THE BELGIAN DIABETES REGISTRY 7OBJECTIVE -A worldwide increase in the incidence of childhood type 1 diabetes has been observed. Because in various countries the majority of new type 1 diabetic patients are diagnosed in adulthood, we investigated whether the rising incidence of this disorder in children reflects a global increase in the incidence of diabetes or a shift toward earlier clinical presentation.RESEARCH DESIGN AND METHODS -The incidence of type 1 diabetes presenting before age 40 years was prospectively measured in the Antwerp district over a 12-year period (1989 -2000). The completeness of ascertainment was evaluated by the capture-recapture method. Trends in incidence during the study period were analyzed by Poisson regression.RESULTS -The incidence of type 1 diabetes diagnosed before age 40 years remained constant over the 12-year period, averaging 9.9 cases per 100,000 individuals per year. The incidence was similar in both sexes under age 15 years, but a marked male excess was noted for adult-onset disease, in particular after age 20 years, resulting in a male-to-female ratio of 0.9 under age 15 years vs. 1.6 thereafter (P ϭ 0.001). During the 12-year observation period, there was a significant tendency toward increasing incidence under age 15 years at the expense of a decreasing incidence between ages 15 and 40 years (P ϭ 0.025). The annual increase in incidence averaged 1.8% under age 15 years and 5.0% under age 5 years (P ϭ 0.06).CONCLUSIONS -Our results indicate that in Belgium, the increasing incidence of childhood type 1 diabetes-especially for children under age 5 years-is not attributable to a global increase in disease incidence, but rather to earlier clinical manifestation. The results suggest that an environmental factor may preferentially accelerate the subclinical disease process in young diabetes-prone subjects. Diabetes Care 25:840 -846, 2002

1Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator of insulin signaling and sensitivity in vivo and is thus a good candidate gene. Here we report the presence of SHIP2 gene mutations associated with type 2 diabetes in rats and humans. The R1142C mutation specifically identified in Goto-Kakizaki (GK) and spontaneously hypertensive rat strains disrupts a potential class II ligand for Src homology (SH)-3 domain and slightly impairs insulin signaling in cell culture. In humans, a deletion identified in the SHIP2 3 untranslated region (UTR) of type 2 diabetic subjects includes a motif implicated in the control of protein synthesis. In cell culture, the deletion results in reporter messenger RNA and protein overexpression. Finally, genotyping of a cohort of type 2 diabetic and control subjects showed a significant association between the deletion and type 2 diabetes. Altogether, our results show that mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in rats and humans. Diabetes 51: [2012][2013][2014][2015][2016][2017] 2002 R ecent data from knock-out mice (1) and in vitro studies (2-5) have identified type II SH2-domain-containing inositol 5-phosphatase, or "SHIP2," as a critical and essential negative regulator of insulin signaling and sensitivity. Indeed, decreased expression of SHIP2 and SHIP2 deficiency in mice leads to increased insulin sensitivity, whereas SHIP2 overexpression in various insulin-sensitive cell lines leads to decreased insulin signaling, i.e., insulin resistance. Given the importance of SHIP2 in the control of insulin sensitivity, we postulated that mutation(s) positively affecting SHIP2 activity, function, and/or expression might contribute to insulin resistance, a hallmark of type 2 diabetes. RESEARCH DESIGN AND METHODSLocalization of the SHIP2 gene on rat chromosomes. Fluorescent in situ hybridization and radiation hybrids mapping were performed as described (6). The following forward and reverse primers were used to amplify a 140-bp DNA fragment of the rat SHIP2 gene from hybrid DNA: 5Ј-CCAGGGGT GAAAGTTTTGAG-3Ј and 5Ј-CCTGACCCTGGGCCTAAAAG-3Ј. SHIP2 gene amplification and sequencing in humans and rats. Consent was obtained from all subjects after the nature of the procedure was explained, and the investigation was conducted according to the principles expressed in the Declaration of Helsinki. All diabetic subjects were Ͼ35 years of age at diagnosis and met the World Health Organization's criteria defining diabetes status. The control subjects were randomly and anonymously chosen in a DNA library isolated from a large population of women consulting for a genetic diagnosis of mutation in the CFTR gene. The SHIP2 cDNA and gene sequences were obtained after PCR amplification. The sequencing products were run on an Applied Biosystem sequencer. CHO-IR transfection, Akt/protein kinase B, and mitogen-activated protein kinase activities. CHO cells expressing...

