Although overall results remain unsatisfactory, 33% of studied French children with type 1 diabetes had HbA1c < 8%, the value obtained in Diabetes Control and Complications Trial adolescents treated intensively. Diabetes management in specialized centers should be encouraged.

To improve criteria for entry into future trials of immunosuppression, we enrolled 40 children with recent-onset Type I insulin-dependent diabetes in a pilot trial of cyclosporine. Twenty-seven patients were able to discontinue insulin therapy 48 +/- 5 days after the start of immunosuppression. At four months, their fasting and postprandial blood glucose concentrations averaged 110 and 160 mg per deciliter (6.1 and 8.9 mmol per liter) with a mean hemoglobin A1c level of 6.15 percent. Seventy-five percent of these patients with early remission still did not need insulin at 12 months, and their glycemic control was similar to that at 4 months. The major differences between the 27 patients with remission and the 13 without remission were the duration of symptoms before diagnosis (26.8 vs. 48.0 days, P less than 0.01), the degree of weight loss (3.2 vs. 10 percent of body weight, P less than 0.001), the initial hemoglobin A1c level (10.7 vs. 13.2 percent, P less than 0.001), and the frequency of ketoacidosis (11 vs. 61.5 percent, P less than 0.001). The lesser degree of weight loss was the strongest independent predictor of remission. The response of C-peptide to intravenous glucagon (0.50 vs. 0.17 pmol per milliliter, P less than 0.05) was also an independent predictor. No differences were observed between the two groups of patients in age, sex, HLA phenotype, autoantibodies to insulin or islet-cell antigens, or doses or trough levels of cyclosporine. Only minimal manifestations of toxicity were detected over the period of observation. We conclude that early treatment with cyclosporine in children with recent-onset Type I diabetes can induce remission from insulin dependence, with half the patients not requiring insulin after a full year.

No abstract

Mutations in the leptin gene lead to rare obese syndromes of Mendelian inheritance in humans and rodents. However, no relevant mutations are found in the coding region of leptin gene DNA in patients with common multifactorial obesity. These obese patients tend to have an elevation of serum leptin proportional to their adiposity but with a rather wide dispersion of leptin levels for a given body fat content, which in part is attributable to sexual dimorphism. The current study, performed in two independent Caucasian cohorts of obese girls, shows that a frequent promoter variant of the leptin gene is associated with changes in the relationship between serum leptin and body fatness. Girls of comparable adiposity have different circulating leptin levels, depending on their genotype at this locus. Girls with the -/-Lep -2,549 genotype have 25% lower mean leptin levels than the girls with other genotypes, as reflected by differences in the regression slopes of leptin-to-fat mass. Therefore, genetic factors related to the leptin gene may be important in defining the set point of obese individuals (i.e., the circulating leptin level for a given degree of body fatness). This definition may be of both physiological and therapeutic relevance, although a phenotypic association with an individual single-nucleotide polymorphism is not sufficient to assign function to this particular nucleotide site. Diabetes 49:2196-2200, 2000 R are massive obesity syndromes are associated with mutations of the leptin gene in humans (1,10) and several animals models (2,3,11). No mutations are found, however, in the coding region of this gene in patients with more common forms of obesity (4)(5)(6)(12)(13)(14). Obese patients have elevated levels of leptin in serum and of leptin gene mRNA in white adipocytes (7-9,15), the major leptin-producing cells. Circulating leptin levels correlate with body fat according to a well-established linear relationship (7-9). This relationship is of physiological importance, because it allows leptin to act as a quantitative endocrine signal that ensures that target cells (mainly in hypothalamic areas) are informed of the amount of fat stored in adipose tissue.Because of hyperleptinemia, most humans with multifactorial obesity, including our young patients (9), are considered resistant to leptin (16,17). Of obese humans, however, 5-10% have relatively low leptin levels (7-9). Based on results in a transgenic mouse model (18), it has been postulated that a decreased production of leptin by the adipose tissue can cause the obese state in these "low-leptin" individuals (18).To address the question of underlying individual differences in the regulation of circulating of leptin levels in humans, we studied Caucasian girls in the dynamic phase of early-onset obesity, spanning a wide range of body fat content. These obese children underwent measurement of fasting serum leptin and were genotyped for a single-nucleotide polymorphism (SNP) within the 5Ј untranslated region (UTR) of the leptin gene, as described by Mammès e...