HLA class II alleles in Norwegian patients with coexisting type 1 diabetes and celiac disease.

BACKGROUND: Type 1 diabetes (T1D) and celiac disease (CeD) are 2 distinct diseases, but there is an increased risk of developing CeD for T1D patients. Both diseases are associated with HLA-class II alleles, such as DQB1 *02:01 and DQB1 *03:02; however, their risk contribution vary between the diseases. MATERIALS AND METHODS: We genotyped HLA-DRB1 and - DQB1 in 215 patients with coexisting T1D and CeD identified from a T1D cohort, and compared them to patients with T1D (N = 487) and CeD (N = 327), as well as healthy controls (N = 368). RESULTS: The patients with coexisting T1D and CeD had an intermediate carrier frequency (72.8%) of the DRB1 *03:01- DQB1 *02:01- DQA1 *05:01 haplotype compared to T1D (64.1%) and CeD (88.7%) patients. The DRB1 *03:01- DQB1 *02:01- DQA1 *05:01/ DRB1 *04- DQB1 *03:02- DQA1 *03 haplotype combination, encoding DQ2.5 and DQ8 molecules, was equally frequent among patients with both T1D and CeD (52.6%) and T1D patients (46.8%) but significantly lower in CeD patients (9.5%). CONCLUSION: Overall, the patients with coexisting T1D and CeD had an HLA profile more similar to T1D patients than CeD patients.

Coxsackie-adenovirus receptor expression is enhanced in pancreas from patients with type 1 diabetes.

OBJECTIVES: One of the theories connecting enterovirus (EV) infection of human islets with type 1 diabetes (T1D) is the development of a fertile field in the islets. This implies induction of appropriate proteins for the viral replication such as the coxsackie-adenovirus receptor (CAR). The aim of this study was to investigate to what extent CAR is expressed in human islets of Langerhans, and what conditions that would change the expression. DESIGN: Immunohistochemistry for CAR was performed on paraffin-embedded pancreatic tissue from patients with T1D (n=9 recent onset T1D, n=4 long-standing T1D), islet autoantibody-positive individuals (n=14) and non-diabetic controls (n=24) individuals. The expression of CAR was also examined by reverse transcription PCR on microdissected islets (n=5), exocrine tissue (n=5) and on explanted islets infected with EV or exposed to chemokines produced by EV-infected islet cells. RESULTS: An increased frequency of patients with T1D and autoantibody-positive individuals expressed CAR in the pancreas (p<0.039). CAR staining was detected more frequently in pancreatic islets from patients with T1D and autoantibody-positive subjects (15/27) compared with (6/24) non-diabetic controls (p<0.033). Also in explanted islets cultured in UV-treated culture medium from coxsackievirus B (CBV)-1-infected islets, the expression of the CAR gene was increased compared with controls. Laser microdissection of pancreatic tissue revealed that CAR expression was 10-fold higher in endocrine compared with exocrine cells of the pancreas. CAR was also expressed in explanted islets and the expression level decreased with time in culture. CBV-1 infection of explanted islets clearly decreased the expression of CAR (p<0.05). In contrast, infection with echovirus 6 did not affect the expression of CAR. CONCLUSIONS: CAR is expressed in pancreatic islets of patients with T1D and the expression level of CAR is increased in explanted islets exposed to proinflammatory cytokines/chemokines produced by infected islets. T1D is associated with increased levels of certain chemokines/cytokines in the islets and this might be the mechanism behind the increased expression of CAR in TID islets.

The associations between maternal pre-pregnancy body mass index or gestational weight change during pregnancy and body mass index of the child at 3 years of age.

OBJECTIVE: To estimate the associations between maternal pre-pregnancy body mass index (BMI) or gestational weight change (GWC) during pregnancy and offspring BMI at 3 years of age, while taking several pre-and postnatal factors into account. DESIGN: The Norwegian Mother and Child Cohort Study is a population-based pregnancy cohort study of women recruited from all geographical areas of Norway. SUBJECTS: The study includes 31 169 women enrolled between 2000 and 2009 through a postal invitation sent to women at 17-18 weeks of gestation. Data collected from 5898 of the fathers were included. MAIN OUTCOME MESURES: Offspring BMI at 3 years was the main outcome measured in this study. RESULTS: Mean maternal pre-pregnancy BMI was 24.0 kg m(-2) (s.d. 4.1), mean GWC in the first 30 weeks of gestation was 9.0 kg (s.d. 4.1) and mean offspring BMI at 3 years of age was 16.1 kg m(-2) (s.d. 1.5). Both maternal pre-pregnancy BMI and GWC were positively associated with mean offspring BMI at 3 years of age. Pre-pregnancy BMI and GWC also interacted, and the strength of the interaction between these two factors was strongly associated with the increase in offspring BMI among mothers who gained the most weight during pregnancy and had the highest pre-pregnancy BMI. Our findings show that results could be biased by not including pre-pregnant paternal BMI. CONCLUSION(S): This large population-based study showed that both maternal pre-pregnancy BMI and GWC were positively associated with mean offspring BMI at 3 years of age.

