1122) were IDDM1 and IDDM2 genotyped. Offspring were followed for islet autoantibodies and T1D from birth until the age of 2 to 12 years. RESULTS: Compared to the I/I INS VNTR genotype, the I/III and III/III genotypes reduced T1D risk conferred by IDDM1/HLA in all HLA genotype categories of the case-control cohort by 1.6-fold to three-fold. The highest T1D risk was associated with INS VNTR class I/I plus HLA DR3/DR4-DQ8 (20.4% in patients, 0.6% in control subjects) or HLA DR4-DQ8/DR4-DQ8 (6.3% in patients, 0.2% in control subjects). In the offspring, HLA DR3/DR4-DQ8 and DR4-DQ8/DR4-DQ8 conferred increased risk for early development of islet autoantibodies (14.6% and 12.9% by age 2 years). Offspring with these high risk IDDM1 genotypes plus the INS VNTR class I/I genotype (n=71; 6.3%) had the highest risk of developing islet autoantibodies (21.8% by age 2 years vs 8.9% in offspring with high risk IDDM1 plus INS VNTR class I/III or III/III genotypes, p<0.05) and T1D (8.5% by age 6 years vs 4.3%). Offspring who developed autoantibodies to multiple antigens had increased frequencies of both high risk IDDM1 and IDDM2 genotypes (p<0.0001), whereas offspring who developed autoantibodies to GAD only had increased frequencies of high risk IDDM1 and protective IDDM2 genotypes, suggesting that IDDM2 influences the autoimmune target specificity. CONCLUSION/INTERPRETATION: Combining IDDM1 and IDDM2 genotyping identifies a minority of children with an increased T1D risk.     

Difference in the influence of maternal and paternal NIDDM on pancreatic beta-cell activity and blood lipids in normoglycaemic non-diabetic adult offspring

Summary The 75-g oral glucose tolerance test was performed in 38 normoglycaemic (World Health Organization criteria) non-diabetic volunteers, aged 31–40 years, of whom 20 had a non-insulin-dependent diabetic (NIDDM) mother and 18 had an NIDDM father. At the time of the study the offspring of NIDDM mothers had a somewhat higher body mass index (BMI) (males: 26.5 ± 1.0 (mean ± SEM), females: 27.5 ± 1.5 kg/m²) than the offspring of NIDDM fathers (males: 23.4 ± 0.9, females: 24.2 ± 1.2 kg/m²). There was no difference in the time-course of glycaemia; however the serum concentrations of immunoreactive insulin (IRI), C-peptide and proinsulin were significantly higher in offspring of NIDDM mothers than in offspring of NIDDM fathers: area under the curve (AUC) serum IRI: 0.928 ± 0.091 vs 0.757 ± 0.056 nmol · l^–1· h^–1, p = 0.019; serum C-peptide: 6.379 ± 0.450 vs 4.753 ± 0.242 nmol · l^–1· h^–1, p = 0.004; serum proinsulin: 172 ± 40 vs 51 ± 7 pmol · l^–1· h^–1, p = 0.008). Serum IRI correlated with BMI, but C-peptide and proinsulin did not, and after accounting for BMI by covariance analysis they remained significantly higher in offspring of NIDDM mothers. In this group serum proinsulin was significantly higher in male than in female offspring (AUC serum proinsulin: 289 ± 68 vs 77 ± 27 pmol · l^–1· h^–1, P = 0.015). Male offspring of NIDDM mothers also had significantly higher serum triglyceride levels than females of the same group and than offspring of NIDDM fathers. The offspring (male and female) of NIDDM mothers had slightly lower serum apolipoprotein A-I levels than the offspring of NIDDM fathers. Significant correlations were found between serum triglycerides, HDL-cholesterol and apolipoprotein B, and serum concentrations of pancreatic beta-cell peptides, mostly in the offspring of NIDDM mothers; however, they did not display unequivocal association with gender within this group. The data are consistent with clinical observations of a greater risk of NIDDM transmission from the mother than from the father, and may suggest that male offspring are more exposed to this risk than female offspring. [Diabetologia (1996) 39: 831–837] Received: 2 June 1995 and in final revised form: 19 January 1996     

Familial factors determine the development of diabetic nephropathy in patients with IDDM

