We advocate an approach to the analysis of CGMS data based upon a hierarchy of relevant clinical questions alluding to the representative nature of the data, the amount of time spent in glycemic excursions, and the degree of glycemic variation. Integrated use of these algorithms distinguishes between various patterns of glycemic control in those with and without diabetes.

No abstract

Objectives: To determine the utility of various autoantibodies in predicting progression to clinical diabetes in first‐degree relatives of patients with type 1 diabetes mellitus. Participants: 3315 first‐degree relatives of patients with type 1 diabetes (1161 parents, 1206 siblings and 948 offspring) recruited through diabetes clinics, private endocrinologists, Diabetes Australia and the Juvenile Diabetes Foundation. Main outcome measures: Prevalence of islet cell antibodies (ICA) levels ≥20 JDFu, insulin autoantibodies (IAA) levels > 100nU/ml, and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine phosphatase IA2 (IA2Ab); change in cell function over time; and development of clinical diabetes. Results: 2.6% of relatives had elevated ICA levels, 1.3% had elevated IAA levels and 0.3% had both. High ICA levels were significantly more frequent in siblings than in offspring or parents, and were more frequent in relatives younger than 20 years. GADAb were detected in 68% and IA2Ab in 57% of relatives with elevated ICA and/or IAA levels. Diabetes developed in 33 relatives (25 siblings, 2 offspring and 6 parents). Before diagnosis of clinical diabetes, high ICA levels were detected in 18 (58%), high IAA levels in 7 (23%), both in 5 (15%), and either in 19 (61%); GADAb were detected in 26 (84%), IA2Ab in 13 (42%), both in 11 (35%), and either in 28 (90%). First phase insulin release (FPIR) less than 50mU/L was very strongly associated with progression to diabetes. In relatives with FPIR initially greater than 50mU/L who eventually developed diabetes, there was a gradual and continuous reduction in FPIR over time before diagnosis. Conclusions: Type 1 diabetes can be diagnosed in the preclinical stage. The recently described antibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 appear superior to ICA as screening tools for the preclinical diagnosis of type 1 diabetes.

Previous studies have shown that serum levels of the somatomedin, nonsuppressible insulin-like activity (NSILA-S), are extremely low in patients with thalassemia major. Since these patients are not GH deficient, several other possible mechanisms for the reduced levels of NSIL-S have been explored. No evidence for the presence of NSILA inhibitors was obtained either in mixing experiments of normal serum and thalassemic sera or after acid gel chromatography of thalassemic sera. The high iron and ferritin levels of thalassemia had no effects on the NSILA-S bioassay itself or on the binding of GH to its hepatic receptors. GH molecules secreted as a result of exercise-induced GH stimulation tests were shown to be both immunologically and biologically reactive. No circulating GH-binding proteins were present in thalassemic sera. Since the liver function in the group of patients included in this study was only slightly abnormal, it is considered unlikely that generalized hepatic damage due to the severe iron overload of thalassemia is a major cause. These results suggest that neither NSILA-S inhibitors, abnormal GH molecules, nor hepatic damage contribute to the failure of these patients to produce NSILA-S and that a specific defect may exist at the hepatic GH receptor or postreceptor level.

We have recently demonstrated that nonsuppressible insulin-like activity (NSILA-S) is very low or undetectable in beta-thalassemia major. The mechanism for this deficiency has been proposed to result from a defect at the GH receptor level or at a site distal to the receptor in the pathway leading to NSILA-S generation. To study this proposal further, the NSILA-S response to exogenous human GH (hGH) was assessed in six affected subjects (aged 12-20 yr), four of whom were on or below the third percentile for height and three of whom were prepubertal. On the basis of immunoreactive and receptor-active hGH responses to exercise, GH deficiency as a primary cause of low NSILA-S levels was essentially ruled out in five of the six patients. hGH (5 mg) was administered im daily for 3 days. Bioassayable NSILA-S failed to rise normally in response to the exogenous hGH in four of the six subjects. In the other two, a limited response was seen only on day 4, reaching 54% and 29%, respectively, of the mean peak response in normal adults. The impaired production of NSILA-S in thalassemia major thus appears to be due to hGH insensitivity and not to a biologically inactive endogenous hGH molecule. These results confirm that the site of the defect may therefore be at the membrane receptor for hGH or at a subsequent step in the NSILA-S synthetic pathway, perhaps related to excessive hepatic iron deposition. These results also suggest that in subjects where the defect is partial, treatment of their short stature with hGH may be beneficial.