A TLR2 polymorphism is associated with type 1 diabetes and allergic asthma.

Type 1 diabetes (T1D) and allergic asthma are immune-mediated diseases. Pattern recognition receptors are proteins expressed by cells in the immune system to identify microbial pathogens and endogenous ligands. Toll-like receptors (TLRs) and CD14 are members of this family and could represent a molecular link between microbial infections and immune-mediated diseases. Diverging hypotheses regarding whether there exists a common or inverse genetic etiology behind these immune-mediated diseases have been presented. We aimed to test whether there exist common or inverse associations between polymorphisms in the pattern recognition receptors TLR2, TLR4 and CD14 and T1D and allergic asthma. Eighteen single nucleotide polymorphisms (SNPs) were genotyped in TLR2 (2), TLR4 (12) and CD14 (4) in 700 T1D children, 357 nuclear families with T1D children and 796 children from the 'Environment and Childhood Asthma' study. Allele and haplotype frequencies were analyzed in relation to diseases and in addition transmission disequilibrium test analyses were performed in the family material. Both T1D and allergic asthma were significantly associated with the TLR2 rs3804100 T allele and further associated with the haplotype including this SNP, possibly representing a susceptibility locus common for the two diseases. Neither TLR4 nor CD14 were associated with T1D or allergic asthma.

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families.

The main genetic predisposition to type 1 diabetes (T1D) is known to be conferred by the HLA-DRB1, -DQA1 and -DQB1 genes in the major histocompatibility complex (MHC). Other genetic factors within this complex are known to contribute, but their identity has often been controversial. This picture is shared with several other autoimmune diseases (AIDs). Moreover, as common genetic factors are known to exist between AIDs, associations reported with other AIDs may also be involved in T1D. In this study, we have used these observations in a candidate gene approach to look for additional MHC risk factors in T1D. Using complementary conditional methods (involving conditional logistic regression and family-based haplotype tests) and analyses of linkage disequilibrium (LD) patterns, we confirmed association for alleles of the HLA-A and HLA-B genes and found preliminary evidence for a novel association of a single-nucleotide polymorphism (rs2259571) in the AIF1 gene, independent of the DRB1-DQA1-DQB1 genes and of each other. However, no evidence of independent associations for a number of previously suggested candidate polymorphisms was detected. Our results illustrate the importance of a comprehensive adjustment for LD effects when performing association studies in this complex.

Sweets, snacking habits, and skipping meals in children and adolescents on intensive insulin treatment.

AIM: To examine the association between skipping meals and snacking events and dietary and clinical characteristics in children and adolescents using modern insulin treatment. METHODS: Dietary intake was recorded for 4 d in food diaries in 655 young diabetic patients. Number of meals and snacking events was recorded in a separated questionnaire, while clinical data were obtained from case record forms. Skipping meals refer to consuming a main meal (e.g., breakfast) five times a week or less. RESULTS: Modern insulin treatment may favor a more flexible lifestyle. This study shows that there are fewer young diabetic patients who skip meals than non-diabetic controls (p < 0.001) even when using modern intensified insulin treatment. However, skipping meals among young diabetic patients was associated with negative characteristics such as having suboptimal hemoglobin A1c (HbA1c) (OR 4.7, p = 0.02), higher low-density lipoprotein (LDL) cholesterol levels (OR 4.0, p < 0.001), watching more TV (OR 3.6, p < 0.001), being overweight (OR 2.8, p = 0.03), as well as having a higher intake of added sugar (OR 2.1, p = 0.01) and lower intake of fiber (OR 0.2, p = 0.04) compared with those not skipping meals. Having more than two snacking events during the day was associated with higher HbA1c, higher intake of added sugar and sweets, and spending more hours in front of the TV or personal computer. CONCLUSIONS: In general, fewer children and adolescents with type 1 diabetes skip meals compared with healthy peers. Those who skip meals and have more snacking events have poorer glycemic control and less healthy dietary and leisure habits.

Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes.

BACKGROUND/HYPOTHESIS: HLA, INS, PTPN22 and CTLA4 are considered to be confirmed type 1 diabetes susceptibility genes. HLA, PTPN22 and CTLA4 are known to be involved in immune regulation. Few studies have systematically investigated the joint effect of multiple genetic variants. We evaluated joint effects of the four established genes on the risk of childhood-onset type 1 diabetes. METHODS: We genotyped 421 nuclear families, 1,331 patients and 1,625 controls for polymorphisms of HLA-DRB1, -DQA1 and -DQB1, the insulin gene (INS, -23 HphI), CTLA4 (JO27_1) and PTPN22 (Arg620Trp). RESULTS: The joint effect of HLA and PTPN22 on type 1 diabetes risk was significantly less than multiplicative in the case-control data, but a multiplicative model could not be rejected in the trio data. All other two-way gene-gene interactions fitted multiplicative models. The high-risk HLA genotype conferred a very high risk of type 1 diabetes (OR 20.6, using the neutral-risk HLA genotype as reference). When including also intermediate-risk HLA genotypes together with risk genotypes at the three non-HLA loci, the joint odds ratio was 61 (using non-risk genotypes at all loci as reference). CONCLUSION: Most established susceptibility genes seem to act approximately multiplicatively with other loci on the risk of disease except for the joint effect of HLA and PTPN22. The joint effect of multiple susceptibility loci conferred a very high risk of type 1 diabetes, but applies to a very small proportion of the general population. Using multiple susceptibility genotypes compared with HLA genotype alone seemed to influence the prediction of disease only marginally.

High prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes: a population-based study.

AIMS/HYPOTHESIS: The risk of dying of cardiovascular disease (CVD) before the age of 40 years is increased nearly 20-fold in patients with type 1 diabetes compared with non-diabetic persons. The aim of this study was to evaluate the prevalence of CVD risk factors in a population-based study of children and adolescents with type 1 diabetes. METHODS: CVD risk factors were examined according to the American Diabetes Association criteria in 2005. Of 26 paediatric clinics in Norway, 25 participated with 1,658 patients, 85% of those eligible. Mean age was 13.1 years and mean diabetes duration 5.7 years. RESULTS: HbA(1c) was above the target level in 71.4%. A positive family history of early CVD and/or diabetes was found in 33% of participants. LDL-cholesterol was >2.6 mmol/l in 34.5% and HDL-cholesterol was <1.1 mmol/l in 6.9% of participants. Blood pressure was above the 90th percentile by age, sex and height in 7% and above the 95th percentile in 4% of participants. Four per cent of participants were obese, 3% of those >or=12 years of age reported smoking and 1% of all participants had persistent microalbuminuria. Only 0.2% of the patients were receiving statin and 0.3% anti-hypertensive treatments. Dietary habits and physical activity level were evaluated in some patients. Almost all had higher intake of dietary fat and lower intake of fibre than recommended. A large part was less active and watched more TV than recommended. CONCLUSIONS/INTERPRETATION: Of the participants, 86% had at least one, 45% at least two and 15% at least three CVD risk factors. Few patients were treated with statins and anti-hypertensive drugs.

The FCRL3 -169T>C polymorphism is associated with rheumatoid arthritis and shows suggestive evidence of involvement with juvenile idiopathic arthritis in a Scandinavian panel of autoimmune diseases.

BACKGROUND AND OBJECTIVES: The Fc receptor-like 3 (FCRL3) gene -169T>C single nucleotide polymorphism (SNP) has been reported to be associated with several autoimmune diseases (AIDs) in Japanese populations. However, association results in other populations have been conflicting. Therefore, we investigated this SNP in a Scandinavian panel of AIDs. METHODS: We genotyped patients with rheumatoid arthritis (RA; n = 708), juvenile idiopathic arthritis (JIA; n = 524), systemic lupus erythaematosus (SLE; n = 166), ulcerative colitis (UC; n = 335), primary sclerosing cholangitis (PSC; n = 365), Crohn disease (CD; n = 149), a healthy control group (n = 1030) and 425 trio families with type 1 diabetes (T1D). Statistical analysis consisted of case-control and family-based association tests. RESULTS: RA was associated with the C allele (odds ratio (OR) = 1.16, 95% CI 1.01 to 1.33) and the CC genotype (OR = 1.30, 95% CI 1.01 to 1.67) of the FCRL3 -169T>C SNP in our material. Suggestive evidence for association was also found for JIA (CC genotype: OR = 1.30, 95% CI 0.99 to 1.70), and clinical subgroup analysis indicated that this was connected to the polyarticular subgroup. No significant association was found with SLE, UC, CD, PSC or T1D. In patients with RA, we found no significant interaction between the FCRL3 -169T>C and PTPN22 1858C>T SNPs, nor between the FCRL3 -169CC genotype and IgM-rheumatoid factor or anti-cyclic citrullinated peptide titre levels. CONCLUSION: We found an association between the FCRL3 -169T>C SNP and RA, and suggestive evidence for involvement with JIA, in a Norwegian population. These findings lend support for a role for this SNP in RA across ethnically diverse populations, and warrant follow-up studies in JIA.

