OBJECTIVE -The study goal was to assess and predict the risk of developing retinopathy in type 1 diabetic patients with extreme metabolic control.RESEARCH DESIGN AND METHODS -Based on material from the Diabetes Control and Complications Trial (DCCT) study (n ϭ 1,441 patients), patients without retinopathy at baseline (DCCT primary cohort) were considered under good or poor metabolic control if the mean HbA 1c level (until the last visit) fell in the lower or upper 20% of the overall HbA 1c distribution, respectively. Retinopathy was recorded as either absent or present. Logistic regression was used to predict retinopathy from covariates used in the DCCT retinopathy study.RESULTS -Among the 153 DCCT patients with "good metabolic control" (mean HbA 1c Յ6.87%), three-step change retinopathy developed in 15 (9.8%), and 138 (90%) remained free of retinopathy. Conversely, among the 166 patients with "poor metabolic control" (mean HbA 1c Ն9.49%), the complication did not develop in 71 (43%) and did develop in 95 (57%). Whereas occurrence of diabetic retinopathy was primarily due to metabolic control (P Ͻ 0.0001) and duration of participation in the study (P Ͻ 0.0001), two other covariates were found to be significant prognostic factors of the complication: HbA 1c at baseline (OR 1.37, P Ͻ 0.001) and BMI (OR 1.11, P Ͻ 0.05).CONCLUSIONS -This study confirms that retinopathy develops in ϳ10% of patients with type 1 diabetes under good metabolic control, whereas Ͼ40% of patients with type 1 diabetes remain free of retinopathy despite poor metabolic control. After adjusting for metabolic control and duration of participation in the study, it was found that previous glycemic exposure (HbA 1c ) and BMI may provide a possible explanation to such paradoxical clinical situations.

OBJECTIVE -To study the presence and levels of GAD65 antibodies (GADA), IA-2 antibodies (IA-2-A), and islet cell antibodies (ICA) during the first years after clinical onset of type 1 diabetes in relation to age at diagnosis.RESEARCH DESIGN AND METHODS -Type 1 diabetic patients (n = 194) Ͻ40 years of age were consecutively recruited at the time of diagnosis by the Belgian Diabetes Registry and followed during the first 4 years of insulin treatment. ICA were determined by indirect immunofluorescence assay and IA-2-A, GADA, and insulin autoantibodies by a radioligand assay.RESULTS -Overall, 94% of initially antibody-positive patients (n = 180) remained positive for at least 1 antibody type 4 years after diagnosis. In the case of diagnosis after 7 years of age, GADA, IA-2-A, and ICA persisted in 91, 88, and 71%, respectively, of the initially antibody-positive patients. Antibody persistence was lower in those diagnosed at Ͻ7 years of age, amounting to 60% for GADA, 71% for IA-2-A, and 39% for ICA. In 57% of the initially antibody-positive patients, at least 1 type of autoantibody reached peak values after diagnosis. This occurred more frequently for clinical onset after 7 years of age and more often for GADA (49%) than for IA-2-A (29%) or ICA (19%). Of the patients, 24% that were negative for GADA at onset became GADApositive during the following 4 years. Among the 7% initially antibody-negative patients, 2 of 14 subjects developed antibodies after clinical onset.CONCLUSIONS -In particular, for diagnosis after 7 years of age, islet cell-specific autoantibodies generally persist for many years after diagnosis. There is also a high frequency of increasing antibody levels and of conversion to antibody positivity in the first 4 years after diagnosis and start of insulin treatment. Thus, determination of antibodies at diagnosis can underestimate the number of cases with autoimmune type 1 diabetes, in particular with assays of lower sensitivity. The divergent temporal patterns of ICA, GADA, and IA-2-A suggest that the ICA test recognizes other antibody specificities besides GADA and IA-2-A and reflects other autoimmune processes; it also indicates that GADA assays have a higher diagnostic sensitivity in the period after clinical onset.

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...

The extent to which an oral load of glucose is absorbed from the gut and oxidized during prolonged exercise is a matter of controversy. Four healthy volunteers, 18-28 yr, were submitted on 4 different days to a 105-min treadmill exercise at 22, 39, 51, and 64% of their individual VO2max. After 15 min adaptation to exercise, they received orally 100 g naturally labeled [13C]glucose. Oxidation of the exogenous glucose was followed by 13CO2 measurements in the expired air; total carbohydrate and lipid oxidation were evaluated by indirect calorimetry. Between 22 and 51% VO2 max, total carbohydrate, lipid oxidation, and exogenous glucose oxidation were linearly correlated with the relative work load (r = 0.81; P less than 0.01). Between 51 and 64% VO2 max, exogenous glucose oxidation and lipid oxidation tended to level off, whereas endogenous carbohydrate oxidation was markedly enhanced. The lesser contribution of exogenous glucose during the most intense exercise might be due to a decrease in the oxidation in the muscles or to a lesser availability of this exogenous glucose.

To investigate further the hormonal and metabolic adaptations occurring when carbohydrates are ingested after prolonged exercise, we have compared the fate of a 100-g oral glucose load (using 'naturally labelled' 13C-glucose) in healthy volunteers after an overnight fast at rest either without previous exercise or after a 3-h exercise performed on a treadmill at about 50% of the individual VO2 max. In comparison to the control conditions, the oral glucose tolerance test (OGTT) performed in the post-exercise recovery period was characterized by a greater rise in peripheral blood glucose levels and delayed insulin response. Plasma glucagon values were significantly elevated at the time glucose was given (+48 +/- 13 pg ml-1) and at the end of the OGTT. Plasma-free fatty acid (FFA) levels were 1675 +/- 103 microEq 1-1 when glucose was given, and subsequently reduced to values similar to those observed in the control conditions. Indirect calorimetry indicated that OGTT in post-exercise recovery was associated with decreased carbohydrate and increased lipid oxidation when compared to control conditions. Exogenous glucose oxidation was also significantly reduced: 21.1 +/- 2.6 vs. 35.9 +/- 1.9 g per 7 h. We suggest that the higher plasma glucagon levels and the delayed insulin response played a role in the decreased hepatic glucose retention previously described by others in post-exercise recovery. Our data also suggest that the higher lipid oxidation rate observed at the time glucose was given in the post-exercise period could explain, according to the Randle 'glucose-fatty acid cycle', the decreased carbohydrate oxidation and the preferential muscle glycogen repletion already well documented. The reason why the lipid oxidation rate remains increased 3-7 h after glucose ingestion in spite of the fact that FAA levels at that time are similar to those observed in control conditions is still unknown; further kinetic studies are needed to clarify this point.