Summary To evaluate familial factors in the development of diabetic nephropathy in insulin-dependent diabetes mellitus (IDDM) we examined concordance for diabetic nephropathy in families with multiple IDDM siblings. Families (n=110) were identified through Joslin Clinic patients (probands) with a sibling having IDDM. To be eligible, the probands' and siblings' ages at IDDM diagnosis were less than 21 years, and IDDM duration was more than 15 years for probands and more than 10 years for siblings. Mean post-pubertal diabetes duration was 23 years for probands (n=110) and 21 years for siblings (n=125). Nephropathy history was determined by medical record review for deceased patients and those with persistent proteinuria or end-stage renal disease to ascertain the date of onset of persistent proteinuria. For patients without documented nephropathy, the albumin/creatinine ratio was measured in multiple urine samples. The cumulative incidence of persistent proteinuria according to post-pubertal duration of IDDM was determined by life-table analysis. For probands and siblings combined, the cumulative incidence of advanced diabetic nephropathy after 30 years of IDDM was 35%, but the risk in siblings varied according to the proband's renal status. The cumulative risk in siblings after 25 years of IDDM (post-puberty) was 71.5% if the proband had persistent proteinuria but only 25.4% if the proband did not (p<0.001). A difference of nearly 50% in the risk to IDDM siblings, depending upon the IDDM proband's renal status, is consistent with a major gene effect that predisposes an individual with IDDM to develop advanced diabetic nephropathy.Abbreviations IDDM Insulin-dependent diabetes mellitus - C.I. confidence interval     

Reduced beta cell function in offspring of mothers with young-onset type 2 diabetes

Aims/hypothesis Animal models indicate that even exposure to mild maternal hyperglycaemia in utero is detrimental to the beta cell function of the offspring, but evidence of this in humans is limited. In Europids who are diagnosed with type 2 diabetes before the age of 50 years, the risk of diabetes in the offspring of the diabetic mothers is greatly increased compared with the risk in those born to diabetic fathers. We hypothesised that offspring born to mothers with young-onset type 2 diabetes would have been exposed to mild hyperglycaemia in utero, so we studied the impact of this on their beta cell function.Subjects and methods We measured beta cell function using early insulin response (EIR) after oral glucose; insulin resistance using HOMA; and HbA_1c in 568 non-diabetic adult offspring born to parents with type 2 diabetes (mean age 55.8 years), split according to which parent was affected (in 327 it was the mother) and parental age of diagnosis: <50 years (n=117) or ≥50 years. To reduce the impact of genetic susceptibility, the offspring of affected fathers were used as control subjects.Results Offspring of mothers with young-onset type 2 diabetes had lower EIR (log EIR 4.32, 95% CI [4.14–4.51] vs 4.63 [4.43–4.83] p=0.02) and higher HbA_1c (4.89% [4.79–4.99] vs 4.68% [4.57–4.79] p=0.02) than the offspring of fathers with young-onset type 2 diabetes. Insulin sensitivity was similar in the two groups. There were no differences in EIR or HbA_1c between the offspring born to mothers and fathers who were diagnosed after the age of 50 years.Conclusions/interpretation We conclude that the offspring of mothers with young-onset type 2 diabetes have a reduction in beta cell function. This is consistent with exposure to mild maternal hyperglycaemia programming beta cell function.     

Is autonomic neuropathy a risk factor for severe hypoglycaemia? The EURODIAB IDDM Complications Study

Summary The hypothesis that diabetic patients with autonomic neuropathy are at increased risk of severe hypoglycaemia was examined in an epidemiological study of over 3000 IDDM patients in Europe (EURODIAB IDDM Complications Study). Autonomic function was assessed by two standard cardiovascular tests: change in heart rate and systolic blood pressure on standing. Severe hypoglycaemia was defined as an attack serious enough to require the help of another person. Compared to patients (68 %) reporting no attacks in the last year, those reporting one or more attacks were older (34.0 ± 10.7 vs 32.1 ± 9.9 years, mean ± SD, p < 0.0001), had had diabetes for a longer period (16.6 ± 9.5 vs 13.8 ± 9.1 years, p < 0.0001), had better glycaemic control (HbA_1c 6.4 ± 1.8 vs 6.9 ± 1.9 %, p < 0.0001) and were more likely (p = 0.002) to have abnormal responses to both autonomic tests (13.0 vs 7.7 %). A single abnormal autonomic response was not associated with an increased risk of severe hypoglycaemia. The odds ratio for severe hypoglycaemia in people with abnormal responses to both autonomic tests, compared to those with normal responses, was 1.7 (95 % confidence interval 1.3, 2.2) after controlling for age, duration of diabetes, glycaemic control and study centre. In conclusion, a combined autonomic deficit in heart rate and blood pressure responses to standing is associated with only a modest increase in the risk of severe spontaneous hypoglycaemia. Although the increase in risk is not large, severe hypoglycaemia was a frequently reported event in this study. IDDM patients with deficient autonomic responses who strive for tight glycaemic control may therefore be at particular risk of severe hypoglycaemia. [Diabetologia (1996) 39: 1372–1376] Received: 28 December 1995 and in final revised form: 11 June 1996     

Assessment of baroreceptor-cardiac reflex sensitivity using time domain analysis in patients with IDDM and the relation to left ventricular mass index

Summary Autonomic dysfunction in insulin-dependent diabetic (IDDM) patients has been associated with abnormalities of left ventricular function and an increased risk of sudden death. A group of 30 patients with IDDM and 30 age, sex and blood pressure matched control subjects underwent traditional tests of autonomic function. In addition, baroreceptor-cardiac reflex sensitivity (BRS) was assessed using time domain (sequence) analysis of systolic blood pressure and pulse interval data recorded non-invasively using the Finapres beat-to-beat blood pressure recording system. ’Up BRS' sequences–increases in systolic blood pressure associated with lengthening of R-R interval, and ’down BRS' sequences–decreases in systolic blood pressure associated with shortening of R-R interval were identified and BRS calculated from the regression of systolic blood pressure on R-R interval for all sequences. We also assessed heart rate variability using power spectral analysis and, after expressing components of the spectrum in normalised units, assessed sympathovagal balance from the ratio of low to high frequency powers. IDDM subjects underwent 2-D echocardiography to assess left ventricular mass index. Standard tests of autonomic function revealed no differences between IDDM patients and control subjects, but dramatic reductions in baroreceptor-cardiac reflex sensitivity were detected in IDDM patients. ’Up BRS' when supine was 11.2 ± 1.5 ms/mmHg (mean ± SEM) compared with 20.4 ± 1.95 in control subjects (p < 0.003) and when standing was 4.1 ± 1.9 vs 7.6 ± 2.7 ms/mmHg (p < 0.001). Down BRS when supine was 11.5 ± 1.2 vs 22 ± 2.6 (p < 0.001) and standing was 4.4 ± 1.9 vs 7.3 ± 2.5 ms/mmHg (p < 0.003). There were significant relations between impairment of the baroreflex and duration of diabetes (p < 0.001) and poor glycaemic control (p < 0.001). From a fast Fourier transformation of supine heart rate data and using a band width of 0.05–0.15 Hz as low-frequency and 0.2–0.35 Hz as high frequency total spectral power of R-R interval variability was significantly reduced in the IDDM group for both low-frequency (473 ± 62.8 vs 746.6 ± 77.6 ms² p = 0.002) and high frequency bands 125.2 ± 12.9 vs 459.3 ± 89.8 ms² p < 0.0001. When the absolute powers were expressed in normalised units the ratio of low frequency to high frequency power (a measure of sympathovagal balance) was significantly increased in the IDDM group (2.9 ± 0.53 vs 4.6 ± 0.55, p < 0.002 supine: 3.8 ± 0.49 vs 6.6 ± 0.55, p < 0.001 standing). Thus, time domain analysis of baroreceptor-cardiac reflex sensitivity detects autonomic dysfunction more frequently in IDDM patients than conventional tests. Impaired BRS is associated with an increased left ventricular mass index and this abnormality may have a role in the increased incidence of sudden death seen in young IDDM patients. [Diabetologia (1996) 39: 1385–1391] Received: 9 April 1996 and in revised form: 19 July 1996     

Prospective study of development of microalbuminuria and retinopathy in Brazilian IDDM patients