Weight reduction is essential in the management of most noninsulin‐dependent diabetics, but this therapeutical goal is difficult to obtain. In this double‐blind parallel study, 82 noninsulin‐dependent diabetics, moderately obese (BMI = 30–39 kg/nr2), were given for an 8‐week period either placebo (P) or fluoxetine (F), a specific serotonin reuptake inhibitor, in addition to their usual antidiabetic treatment. Thirty‐nine of them received 60 mg fluoxetine a day and 43 were given the placebo. At admission, both groups had similar weight excess, metabolic control and serum lipid values. In comparison with the P‐treated subjects, those treated with fluoxetine (F) lost more weight after 3 weeks (‐1.9 vs. −0.7 kg, p<0.0009) and after 8 weeks (‐3.1 vs. −0.9 kg, p<0.0007). Fasting blood glucose decreased in group F after 3 weeks (‐ 1.5 vs. −0.4 mmol/L, p<0.003) and after 8 weeks (‐1.7 vs. −0.02 mmol/L, p<0.0004). HbAlc decreased from 8.5% to 7.7% in group F and from 8.6% to 8.3% in group P (p=0.057). Mean triglyceride level was also reduced in group F after 8 weeks (p=0.042). Fasting C‐pep‐tide did not change in either group, but fasting insulin values decreased in group F after 3 weeks (p<0.02) and after 8 weeks (p<0.05). The insulin/C‐peptide molar ratio decreased significantly in group F after 3 weeks (p<0.04) and after 8 weeks (p<0.05) in comparison with group P. The drug was generally well tolerated and no major side effects were reported. In conclusion, the addition of fluoxetine to the usual oral hypoglycemic agent therapy might be beneficial in obese non‐insulin‐dependent diabetics, at least on a short‐term basis.

Plasma lipids and lipoproteins were studied in a group of chronic uraemia patients some of whom were maintained by regular haemodialysis. Compared with healthy individuals, there was a significant increase in plasma triglycerides and in the prebeta-1- and prebeta-2-lipoprotein plasma concentrations. There was no difference between dialyzed and undialyzed patients. Carbohydrate intake was normal, basal plasma insulin and free fatty acid levels were within the normal range. There was no correlation between plasma triglyceride levels and the degree of hypoalbuminaemia, the latter being marked in 30% of the patient. Basal plasma glucagon levels were very high in nearly all dialyzed patients and post-heparin lipoprotein-lipase activity was very low in dialyzed patients. In our experience, regular haemodialysis for 32 weeks did not improve hypertriglyceridaemia.

Abbreviations:BDR Belgian Diabetes Registry BMI body mass index CI confidence interval GADA glutamate decarboxylase autoantibodies HbA lc glycosylated hemoglobin HLA human leukocyte antigen genes IAA insulin autoantibodies IA-2A insulinoma-associated antigen 2 antibodies ICA islet cell antibodies INS insulin (gene) JDF Juvenile Diabetes Foundation OR odds ratioWe investigated inaugural disease phenotype in relation to the presence or absence of diabetes-associated autoantibodies and human leukocyte antigen (HLA) DQ risk genotypes in adult-onset diabetic patients. Blood samples and questionnaires were obtained from 1584 recent-onset Belgian Caucasian patients (age 15-39 yr at diagnosis of primary diabetes) who were recruited by the Belgian Diabetes Registry over an 11-yr period. At clinical diagnosis, antibody-positive patients (n = 1198) were on average younger and had more symptoms, a more acute disease onset, lower body mass index, and random C-peptide levels, but higher insulin needs, glycemia, and prevalence of ketonuria, HLA-DQ, and 5' insulin gene susceptibility genotypes (P < 0.001 vs. antibody-negative patients; n = 386). In antibody-positive patients, these characteristics did not differ according to HLA-DQ genotype. However, in antibody-negative subjects, we found that patients were younger (P = 0.001); had a lower body mass index (P < 0.001), higher insulin needs (P = 0.014), and amylasemia (P = 0.001); and tended to have a higher glycemia and lower C-peptide in the presence of susceptible HLA-DQ genotypes. Differences according to HLA-DQ genotype subsisted after careful age-matching. In conclusion, we found no relation between initial disease phenotype and HLA-DQ genotype in antibody-positive diabetic young adults. In contrast, antibody-negative patients displayed more type 1-like features when carrying susceptible HLA-DQ genotypes known to promote the development of antibody-positive diabetes. The overrepresenta-tion of these susceptibility genotypes in antibody-negative patients suggests the existence of an immune-mediated disease process with as yet unidentified immune markers in a subgroup of seronegative patients. ( J Clin Endocrinol