Could the high consumption of high glycaemic index carbohydrates and sugars, associated with the nutritional transition to the Western type of diet, be the common cause of the obesity epidemic and the worldwide increasing incidences of Type 1 and Type 2 diabetes?

The globally increasing incidences of Type 1 diabetes (T1DM) and Type 2 diabetes (T2DM) can have a common background. If challenged by the contemporary high level of nutritional glucose stimulation, the ß-cells in genetically predisposed individuals are at risk for damage which can lead to the diseases. The fat to carbohydrate dietary shift can also contribute to the associated obesity epidemic.

Atherogenic vascular and lipid phenotypes in young patients with Type 1 diabetes are associated with diabetes high-risk HLA genotype.

Expression of human leukocyte antigen (HLA) class II molecules on islet endothelial cells is a central vascular event in the pathogenesis of Type 1 diabetes. Previous studies demonstrated the ability of other vascular endothelial cells to express HLA and thereby to process islet autoantigens on their surface. We investigated whether the HLA-DQ2/8 genotype, which confers the highest risk for Type 1 diabetes, is associated with early atherosclerosis in youths with this disease. Brachial artery endothelium-dependent, flow-mediated dilation (BA-FMD) and carotid artery intima-media thickness (CA-IMT), as well as markers of systemic inflammation [C-reactive protein (CRP), fibrinogen, and orosomucoid], HbA(1C), LDL, HDL, and total cholesterol, were assessed in 86 children and adolescents with Type 1 diabetes (mean age and diabetes duration, 15 and 7 yr, respectively) between 2004 and 2006. HLA genotypes were determined in dried blood spots by an oligoblot hybridization method. As a result, HLA-DQ2/8 was detected in 34 patients (DQ2/8). When this group was compared with the remaining patients (non-DQ2/8, n = 52), there were no differences in age, diabetes duration, HbA(1C), body mass index, inflammatory markers, and IMT (P > or = 0.4). In the DQ2/8 group, LDL-to-HDL ratio was elevated compared with that in the non-DQ2/8 group (1.8 vs. 1.3, respectively; P = 0.001), whereas FMD did not significantly differ between the groups (5.3% vs. 6.7%, respectively; P = 0.08). When patients were further categorized in relation to CRP (cut-off value, 1 mg/l), BA-FMD was significantly lower (3%, P < 0.01), whereas LDL-to-HDL ratio increased further (2.2, P < 0.001) in the subgroup of DQ2/8 and CRP > or = 1 patients compared with the remaining three subgroups. These associations remained significant after adjustment for age, diabetes duration, and HbA(1C) by analysis of covariance. The brachial artery responses to nitroglycerine were similar in all subgroups. In conclusion, the diabetes-predisposing HLA-DQ2/8 genotype in children and adolescents with Type 1 diabetes interferes with endothelial and lipid-related mechanisms of early atherosclerosis, possibly in part through inflammatory pathways.

Rapid genetic analysis in congenital hyperinsulinism.

BACKGROUND: In severe, medically unresponsive congenital hyperinsulinism (CHI), the histological differentiation of focal versus diffuse disease is vital, since the surgical management is completely different. Genetic analysis may help in the differential diagnosis, as focal CHI is associated with a paternal germline ABCC8 or KCNJ11 mutation and a focal loss of maternal chromosome 11p15, whereas a maternal mutation, or homozygous/compound heterozygous ABCC8 and KCNJ11 mutations predict diffuse-type disease. However, genotyping usually takes too long to be helpful in the absence of a founder mutation. METHODS: In 4 patients, a rapid genetic analysis of the ABBC8 and KCNJ11 genes was performed within 2 weeks on request prior to the decision of pancreatic surgery. RESULTS: Two patients had no mutations, rendering the genetic analysis non-informative. Peroperative multiple biopsies showed diffuse disease. One patient had a paternal KCNJ11 mutation and focal disease confirmed by positron emission tomography scan and biopsies. One patient had a de novo heterozygous ABBC8 mutation and unexplained diffuse disease confirmed by positron emission tomography scan and biopsies. CONCLUSION: A rapid analysis of the entire ABBC8 and KCNJ11 genes should not stand alone in the preoperative assessment of patients with CHI, except for the case of maternal, or homozygous/compound heterozygous disease-causing mutations.