The influence of dietary intake and meal pattern on blood glucose control in children and adolescents using intensive insulin treatment.

AIMS/HYPOTHESIS: We studied dietary factors and their association with blood glucose control in type 1 diabetic children and adolescents using intensive insulin treatment. MATERIALS AND METHODS: A total of 550 children and adolescents with type 1 diabetes mellitus (age 2-19 years) recorded their diet for 4 days in pre-coded food diaries. Of the study group, 34% used insulin pumps, 43% used four or more injections and 16% three injections per day. HbA(1c) was related to targets of optimal blood glucose control defined by the International Society for Pediatric and Adolescent Diabetes (ISPAD). RESULTS: Adolescents with optimal glucose control (HbA(1c) < or = 7.5%) had a lower intake of added sugar (7.7 vs 9.1% of energy intake, p = 0.004), a higher intake of fibre (19.3 vs 17.0 g/day, p = 0.01) and a higher intake of fruits and vegetables (257 vs 227 g/day, p = 0.04) than those with suboptimal metabolic control (HbA(1c) > 7.5%). Multiple regression analysis in adolescents showed that fibre and meal pattern were significantly associated with blood glucose control (effect fibre intake = -0.02, p = 0.04, effect having breakfast regularly = -0.89, p = 0.009). In children meal pattern was associated with blood glucose control (effect having dinner regularly = -0.66, p = 0.02, effect having supper regularly = -0.78, p = 0.03). CONCLUSIONS/INTERPRETATION: In diabetic adolescents both intake of fibre and having a regular meal pattern are associated with blood glucose control. Lower intake of added sugar and sugar-sweetened soft drinks and higher intake of fruits and vegetables are observed among those with optimal compared with those with suboptimal blood glucose control. Dietary guidance should be intensified during adolescence to improve dietary intake and blood glucose control.

Children and adolescents with type 1 diabetes eat a more atherosclerosis-prone diet than healthy control subjects.

AIMS/HYPOTHESIS: We evaluated how well the diet of Norwegian children and adolescents with type 1 diabetes fulfils the Nordic and European dietary recommendations, focusing on parameters affecting prevention of atherosclerosis. We also compared the diet of this patient group with that of healthy same-age control subjects. MATERIALS AND METHODS: A total of 177 children and adolescents with type 1 diabetes (9-10-year-olds, 12-13-year-olds) and 1,809 healthy same-age control subjects recorded their food intake for 4 days in precoded food diaries. RESULTS: In children and adolescents with type 1 diabetes the percentage of energy (E%) from fat (33-35 E%) and saturated fat (14-15 E%) was higher than recommended for that group. Furthermore their intake of fibre was lower (16-19 g/day) than current recommendations. There were no differences in energy intake between diabetic subjects and healthy control subjects. Percentage of energy from fat (mean difference: 3.4 E%, p < 0.001) and saturated fat (mean difference: 1.0 E%, p < 0.001) was significantly higher among diabetic subjects than control subjects. Intake of fruits and vegetables was low (210 g/day) compared with recommendations, both in the diabetic and control subjects. CONCLUSIONS/INTERPRETATION: Diabetic children and adolescents had a high intake of energy from saturated fat and low intake of fibre, fruits and vegetables, which could increase the risk of development of atherosclerosis. This study supports the idea that nutritional guidance in the treatment of children and adolescents with type 1 diabetes should be more focused, especially with regard to intake of fibre, fruits and vegetables and to quality and quantity of fat intake.

Atherosclerosis in childhood and adolescent type 1 diabetes: early disease, early treatment?

