Increased maternal Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) associated with older age at diagnosis of Type 1 diabetes in offspring.

AIMS: Obesity and insulin resistance have been linked to rising incidence and earlier onset of Type 1 diabetes. Inherited differences in insulin action might also influence the evolution of Type 1 diabetes.Our aim was to determine whether parental BMI and insulin resistance influences age of onset of Type 1 diabetes in their offspring. METHODS: BMI standard deviation score and age at diagnosis of Type 1 diabetes was examined in 227 children, and in 206 of these was compared with local matched control subjects. Non-diabetic parents of a subgroup of 80 children with Type 1 diabetes were recruited. Parental BMI was compared with local adult control subjects. The relationship between parental BMI, waist-hip ratio, homeostasis model assessment of insulin resistance (HOMA-IR), leptin and adiponectin levels and age at diagnosis of Type 1 diabetes in offspring was examined. RESULTS: We found no relationship between age at diagnosis of Type 1 diabetes in children and BMI standard deviation score (P = 0.5). Children with Type 1 diabetes and their parents were heavier than matched control subjects (mean BMI standard deviation score sd in children = 0.66 1.06 vs. 0.32 1.16 in control subjects, P = 0.002; mean parental BMI sd 27.7 0.4 vs. 25.5 0.4 kg /m2 in control subjects; P < 0.0001). Maternal HOMA-IR accounted for 20% of variation in age at diagnosis (P < 0.001) with increasing maternal insulin resistance associated with later age at diagnosis of Type 1 diabetes. CONCLUSIONS: Childrenwith Type 1 diabetes and their parents have an increased BMI at diagnosis.Maternal insulin resistance is associated with later onset of Type 1 diabetes in children.

Acute Pancreatitis Secondary to Severe Hypertriglyceridaemia in a Patient with Type 1a Glycogen Storage Disease: Emergent Use of Plasmapheresis.

Acute pancreatitis is a well-recognised complication of hypertriglyceridaemia. High serum triglycerides may develop in the autosomal recessive disorder glycogen storage disease (GSD). Plasmapheresis has been effective in reducing triglyceride levels in pancreatitis secondary to other conditions but not previously described in GSD. We describe a 16-year-old male with type 1a GSD who presented with severe abdominal pain, tachycardia and tachypnoea. Abdominal computed tomography (CT) demonstrated acute pancreatitis. Serum triglycerides were 91.8 mM. Despite intravenous fluids and morphine sulphate, he remained seriously ill, and plasmapheresis was therefore started. After daily plasma exchange for 6 days, triglyceride levels dropped to 5 mM. This was associated with a rapid resolution of pancreatitis. Plasmapheresis is effective in rapidly reducing hypertriglyceridaemia from numerous causes, including glycogen storage disease, and may facilitate recovery from acute pancreatitis.

High genetic risk for IDDM in the Pacific Northwest. First report from the Washington State Diabetes Prediction Study.

A combination of immune, genetic, and metabolic markers potentially implicated in the development of insulin-dependent diabetes mellitus (IDDM) was studied in the general population. We screened 3,992 healthy schoolchildren, 12-18 years of age with no family history of IDDM, for islet cell antibodies (ICAs). Of the children, 69 (1.7%) were found to be ICA positive (ICA+), of whom 7 (0.17%) also were positive for insulin autoantibodies (IAAs). ICA+ children (group 1) were human leukocyte antigen (HLA) typed at the DQ locus along with 123 matched (group 2) and 235 random (group 3) control subjects (from the original cohort of 3,992). Of the ICA+ children, 28 underwent beta-cell function (beta-CF) studies. High-risk DQ types were surprisingly prevalent in all groups with 35.8% of random control subjects carrying DQB1*0302 and 8.9% carrying the highest risk HLA type for IDDM, DQB1*0302/*0201. Those individuals with higher ICA titer (> 19 Juvenile Diabetes Foundation units [JDF U]) had a significantly higher prevalence of DQB1*0302 than those with lower titer ICA or normal control subjects. Six of 7 individual positive for both ICA and IAA and typed at the DQ locus were DQB1*0302/*0201 heterozygotes or DQB1*0302 or DQB1*0201 homozygotes, representing three of the highest risk genotypes for IDDM. No correlation was observed between ICA titer or DQ type and beta-CF except that all those with beta-CF below the 5th percentile carried either DQB1*0302 or DQB1*0201. Prospective follow-up is underway to determine if any combination of DQ type and immune markers predicts decline in beta-CF and the development of IDDM.

Genetic and immunological markers of insulin dependent diabetes in Black Americans.

ICA and GAD65 autoantibody profiles and HLA-DR and DQ analysis were performed on 43 Black juvenile onset IDDM patients and 34 unrelated Black controls from Tennessee, USA. 75% of patients were positive for GAD65 autoantibodies but only 53% had ICA; 39% both ICA and GAD65 antibodies. The strongest HLA association was with the DR3 haplotype DRB1*03 DQA1*0501 DQB1*0201 (63% of patients v 12% of controls RR = 13.0, p < 0.00002). DRB1*04 DQA1*0301 DQB1*0302, associated with IDDM in Caucasians but rare in Negroids, occurred in 27% of patients and 6% of controls (RR = 5.9, p < 0.04). All patients carried DQB1*0302 or DQB1*0201. DQB1*0602 was significantly reduced in patients (2.4% v 41%, RR = 0.036, p < 0.008) and DRB1*1501 was absent in patients (0% v 35%). The frequency of GAD65 autoantibodies in Black American IDDM patients is comparable to that in Caucasians; however ICA positivity is reduced. GAD65 antibodies may therefore be a more sensitive serological test to identify individuals in the Black American general population for markers associated with increased risk of developing IDDM. Current screening methods for predicting preclinical IDDM in Caucasians relies on a combination of immune and HLA markers of IDDM; studies of these markers in the Black Americans will make it possible to extend these options to additional genetically diverse populations.