With the aim to study potential risk factors for the development of microalbuminuria and retinopathy, baseline characteristics were examined in 50 Brazilian IDDM patients folowed for 4.48 years with a 2-year reexamination. During the study, 3 patients (6%) aged 25.9 ± 4.4 years, duration of diabetes 8.1 ± 4.2 years, died from acute complications without microalbuminuria and retinopathy after a follow-up of 2.1 ± 0.7 years. The standardized mortality rate for the group was 0.84 per 1000 (95% CL, 0.31, 1.83) in comparison to 0.14 per 1000 in the general population. From 34 normoalbuminuric individuals ate baseline (urinary albumin excretion rate (AER) ≤ 20 μg/min in ≥ 2 overnight urine collections), 10 developed microalbuminuria with an incidence density of 6.5 cases per 100 person-years (95%CL, 2.23, 10.16). Spontaneous normalization of AER was found in 2 of 4 patients with microalbuminuria at cycle 2. Multiple stepwise regression analysis demonstrated that baseline AET (p = 0.03), but not glycated hemoglobin, blood pressure or duration of diabetes, predicted end-of-study AER. From 36 patients without retinopathy, 10 developed nonproliferative retinopathy with an incidence density of 6.6 cases per 100 person-years (95%CL, 2.85, 10.54). Retinopathy was associated with duration (p = 0.05) and age at diagnosis of diabetes (p = 0.01). A tendency with baseline AER (p = 0.06) was also noted. No patient developed macroalbuminuria, proliferative retinopathy or hypertension. By the end of our study, in a cohort of young IDDM patients followed in a developing country, 6% died from acute complications and 15 patients (44.1%) developed retinopathy and/or microalbuminuria. Our results suggest that the only predictor of end-of-study AER was baseline AER. Also, duration of diabetes and age at diagnosis appear to be risk factors for retinopathy. Received: 22 May 1999 / Accepted in revised form: 3 March 2000     

Activated platelets in subjects at increased risk of IDDM

Summary Activated platelets respond to activated leukocytes and endothelial cells via adhesion molecules linking inflammation and thrombosis. Platelets of recent-onset insulin-dependent diabetic (IDDM) patients have been shown to be activated independent of metabolic control. This study evaluates the levels of circulating activated platelets exposing adhesion molecules in healthy subjects at increased risk of IDDM (surface markers were: P-selectin (CD62), thrombospondin, lysosomal GP53 (CD63) ). From the DENIS and the ENDIT screening programmes 19 identified islet cell antibody positive (titre ≥ 20 Juvenile Diabetes Foundation units) first degree relatives of IDDM patients (male/female 9/10; age 22 ± 15 years; body mass index (BMI): 20.0 ± 4.3 kg/m²) with clearly normal metabolism (HbA₁: 6.1 ± 0.8 %; fasting blood glucose: 4.95 ± 0.67 mmol/l) were available for this investigation. Platelet CD62 as well as thrombospondin and CD63 expression were determined by flow cytometry. We matched 50 normal volunteers for age (29 ± 6 years), anthropometric measures (male/female 26/24; BMI: 22.3 ± 2.8 kg/m²) and metabolic parameters (HbA₁: 5.8 % ± 0.3; fasting blood glucose: 4.41 ± 0.53 mmol/l) served as control subjects. The mean number of CD62⁺ platelets was increased 3.2-times in prediabetic patients: 1.94 × 2.91^±1 vs 0.60 × 1.83^±1 %, p < 0.0001. Thrombospondin⁺ and CD63⁺ platelet levels were concomitantly increased (1.45 × 2.38^±1/5.97 × 2.89^±1 % vs 0.52 × 2.01^±1/1.64 × 2.26^±1 %, p < 0.0001 for both comparisons). Thus, intravasal platelet activation is already present in potentially prediabetic subjects representing an antecedent, potentially pathogenic feature of IDDM. [Diabetologia (1997) 40: 573–577] Received: 6 September 1996 and in revised form: 16 January 1997     

A Case-control Study of Environmental Factors Associated with Diabetes in the Under 5s

In 1992 a national case–control study was conducted through the British Paediatric Association Surveillance Unit (BPASU) framework to evaluate both the incidence of IDDM in children under 5 in that year and the effects of various putative trigger factors in the disease pathogenesis. A total of 218 sets of matched case–control questionnaire data established that paternal IDDM (odds ratio (OR) = 16.11, 95 % confidence interval (CI) 1.94–133.7, p < = 0.001) is independently associated with increased risk, and higher birth order (OR = 0.64, CI 0.44–0.94, p = 0.021) and paternal age greater than 25 years (age 25–39 OR = 0.52, CI 0.30–0.89; age 40 + OR = 0.23, CI 0.08–0.67, p = 0.009) with decreased risk of diabetes. Other factors previously implicated in the disease pathogenesis (birthweight, parental socio–economic status, infant feeding, and immunization record) showed no significant independent association with disease development. © 1997 by John Wiley & Sons, Ltd.     

Altered properties of the fibrin gel structure in patients with IDDM

Summary High plasma fibrinogen levels are associated with vascular complications in the general population. Fibrin, the structural element in a clot, is derived from fibrinogen by activation of thrombin. An abnormal fibrin gel structure has been demonstrated in patients with myocardial infarction and in diabetic patients during poor metabolic control. In the present study the properties of fibrin gel structure were investigated in 20 patients with insulin-dependent diabetes mellitus (IDDM): 10 patients without (age: 30 ± 8; diabetes duration: 7 ± 6 years), and 10 patients (age: 44 ± 7; diabetes duration: 27 ± 9 years) with microangiopathy. Fifteen healthy subjects served as controls (age: 40 ± 8 years). The glycosylated haemoglobin level (HbA_1c) was elevated (p < 0.001) in the patients: 6.5 ± 1.5 % in diabetic patients without, and 7.1 ± 1.0 % in diabetic patients with microangiopathy. C-reactive protein and plasma fibrinogen were similar as compared to healthy control subjects. The properties of the fibrin gel structure; i. e. the permeability coefficient (Ks) and the fibre mass length ratio (μ) formed in recalcified plasma on addition of thrombin were investigated. Ks was decreased in the diabetic patients, with (6.5 ± 2.0 cm²; p < 0.01) and without microangiopathy (6.5 ± 2.7 cm²; p < 0.05), as compared to healthy subjects (10.0 ± 3.4 cm²), while μ was not significantly (p = 0.14) altered. The results indicate a lower fibrin gel porosity in patients with IDDM, despite normal plasma fibrinogen and irrespective of microangiopathy. The abnormal fibrin gel structure may be due to an increased glycosylation of the fibrin (-ogen) molecule caused by long-term hyperglycaemia and may be of importance for the development of angiopathy in diabetic patients. [Diabetologia (1996) 39: 1519–1523] Received: 7 May 1996 and in revised form: 9 September 1996     

High prevalence of risk factors for cardiovascular disease in parents of IDDM patients with albuminuria

Summary Life expectancy is shorter in the subset of insulin-dependent diabetic (IDDM) patients who are susceptible to kidney disease. Familial factors may be important. In this study the prevalence of cardiovascular disease mortality and morbidity and of risk factors for cardiovascular disease was compared in the parents of 31 IDDM patients with elevated albumin excretion rate (AER > 45 μg/min; group A) with that of parents of 31 insulin-dependent diabetic patients with normoalbuminuria (AER < 20 μg/min; group B). The two diabetic patient groups were matched for age and duration of disease. Information on deceased parents was obtained from death certificates and clinical records and morbidity for cardiovascular disease was ascertained using the World Health Organization questionnaire and Minnesota coded ECG. Hyperlipidaemia was defined as serum cholesterol higher than 6 mmol/l and/or plasma triglycerides higher than 2.3 mmol/l and/or lipid lowering therapy; arterial hypertension as systolic blood pressure higher than 140 mmHg and/or diastolic blood pressure higher than 90 mmHg and/or antihypertensive treatment. The percentage of dead parents was similar in the two groups (26 vs 20 % for parents of group A vs group B, respectively), but the parents of the diabetic patients with elevated AER had died at a younger age (58 ± 10 vs 70 ± 14 years; p < 0.05). Parents of diabetic patients with nephropathy had a more than three times greater frequency of combined mortality and morbidity for cardiovascular disease than that of the parents of diabetic patients without nephropathy (26 vs 8 %; odds ratio 3.96, 95 % CI 1.3 to 12.2; p < 0.02). Living parents of group A had a higher prevalence of arterial hypertension (42 vs 14 % p < 0.01) and hyperlipidaemia (49 vs 26 % p < 0.05) as well as higher levels of lipoprotein (a) [median (range) 27.2 (1–107) vs 15.6 (0.2–98) mg/dl; p < 0.05]. They also had reduced insulin sensitivity [insulin tolerance test: median (range) K_itt index: 3.7 (0.7–6.2) vs 4.8 (0.7–6.7)% per min; p < 0.05]. In the families of IDDM patients with elevated AER there was a higher frequency of risk factors for cardiovascular disease as well as a predisposition to cardiovascular disease events. This may help explain, in part, the high prevalence of cardiovascular disease mortality and morbidity in those IDDM patients who develop nephropathy. [Diabetologia (1997) 40: 1191–1196] Received: 4 March 1997 and in revised form: 9 May 1997     

