Family history of type 1 diabetes and autoantibodies to the islet antigens insulin (IAA), glutamate decarboxylase (GADA), and the protein tyrosine phosphatase-like protein IA-2 (IA-2A) are strong predictors of type 1 diabetes, but the rate of progression to diabetes in multiple islet autoantibody-positive relatives varies widely. We asked whether detailed characterization of islet autoantibodies that included determination of titer, epitope specificity, and IgG subclass would improve diabetes prediction in a large cohort of autoantibodypositive relatives. The study shows a strong association between risk and high titer, broad antibody responses to IA-2 and insulin. The highest risks were associated with high-titer IA-2A and IAA, IgG2, IgG3, and/or IgG4 subclass of IA-2A and IAA, and antibodies to the IA-2-related molecule IA-2␤. Using models based on these antibody characteristics, autoantibody-positive relatives can be classified into groups with risks of diabetes ranging from 7 to 89% within 5 years. Diabetes 53: 384 -392, 2004 A utoantibodies to islet cell antigens such as insulin (IAA), the 65-kDa isoform of glutamate decarboxylase (GADA), and the protein tyrosine phosphatase (PTP)-like antigen IA-2 (IA-2A) are markers of the autoimmune process that precedes type 1 diabetes (1-9). At-risk relatives can be identified on the basis of positivity for these autoantibodies. Diabetes risk is highest in relatives with more than one islet autoantibody (4 -11) or with high-titer islet cell antibodies (10,12), suggesting that the intensity of the humoral response may reflect the stage of ␤-cell destruction. It has however been shown that a proportion of relatives with multiple islet autoantibodies do not develop diabetes for many years (6,13), indicating that additional tests are necessary for accurate prediction of diabetes. IgG subclass and the epitope specificity of autoantibodies may reflect qualitative and quantitative differences in the autoimmune response (14 -16), and their measurement could, therefore, improve our ability to predict diabetes. We have examined islet autoantibody titer, epitope specificity and IgG subclass in prospectively followed islet autoantibodypositive first-degree relatives of patients with type 1 diabetes, and determined how these can be used to stratify the likelihood of progression to clinical diabetes. The findings are consistent with the concept that high-titer multitarget responses signal late or aggressive preclinical diabetes and allow staging of diabetes risk on the basis of antibody measurements. RESEARCH DESIGN AND METHODSSera of all first-degree relatives of patients with type 1 diabetes from the Bart's Oxford (BOX) and the Munich family studies (13,17) were tested for IAA, GADA, and IA-2A. A total of 180 nondiabetic relatives (76 from BOX study and 104 from Munich family study) were selected on the basis of positivity for at least one of these antibodies on two or more occasions and whether a sufficient volume of the first positive sample was available for complete testing...

Aims/hypothesis Combinations of autoantibody characteristics, including antibody number, titre, subclass and epitope have been shown to stratify type 1 diabetes risk in islet autoantibody-positive relatives. The aim of this study was to determine whether autoantibody characteristics change over time, the nature of such changes, and their implications for the development of diabetes. Methods Five-hundred and thirteen follow-up samples from 141 islet autoantibody-positive first-degree relatives were tested for islet autoantibody titre, IgG subclass, and GAD and IA-2 antibody epitope. All samples were categorised according to four risk stratification models. Relatives had a median follow-up of 6.8 years and 48 developed diabetes during follow-up. Survival analysis was used to determine the probability of change in risk category and of progression to diabetes. Results For each stratification model, the majority of relatives (71-81%) remained in the same risk category throughout follow-up. In the remainder, changes occurred both from lower to higher and from higher to lower risk categories. For all four models, relatives aged <15 years were more likely to change risk category than those aged >15 years (0.001

A B S T R A C T Glucogon immunoreactivity (IRG) was measured in plasma of duodenopancreatectomized subjects with a nonspecific (K-4023) and a specific (30-K) glucagon antiserum. After an overnight fast, plasma IRG (K-4023) was significantly (P < 0.05) higher in the subjects without pancreas, averaging 782±79 (SEM) pgeq/ml, than in the controls (482±80 pgeq/ml). IRG (30-K) of 162±68 pglml did not change during an infusion ofarginine (450 mg/kg per 40 min). Insulin deprivation during 3 d in one patient did not restore the IRG response to arginine as reported in depancreatized dogs.Bio-Gel P-30 column chromatography revealed that virtually all IRG (30-K) measured in whole plasma was of different molecular weight than glucagon, and primarily of a mol wt 2 40,000. Intravenous arginine did not significantly alter the chromatographic pattern of these plasmas. Thus, as postulated by others, duodenopancreatectomized humans have virtually no circulating 3,500-dalton glucagon. Hence, the presence of 3,500-dalton glucagon in plasma is not a condition for the diabetic state. It might, nevertheless, when present in normal or excessive amounts, worsen the metabolic state of diabetic patients.Among 14 amino acids measured in plasma of these patients, the concentrations of alanine, serine, ornithine, and arginine were significantly (P < 0.05) elevated to approximately twice that of normal: alanine and serine are both substrates for gluconeogenesis, whereas ornithine and arginine are involved in the formation of urea, the second product of hepatic gluco-

This is a report of 1,403 patients who underwent endoscopic papillotomy (EPT) in 9 endoscopic centers in West Germany from 1973 up to April 1, 1977. The main indication for EPT was stones in the bile ducts causing obstructive jaundice. In 79.5% of the patients, a previous surgical operation on the bile ducts had been done, and in 20.5%, the gallbladder was still present. Other indications for EPT were benign and malignant stenosis of the duodenal papilla, and cholangitis in the blind sack syndrome associated with an existing choledochoduodenostomy. The complication rate of EPT was 7.3%. The main complications were pancreatitis, cholangitis, hemorrhage, and perforation. Incarceration of stones or instruments was rare. Most complications could be treated conservatively. The mortality rate at 1.5% was low, and less than that of transduodenal papillotomy. Late complications that occur after transduodenal papillotomy were not found and should not occur after EPT. EPT eliminates the need for laparotomy and represents an alternative for the aged patient in poor general condition.