Autopsy studies have shown that atherosclerosis begins in adolescence in otherwise healthy individuals, and imaging techniques have shown that atherosclerosis develops earlier and is more prevalent in children with diabetes than in age-matched healthy controls. Cardiovascular disease has now overtaken diabetic nephropathy as the leading cause of premature mortality in young adults with diabetes, and the emphasis on disease prevention has accordingly shifted to a younger age group. The majority of children and adolescents with diabetes have suboptimal blood glucose control, and this contributes to accelerated arterial disease in this age group. Other conventional risk factors for coronary heart disease also need to be considered and treated aggressively. Effective early prevention of cardiovascular disease will involve lifestyle modification and full implementation of existing treatment guidelines, and large-scale prospective studies will be needed to establish the risks and benefits of early pharmacological intervention in children and adolescents.

Mean HbA1c over 18 years predicts carotid intima media thickness in women with type 1 diabetes.

AIMS/HYPOTHESIS: Intima media thickness (IMT) of the common carotid artery (CCA) is a validated surrogate marker of early atherosclerosis. The aim of our study was to assess the association between IMT in CCA and long-term mean HbA1c in type 1 diabetes. We also elucidated the association between carotid IMT and preclinical coronary atherosclerosis. METHODS: In 39 individuals with type 1 diabetes, HbA1c was measured prospectively over 18 years. The IMT examinations were performed with high-resolution ultrasound. The association between carotid IMT and preclinical coronary atherosclerosis (assessed by intravascular ultrasound [IVUS]) was tested in 29 of the patients. RESULTS: Mean HbA1c over 18 years was 8.2% (range: 6.6-11.3%). Mean age at follow-up after 18 years was 43 years and mean duration of diabetes was 30 years. IMT was significantly higher in diabetic patients than in an age- and sex-matched reference population. The IMT values were at the same level as for controls who were 20 years older. In women, HbA1c was significantly associated with mean average CCA IMT (r2=0.77, p<0.0001 when adjusted for age), whereas there was no significant association for men. Among women, a significant association was also found between carotid IMT and the percentage of coronary vessel area stenosis (r=0.65, p=0.03). CONCLUSIONS/INTERPRETATION: The present findings suggest an important role of long-term hyperglycaemia in the development of atherosclerosis, especially in women with type 1 diabetes. Type 1 diabetes patients have earlier development of, and more advanced, atherosclerosis compared with an age- and sex-matched reference population. In women, carotid IMT reflects preclinical coronary atherosclerosis.

[Genetic and immunologic risks for development of type 1 diabetes--experiences from an intervention trial]. / Genetisk og immunologisk risiko for type 1-diabetes--erfaringer fra en intervensjonsstudie. Norsk studiegruppe for barnediabetes.

BACKGROUND: Type 1 diabetes is a common multi-factorial disease. Recently, promising attempts have been made at preventing the disease in individuals at risk. We present our experiences as participants in an international multicentre intervention trial, the European Nicotinamide Diabetes Intervention Trial (ENDIT). The aim is to prevent prediabetic individuals from becoming overtly diabetic by the use of nicotinamide. MATERIAL AND METHODS: First degree relatives of type 1 diabetes children attending paediatric clinics in Norway were recruited. The level of islet cell antibodies (ICA) was determined. Individuals with ICA titer above 20 Juvenile Diabetes Foundation Units (JDFU) were allocated to treatment with nicotinamide or placebo in a double-blind design. In the Norwegian patients in the trial HLA-DQ genotypes were also determined. RESULTS: 56 individuals had ICA > 20 JDFU; 36 agreed to participate in the trial. Assessment of genetic and immunological risk did not seem to emotionally upset the majority of participants; so far, no serious adverse events have been observed. The final results of this trial are expected in year 2003. INTERPRETATION: Prevention of type 1 diabetes may be feasible in the future.

Modern insulin therapy in children and adolescents.

Clear evidence exists that near-normal blood glucose control will prevent serious late diabetic complications. This review summarizes the targets for blood glucose control and discusses why insulin replacement therapy is so complicated in children and adolescents. It is important that diabetes treatment teams have excellent knowledge of insulin preparations, insulin pharmacokinetics and action profiles and the limitations and pitfalls of therapy. This is necessary to be able to optimize and individualize treatment. A detailed summary of different insulin regimens is given and discussed to help treatment teams choose a suitable regimen for the individual patient. The use of home blood glucose measurement is necessary to reach the targets of treatment. If economic resources are limited, alternative strategies are suggested. In wealthy countries the lifestyle of adolescents demands great flexibility and a suggestion for systematic training to increase flexibility in daily life is presented.

The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene.