24-h ambulatory blood pressure and retinopathy in normoalbuminuric IDDM patients

Summary The role of blood pressure elevation in the incidence and progression of diabetic retinopathy is not clearly established and results have been conflicting. Blood pressure and urinary albumin excretion (UAE) are closely related. In order to evaluate the independent relationship between retinopathy and blood pressure elevation, precise information on UAE is essential, as confounding by renal disease (incipient or overt), cannot otherwise be excluded.The aim of the present study was to evaluate the association between diabetic retinopathy and 24-h ambulatory blood pressure (AMBP) in a group of well-characterized normoalbuminuric IDDM patients. In 65 normoalbuminuric (UAE < 20 μg/min) IDDM patients we performed 24-h AMBP (Spacelabs 90 207) with readings at 20-min intervals. Fundus photographs were graded independently by two experienced ophthalmologists. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. HbA_{1 c} was determined by HPLC. Tobacco use and level of physical activity were assessed by questionnaire. Fifteen patients had no detectable retinal changes [grade 1], 35 had grade 2 retinopathy; and 15 had more advanced retinopathy [grade 3–6]. Diastolic night blood pressure was significantly higher in patients with diabetic retinopathy compared to patients without retinopathy (68 ± 8 mmHg [grade 3–6] and 65 ± 6 mmHg [grade 2], compared to 61 ± 4 mmHg [grade 1], p = 0.02). Diurnal blood pressure variation was significantly blunted in the patients with retinopathy as indicated by a higher night/day ratio of diastolic blood pressure (84.6 % ± 4 [grade 3–6], and 81.2 % ± 6 [grade 2] compared to 79.1 % ± 4 [grade 1], p = 0.01). Heart rate tended to be higher in patients in group 2 and 3–6 compared to patients without retinopathy with p values of 0.07 and 0.11 for day-time and 24 h values, respectively. Mean HbA_{1 c} increased significantly with increasing levels of retinopathy (p < 0.01). Patients were similar regarding sex, age, tobacco use, and level of physical activity. Notably, UAE was almost identical in the three groups (5.0 × /÷1.7 [grade 1], 3.9 × /÷1.8 [grade 2], and 5.1 × /÷1.6 μg/min [grade 3–6]). In conclusion, night blood pressure is higher and circadian blood pressure variation blunted in patients with retinopathy compared to patients without retinopathy despite strict normoalbuminuria and similar UAE levels in the groups compared. Our data suggest that the association between blood pressure and diabetic retinopathy is present also when coexisting renal disease is excluded. Disturbed diurnal variation of blood pressure is a pathophysiological feature related to the development of both retinopathy and nephropathy in IDDM patients. [Diabetologia (1998) 41: 105–110] Received: 27 May 1997 and in revised form: 5 September 1997     

IA-2 antibodies – a sensitive marker of IDDM with clinical onset in childhood and adolescence