Retrograde versus antegrade cannulation in the intravenous glucose tolerance test.

To investigate whether drawing blood from a retrogradely cannulated hand vein rather than an antegradely cannulated arm vein improves reproducibility in the intravenous tolerance test (IVGTT) we compared these two methods directly by drawing blood from the two sites on the same arm simultaneously. We found no difference in intrasubject coefficients of variation for the measurement of insulin response to glucose (21.5% vs. 22.5%) or insulin sensitivity (22.8 vs. 24.7%) for these two methods. However, the values for insulin response to glucose were significantly increased when blood was drawn from the hand site (410.1 vs. 328.7 pM, P < 0.05). In addition, the failure rate for studies using the retrogradely cannulated hand vein was significantly increased (5% of arm veins vs. 20% of hand veins cannulated, P < 0.05) particularly in female subjects. In conclusion, drawing blood samples from a retrogradely cannulated hand vein appears to have no effect on the reproducibility of the intravenous glucose tolerance test. The acute insulin response to glucose obtained from samples drawn in this manner is, however, significantly increased and this should be borne in mind when comparing results from centers using these different methods.

Activated T cell subsets in human type 1 diabetes: evidence for expansion of the DR+ CD30+ subpopulation in new-onset disease.

An important limitation in T cell studies of human autoimmune (type 1) diabetes is lack of direct access to cells infiltrating the pancreas. We hypothesized that cells recently released from the pancreas into the blood might express a characteristic combination of markers of activation. We therefore examined the recently activated circulating T cell population [CD3+, human leucocyte antigen D-related (HLA-DR+)] using cytokine production and 10 additional subset markers [CD69, CD25, CD122, CD30, CD44v6, CD57, CD71, CCR3 (CD193), CCR5 (CD195) or CXCR3 (CD183)], comparing newly diagnosed adult (ND) (age 18-40 years) patients (n=19) to patients with diabetes for >10 years [long-standing (LS), n=19] and HLA-matched controls (C, n=16). CD3+ DR+ cells were enriched by two-step immunomagnetic separation. No differences in basal or stimulated production of interleukin (IL)-4, IL-10, IL-13 or interferon (IFN)-gamma by CD3+ DR+ enriched cells were observed between the different groups of subjects. However, among the CD3+ DR+ population, significant expansions appeared to be present in the very small CD30+, CD69+ and CD122+ subpopulations. A confirmatory study was then performed using new subjects (ND=26, LS=15), three-colour flow cytometry, unseparated cells and three additional subset markers (CD38, CD134, CD4/CD25). This confirmed the expansion of the CD3+ DR+ CD30+ subpopulation in ND subjects. We conclude that a relative expansion in the T cell subpopulation with the activated phenotype CD3+ DR+ CD30+ is seen in the peripheral blood of subjects with newly diagnosed type 1 diabetes. This subpopulation represents less than 0 x 7% of circulating T cells and may provide a rich source of disease-specific T cells that can be isolated from blood.

A randomized pilot study in Type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone.

AIM: To determine potential for amelioration of recurrent severe hypoglycaemia without worsening in overall control in individuals with long-standing Type 1 diabetes (T1DM). METHODS: Twenty-one people with T1DM characterized by altered hypoglycaemia awareness and debilitating severe hypoglycaemia were randomized in a pilot 24-week prospective study to optimized analogue therapy (ANALOGUE; lispro/glargine); continuous subcutaneous insulin infusion therapy (CSII; lispro); or re-education with relaxation of blood glucose targets on existing conventional insulin regimen (EDUCATION). Glycaemic profiles and duration of biochemical hypoglycaemia were measured by continuous subcutaneous glucose monitoring and self-monitored blood glucose. RESULTS: Further severe hypoglycaemia was prevented in five participants (71%) in each group (P = 0.06). Incidence of severe hypoglycaemia was: 0.6 (ANALOGUE), 0.9 (CSII), and 3.7 (EDUCATION) episodes per patient year. Restoration of hypoglycaemia awareness was confirmed by validated questionnaire in three (43%) ANALOGUE, four (57%) CSII and five (71%) EDUCATION patients. Glycated haemoglobin (HbA1c) was significantly improved in the ANALOGUE group between weeks 0 and 24 (8.6 +/- 1.1 vs. 7.6 +/- 0.8%; P = 0.04 for change). Non-significant improvement was seen in the CSII group (8.5 +/- 1.9 vs. 7.4 +/- 1.0%; P = 0.06). No change in HbA1c was seen in the EDUCATION group (8.5 +/- 1.1 vs. 8.3 +/- 1.0%; P = 0.54). There were no episodes of diabetic ketoacidosis or any other adverse events in any group. CONCLUSIONS: In this pilot randomized trial comparing optimized ANALOGUE, CSII or EDUCATION alone in unselected individuals with recurrent severe hypoglycaemia, we show potential for restoring hypoglycaemia awareness and preventing further severe hypoglycaemia with concomitant improvement in glycaemic control in ANALOGUE and CSII groups.