The glucose analog streptozotocin (STZ) has long been used as a tool for creating experimental diabetes because of its relatively specific β-cell cytotoxic effect, but the mechanism by which systemic injection of STZ causes β-cell destruction is not well understood. In the current study, we have used insulinoma (RIN) and AtT-20ins cell lines engineered for overexpression of GLUT2 or GLUT1 to investigate the role of glucose transporter isoforms in mediating STZ cytotoxicity. The in vivo effects of STZ were evaluated by implantation of RIN cells expressing or lacking GLUT2 into athymic nude rats. The drug had a potent cytotoxic effect on RIN cells expressing GLUT2, but had no effect on cells lacking GLUT2 expression, as indicated by histological analysis and measurement of the blood glucose levels of treated animals. The preferential cytotoxic effect of STZ on GLUT2-expressing cell lines was confirmed by in vitro analysis of GLUT2-expressing and untransfected RIN cells, as well as GLUT2- and GLUTl-overexpressing AtT-20ins cells. Consistent with these data, only GLUT2-expressing RIN or AtT-20ins cells transported STZ efficiently. We conclude that expression of GLUT2 is required for efficient killing of neuroendocrine cells by STZ, and this effect is related to specific recognition of the drug as a transported substrate by GLUT2 but not GLUT1

Objective: Obesity‐related immune mediated systemic inflammation was associated with the development of the metabolic syndrome by induction of the tryptophan (TRP)–kynurenine (KYN) pathway. The study aimed to assess whether this holds true across the lifespan from juvenility to adulthood.Design and Methods: Five hundred twenty‐seven participants aged between 10 and 65 years were analyzed. Standard anthropometric measures, carotid ultrasound, and laboratory analysis including interleukin‐6, ultra‐sensitive C‐reactive protein, lipids, glucose metabolism, neopterin, TRP, KYN levels, and the KYN/TRP ratio were performed.Results: Overweight/obese (ow/ob) adults had significantly increased KYN serum levels and a significantly increased KYN/TRP ratio. In sharp contrast, ow/ob juvenile males aged ≤18 years showed decreased, females similar KYN and KYN/TRP ratio in comparison to their control counterparts. Also, adult ow/ob subjects with metabolic syndrome showed markedly increased KYN/TRP ratios contrary to decreased KYN/TRP ratios in ow/ob juveniles. Abdominal fat content, characterized by age normalized waist circumference, and not body mass index, had the strongest effect for an increase of the KYN/TRP ratio in adults.Conclusions: TRP metabolism and obesity‐related immune mediated inflammation differs markedly between juveniles and adults. While childhood obesity seems to be dominated by a Th2‐driven activation, an accelerated production of Th1‐type cytokines may pave the way for later atherosclerotic endpoints.

Cases of deep venous thrombosis in the lower extremities triggered by abnormalities of the vena cava have been reported. To describe anomalies of the inferior vena cava in patients with deep venous thrombosis. Prospective, consecutive case series. University Hospital, Graz, Austria. 97 patients with deep venous thrombosis. Sonography, venography, or both to diagnose deep venous thrombosis; magnetic resonance angiography to image the inferior vena cava. Anomalies of the inferior vena cava imaged by magnetic resonance angiography. 31 of 97 patients showed thrombotic occlusion of iliac veins (common and external iliac vein [n = 29] or external iliac vein [n = 2]). Five of 31 patients (3 men, 2 women) had an anomaly of the inferior vena cava. Anomalies were missing inferior vena cava, hypoplastic hepatic segment, and missing renal or postrenal segments. Patients with anomalies were significantly younger than the 92 patients without (mean age±SD, 25±6 years vs. 53±19 years; P = 0.002). In 2 patients with anomalies, the thrombotic occlusion was recurrent. An anomaly of the inferior vena cava should be suspected if thrombosis involving the iliac veins is seen in patients 30 years of age or younger. Patients with both an anomaly and thrombosis may be at higher risk for thrombotic recurrence.

OBJECTIVE To determine the efficacy and safety of a structured diabetes teaching and treatment program (DTTP) in patients with insulin-dependent diabetes mel-litus (IDDM) in an outpatient setting. RESEARCH DESIGN AND METHODS All patients with IDDM who completed a structured 5-day outpatient DTTP were reevaluated after a mean follow-up of 3 years. A standardized interview was used to assess frequency of severe hypoglycemia, type of insulin treatment, self-monitoring, and other diabetes-related parameters. HbA_1c was measured by high-performance liquid chromatography. RESULTS Of 205 patients, 4 (2%) died during the observation period. HbA_1c in the 201 surviving patients decreased significantly from 8.7 ± 2.0 to 7.5 ± 1.2% at follow-up (P < 0.001); frequency of severe hypoglycemia decreased from a mean of 0.46 to 0.13 per patient per year (P < 0.001). Hospital admission due to acute metabolic disturbances decreased from 4.5 ± 11.1 to 1.4 ± 6.7 days/patient-year (P < 0.001). At follow-up, intensive insulin therapy was carried out by 98% of the patients, and 80% of the patients reported three or more measurements of blood glucose per day. Diabetes-related knowledge had a positive (P < 0.01) and body mass index a negative (P < 0.02) influence on improving HbA_1c assessed by multiple regression analysis. Severe hypoglycemia after DTTP was associated with a history of severe hypoglycemia before DTTP (P < 0.001) and the existence of overt diabetic nephrop-athy (P < 0.05). CONCLUSIONS A structured outpatient DTTP as used in this study is able to improve overall metabolic control and decrease the frequency of severe hypoglycemia in patients with IDDM.

OBJECTIVE: To evaluate commercially available determination methods for HbA1c in patients with hemoglobin variants. RESEARCH DESIGN AND METHODS: HbA1c values were determined with various commercially available methods, including ion-exchange high-performance liquid chromatography (HPLC), boronate affinity assay, and immunoagglutination in patients with the hemoglobin mutations Hb Graz, Hb Sherwood Forest, Hb O Padova, Hb D, and Hb S. RESULTS: The effect of hemoglobinopathies on glycohemoglobin measurements was highly method dependent. The HPLC methods for HbA1c determination lacked the resolution necessary to differentiate hemoglobin variants. They demonstrated additional peaks in the chromatograms and HbA1c results either too low or too high compared with the nondiabetic reference range. With all immunoassays, Hb Graz demonstrated falsely low values. The other hemoglobinopathies in our study caused falsely low and/or high HbA1c results in immunoagglutination methods. The boronate affinity method showed values in an acceptable range for all hemoglobin variants. CONCLUSIONS: Because of the local occurrence of Hb variants and the ethnic origin of a given population, every individual laboratory must establish and validate its own assay method. In managing diabetic patients, knowledge of hemoglobinopathies influencing HbA1c determination methods is essential because hemoglobin variants could cause mismanagement of diabetes resulting from false HbA1c determinations.