Pore size and charge selectivity of the glomerular membrane at the time of diagnosis of diabetes.

The urinary albumin excretion rate is increased at the time of diagnosis of diabetes. We investigated whether this is caused by change in pore size or charge selectivity in the glomerular basement membrane. Urine excretion of immunoglobulins (IgG2, IgG4), glycosaminoglycans (GAG), and albumin was analyzed during the first 20 days after diagnosis of diabetes in children aged 4-15 years; 36 diabetic and 24 age-matched apparently healthy children were included. The excretion of albumin was significantly increased on day 1 in the diabetic children. Between day 1 and 20 the excretion of IgG2 and IgG4 decreased significantly from normal to a level below normal. GAG excretion was not affected. The GAG/creatinine index (GAGCI) was normal. IgG2CI was significantly below normal on days 4-20. IgG4CI was below normal on days 2-20. The albumin creatinine index decreased significantly from day 1 to normal levels on day 4-20. A charge selectivity index, expressed as the ratio between the neutrally charged IgG2 and the negatively charged IgG4, was significantly below the normal level on days 16 and 20. In conclusion, an increased albumin excretion rate in urine did not seem to be caused by a change in charge selectivity. Other explanations such as change in the small pore radius or tubular reabsorption are suggested.

Metabolic status in diabetes mellitus affects markers for glomerular filtration rate.

The present study was performed in newly diagnosed diabetic children to evaluate the effect of metabolic derangement on routine tests for glomerular filtration rate (GFR). Children with ( n=16) and without ( n=10) ketonuria at diagnosis of diabetes followed a routine clinical treatment program. Serum creatinine, creatinine clearance, serum cystatin C, and iohexol clearance were analyzed at diagnosis and after 20 days of treatment. Iohexol clearance was used as the "true GFR". Serum creatinine and iohexol clearances were not affected by the acute metabolic status or ketonuria. In contrast, serum cystatin C was significantly influenced by ketonuria. Creatinine clearance was an unreliable marker for GFR both in the more deranged and in the balanced metabolic situation.

Parent responses to participation in genetic screening for diabetes risk.

Screening for type 1 diabetes (T1DM) risk in newborns has little negative emotional impact on mothers. In this study, the impact on the mother and the father was evaluated both in the general population and in families with diabetes. All parents with a newborn in Skane, Sweden, were invited to a screening for T1DM risk in their children (the Diabetes Prediction in Skane (DiPiS)). Blood was obtained at delivery from the mother and the child. When the child was 2 months old, parents gave written consent and filled out questionnaires, but were not informed about the genetic risk. Of the 10 538 invited families, 6831 (64.8%) consented and 806 (7.7%) declined participation. Five questions addressing both parents were filled out by 6676 (63.4%) mothers and 6099 (57.8%) fathers. In 146/6676 (2.2%) families, one family member had diabetes (D-families). Participation in DiPiS did not affect most parents and the majority was satisfied with the information. The majority of parents (28.9%) were reassured and only 1.1% (140/12,670) reported increased worries because of participation, compared to 2.8% of the mothers in D-families. Parents in D-families more often ascribed diabetes risk to their child as well as the risk being higher. Mothers and fathers differed in their answers on four of the five study questions, with mothers being more satisfied with the information, reporting more knowledge of diabetes, estimating lower risk of their child to get diabetes, but reporting more worries of possible future chronic disease in the child. Parents with lower education, being born abroad, or being younger who reported worries of chronic disease in the child were also reassured by participation in the study. These results confirm that screening for T1DM risk in newborns does not create worries in most parents, but stress that fathers differ from mothers in opinions and reactions, that parents' reactions are affected by diabetes in the family, and that demographic factors might be important for the parents' reports.

Genetic and perinatal factors as risk for childhood type 1 diabetes.

The mechanisms by which gestational infections, blood incompatibility, birth weight, mother's age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population-based prospective studies. The possibility of identifying children at type 1 diabetes risk among first-degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first-degree relative with the disease. Population-based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skåne), which is examining a total of about 10,000 pregnancies expected every year in the Skåne (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high-risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase-related IA-2 antigen (IA-2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high-risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes.