BRAME, LORI A., ROBERT V. CONSIDINE, MIKAKO YAMAUCHI, ALAIN D. BARON, AND KIEREN J. MATHER. Insulin and endothelin in the acute regulation of adiponectin in vivo in humans. Obes Res. 2005;13:582-588. Objective: In vitro, insulin and endothelin (ET) both modulate adiponectin secretion from adipocyte cell lines. The current studies were performed to assess whether endogenous ET contributes to the acute action of insulin infusions on adiponectin levels in vivo in humans. Research Methods and Procedures:We studied 17 lean and 20 obese subjects (BMI 21.8 Ϯ 2.2 and 34.0 Ϯ 5.0 kg/m 2 , respectively). Hyperinsulinemic euglycemic clamp studies were performed using insulin infusion rates of 10, 30, or 300 mU/m 2 per minute alone or with concurrent infusion of BQ123, an antagonist of type A ET receptors. Circulating adiponectin levels were assessed at baseline and after achievement of steady-state glucose with the insulin infusion. Results: Adiponectin levels were lower in obese than lean subjects (6.76 Ϯ 3.66 vs. 8.37 Ϯ 2.79 g/mL, p ϭ 0.0148 adjusted for differences across gender). Insulin infusions suppressed adiponectin by a mean of 7.8% (p Ͻ 0.0001). In a subset of 13 lean and 14 obese subjects for whom data with and without BQ123 were available, there was no evident effect of BQ123 to modulate clamp-associated suppression of adiponectin (p ϭ 0.16). Surprisingly, there was no evident relationship between steady-state insulin concentrations and adiponectin suppression (r ϭ 0.14, p ϭ 0.30), and again no effect of BQ123 to modify this relationship was seen.Discussion: Despite baseline differences in adiponectin levels, we observed equal suppression of adiponectin with insulin infusions in lean and obese subjects. ET receptor antagonism with BQ123 did not modulate this effect, suggesting that endogenous ET does not have a role in modifying the acute effects of insulin on adiponectin production and/or disposition.

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We studied a patient with systemic lupus erythematosus and type B insulin resistance who showed almost complete normalization of postprandial plasma glucose in 3 months and a transient occurrence of fasting hypoglycemia from day 35 (i.e. the 35th day of hospitalization) to day 77. To determine the clinical relevance of the biological ability of anti-insulin receptor antibodies (anti-IRAb), we made multiple preparations of the patient's dialyzed serum and IgG. Dialyzed serum prepared on day 1 showed 95% inhibition of insulin binding. The binding inhibition was, however, decreased parallel to the normalization of insulin sensitivity. For 2DG uptake, 6.2 microM IgG purified on 3 different days (days 7, 35 and 78, designated IgG-NOV, -JAN, and -FEB, respectively) stimulated 2DG uptake into CHO-hIR at 3.4-, 3.1-, and 1.5-fold, respectively. Phosphotyrosine immunoblotting revealed that apparent insulin receptor autophosphorylation was visible only with IgG-NOV, not with the IgG-JAN or -FEB. Mutation of tyrosine-960 or lysine-1018 of the insulin receptor failed to transduce the IgG's stimulatory effect. IgG-NOV was not able to stimulate the autophosphorylation of the human IGF-I receptor. In the present study, the insulin binding inhibitory activities of the dialyzed sera prepared at different time points were shown to be altered parallel to insulin sensitivity in vivo. Stimulatory activities of the patient's IgG were, however, discordant for the occurrence of fasting hypoglycemia observed in vivo. Other pathogenic factors or mechanisms in addition to the insulin-like action of the anti-IRAb may be also required to fully understand the development of fasting hypoglycemia in type B insulin resistance.

Different autoimmune mechanisms may be involved in childhood‐ and adult‐onset type 1 diabetes. Our aim was to explore the differences in IA‐2 autoantibody epitope recognition between childhood‐ and adult‐onset type 1 diabetes. Therefore, in vitro synthesized radiolabeled IA‐2ic (amino acid 601‐979), IA‐2JM (amino acid 557‐629), and IA‐2PTP (amino acid 630‐979) were used to analyze the IA‐2 autoantibody epitope specificities in 93 patients with new‐onset type 1 diabetes. Among 93 patients with type 1 diabetes the prevalences of autoantibodies to GAD, IA‐2ic, and insulin were 69.9%, 58.1%, and 45.2%, respectively. The prevalence of IA‐2ic autoantibodies in patients with childhood‐onset type 1 diabetes (aged ≤18 years, n= 60) was significantly higher than that in patients with adult‐onset diabetes (68.3 vs. 36.4%, P < 0.002). Ninety‐two percent of type 1 diabetic patients positive for IA‐2ic autoantibodies recognized the PTP domain of IA‐2, whereas 8% reacted with the JM region only. Among 60 patients with childhood‐onset type 1 diabetes, 2% recognized the JM region only, 48% bound the PTP domain of IA‐2 only, and 18% recognized both JM and PTP epitopes. Among 33 patients with adult‐onset diabetes, 9% recognized the IA‐2JM only, 18% bound the IA‐2PTP only, and 9% recognized both the IA‐2JM and the IA‐2PTP. IA‐2PTP autoantibodies were prevalent in patients with childhood‐onset type 1 diabetes. By contrast, the proportion of patients with the IA‐2JM autoantibody only in type 1 diabetes who were positive for IA‐2ic autoantibodies was significantly higher in adult‐onset than in childhood‐onset diabetes (P < 0.05). These results demonstrate that autoantibody recognition of the IA‐2 epitope is distinct in childhood‐onset and adult‐onset type 1 diabetes.