Summary To study the relationship of IA-2 antibodies (IA-2A) to other autoantibodies and genetic risk markers in insulin-dependent diabetes mellitus (IDDM), 758 children and adolescents younger than 15 years of age (mean age 8.4 years) with newly diagnosed diabetes were analysed for IA-2A, GAD antibodies (GADA) and insulin autoantibodies (IAA) with radiobinding assays, for islet cell antibodies (ICA) with immunofluorescence and for HLA DR alleles by serology. IA-2A were detected in 85.9 % of cases with no association with gender or age. An overwhelming majority of the patients (71.3 %) tested positive for three or more antibodies, and 90.7 % for at least two. Fifty-four subjects (7.1 %) had one antibody detectable, whereas only 2.1 % of the patients tested negative for all four. A higher proportion of patients was positive for IA-2A and/or GADA than for ICA alone (95.5 vs 84.2 %, p < 0.001). The prevalence and level of IA-2A were increased in cases carrying HLA DR4/non-DR3 compared with other DR combinations. The results indicate that almost all patients with newly diagnosed childhood IDDM can be identified by screening with these four autoantibodies. The combination of IA-2A and/or GADA had a higher sensitivity for IDDM than ICA alone. The close association between IA-2A and HLA DR4, the strongest single allele predisposing to IDDM, suggests that IA-2A may be a more specific marker of beta-cell destruction than GADA, which have been shown to associate with the DR3 allele and thyroid autoimmunity. [Diabetologia (1998) 41: 424–429] Received: 20 August 1997 and in final revised form: 13 November 1997     

Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance

Summary The ability of hyperglycaemia to enhance glucose uptake was evaluated in 9 non-insulin-dependent (NIDDM), 7 insulin-dependent (IDDM) diabetic subjects, and in 6 young and 9 older normal volunteers. Following overnight insulin-induced euglycaemia, a sequential three-step hyperglycaemic clamp (+ 2.8 + 5.6, and + 11.2 mmol/l above baseline) was performed with somatostatin plus replacing doses of basal insulin and glucagon, 3-³H-glucose infusion and indirect calorimetry. In the control subjects as a whole, glucose disposal increased at each hyperglycaemic step (13.1 ± 0.6, 15.7 ± 0.7, and 26.3 ± 1.1 μmol/kg · min). In NIDDM (10.5 ± 0.2, 12.1 ± 1.0, and 17.5 ± 1.1 μmol/kg · min), and IDDM (11.2 ± 0.8, 12.9 ± 1.0, and 15.6 ± 1.1 μmol/kg · min) glucose disposal was lower during all three steps (p < 0.05–0.005). Hepatic glucose production declined proportionally to plasma glucose concentration to a similar extent in all four groups of patients. In control subjects, hyperglycaemia stimulated glucose oxidation (+ 4.4 ± 0.7 μmol/kg · min) only at + 11.2 mmol/l (p < 0.05), while non-oxidative glucose metabolism increased at each hyperglycaemic step (+ 3.1 ± 0.7; + 3.5 ± 0.9, and + 10.8 ± 1.7 μmol/kg · min; all p < 0.05). In diabetic patients, no increment in glucose oxidation was elicited even at the highest hyperglycaemic plateau (IDDM = + 0.5 ± 1.5; NIDDM = + 0.2 ± 0.6 μmol/kg · min) and non-oxidative glucose metabolism was hampered (IDDM = + 1.8 ± 1.5, + 3.1 ± 1.7, and + 4.3 ± 1.8; NIDDM = + 0.7 ± 0.6, 2.1 ± 0.9, and + 7.0 ± 0.8 μmol/kg · min; p < 0.05–0.005). Blood lactate concentration increased and plasma non-esterified fatty acid (NEFA) fell in control (p < 0.05) but not in diabetic subjects. The increments in blood lactate were correlated with the increase in non-oxidative glucose disposal and with the decrease in plasma NEFA. In conclusion: 1) the ability of hyperglycaemia to promote glucose disposal is impaired in NIDDM and IDDM; 2) stimulation of glucose oxidation and non-oxidative glucose metabolism accounts for glucose disposal; 3) both pathways of glucose metabolism are impaired in diabetic patients; 4) impaired ability of hyperglycaemia to suppress plasma NEFA is present in these patients. These results suggest that glucose resistance, that is the ability of glucose itself to promote glucose utilization, is impaired in both IDDM and NIDDM patients. [Diabetologia (1997) 40: 687–697] Received: 20 August 1996 and in revised form: 5 March 1997