The human leukocyte antigen (HLA) complex, encompassing 3.5 Mb of DNA from the centromeric HLA-DPB2 locus to the telomeric HLA-F locus on chromosome 6p21, encodes a major part of the genetic predisposition to develop type 1 diabetes, designated "IDDM1." A primary role for allelic variation of the class II HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci has been established. However, studies of animals and humans have indicated that other, unmapped, major histocompatibility complex (MHC)-linked genes are participating in IDDM1. The strong linkage disequilibrium between genes in this complex makes mapping a difficult task. In the present paper, we report on the approach we have devised to circumvent the confounding effects of disequilibrium between class II alleles and alleles at other MHC loci. We have scanned 12 Mb of the MHC and flanking chromosome regions with microsatellite polymorphisms and analyzed the transmission of these marker alleles to diabetic probands from parents who were homozygous for the alleles of the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes. Our analysis, using three independent family sets, suggests the presence of an additional type I diabetes gene (or genes). This approach is useful for the analysis of other loci linked to common diseases, to verify if a candidate polymorphism can explain all of the association of a region or if the association is due to two or more loci in linkage disequilibrium with each other.

The advanced glycation end product Nepsilon-(carboxymethyl)lysine is increased in serum from children and adolescents with type 1 diabetes.

OBJECTIVE: To investigate whether children and adolescents with type 1 diabetes have increased serum levels of the glycoxidation product Nepsilon-(carboxymethyl)lysine (CML) at an early stage of the disease. RESEARCH DESIGN AND METHODS: The serum levels of CML in 38 patients with type 1 diabetes aged 14+/-3.2 (mean+/-SD) years were compared with those in 26 control subjects aged 16+/-1.7 years. The mean duration of diabetes was 5+/-4.7 years, ranging from 0.5 to 15 years. The mean levels of HbA1c were 10.3+/-2.5% in the patient group. The serum levels of CML were measured using a monoclonal anti-CML antibody in a fluoremetric immunoassay. Serum protein levels of advanced glycation end products (AGEs) were assayed using a polyclonal antibody from rabbit immunized with AGE-RNase (pAGE). RESULTS: The serum levels of CML and pAGE were significantly increased in the patient group versus the control group: 1.08 (0.45-2.97) U/ml CML (median 10-90 percentiles) vs. 0.70 (0.36-1.79) U/ml CML, P < 0.03, and 6.6 (5.1-9.9) U/ml pAGE vs. 5.5 (3.7-8.2) U/ml AGEs, P < 0.01. A significant relationship between CML and pAGE was found in the IDDM group, r = 0.76, P < 0.001. The CML levels were not associated with the HbAlc levels (n = 23, r = -0.02, NS), cholesterol levels (n = 21, r = 0.07, NS), age, sex, or diabetes duration. CONCLUSIONS: Serum levels of CML are increased in patients with type 1 diabetes. This increase precedes the development of micro- and macrovascular complications.

Diabetic microangiopathy.

Microvascular complications of diabetes include retinopathy, nephropathy and neuropathy. The first signs of these complications may develop in children and adolescents, particularly if insulin treatment has been inadequate. The mechanisms by which diabetic microangiopathy develop are not known, but probably include genetic influences. Several biochemical changes may interact, one important change being increased protein glycation. Important functional changes are increased organ blood flow, increased vascular permeability, abnormal blood viscosity and abnormal platelet and endothelial function. The structural hallmark of diabetic microangiopathy is the thickening of the capillary basement membrane. These changes may lead to occlusive angiopathy and to tissue hypoxia and damage. Screening for microangiopathy should start in children and adolescents after 5-y duration of the disease and 10y of age. The screening should include retinal examination through a dilated pupil or fundus photography, urinary albumin excretion rate, blood pressure measurement and neurological examination. Several intervention trials have shown that near normoglycaemia may reduce the risk of microangiopathy. There is a curvilinear association between the risk of development and progression of microangiopathy and mean blood glucose. Therefore, optimal insulin treatment is important in children and adolescents.

Biochemical markers of diabetic microangiopathy. Past, present and future.

The first signs of diabetic microvascular complications in the eyes and kidney, and early signs of neuropathy, may develop in children and adolescents. The development and progression of such complications are clearly related to blood glucose control. The mechanisms by which microangiopathy develops are not exactly known, and there are no excellent biochemical markers with high predictive value for future microangiopathy. The best available markers today are HbA1c and the urinary albumin excretion. New biochemical markers related to advanced glycation end products (AGEs), and recently possible genetic markers, have been described. The predictive value of single markers and the combination of such markers has to be tested in long term clinical studies.