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Leptin Before and After Insulin Therapy in Children with New-Onset Type 1 Diabetes¹

Division of Pediatric Endocrinology, Metabolism, and Diabetes Mellitus, Children’s Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania 15213

Address all correspondence and requests for reprints to: Silva A. Arslanian, M.D., Division of Endocrinology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, Pennsylvania 15213. E-mail: arslans{at}chplink.chp.edu

	Abstract

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Serum leptin levels reflect the amount of body fat. However, several reports suggest that insulin may also regulate serum leptin levels. This study was aimed at testing whether leptin levels are low in newly diagnosed patients with type 1 diabetes and increase after institution of insulin therapy. Nineteen children with new-onset type 1 diabetes were studied. Serum leptin levels were measured at presentation before insulin therapy was initiated (day 0), 1 day after insulin therapy (day 1), 3–5 days after insulin therapy (day 3–5), and at 3 months of follow-up (3 months). The control group consisted of 19 healthy children matched for age and body mass index.

On day 0 leptin levels were lower in the patients compared with those in controls (3.3 ± 0.2 vs. 6.2 ± 0.9 ng/mL; P < 0.005). After insulin therapy, leptin levels increased significantly by day 1 without significant weight change and became comparable to control values by days 3–5. Before insulin therapy, leptin did not correlate with weight, body mass index, or hemoglobin A_1c. After insulin therapy, leptin levels on days 3–5 correlated with insulin dose (r = 0.43; P = 0.03). The results of this study demonstrate that children with new-onset type 1 diabetes have low leptin levels before insulin therapy. Leptin levels increase within 24 h of insulin therapy and become comparable to nondiabetic levels by 3–5 days. This rapid increase in leptin after 24 h of insulinization is independent of changes in body weight and is postulated to be due to a stimulatory effect of insulin on leptin production, nutritional replenishment, or both factors together.

	Introduction

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SERUM LEPTIN levels generally reflect the degree of adiposity and correlate with body fat (1, 2, 3). Because of the association of adiposity with insulinemia, leptin levels have been found to correlate positively with insulin levels also. However, it is still controversial whether insulin per se, independent of adiposity, modulates plasma leptin levels. In vivo insulin infusion was found to be associated with increases in leptin levels in some (4, 5, 6), but not all, studies (7, 8, 9, 10). In vitro studies have shown that insulin stimulates adipocyte leptin production (11, 12). Studies in type 2 diabetes demonstrate a relationship between leptin and insulin regardless of adiposity (13, 14). In our previous study of healthy children, insulin levels correlated directly with leptin independently of body fat mass determined with the H₂¹⁸O dilution principle (3). Patients with new-onset type 1 diabetes who are insulin deficient may present an ideal in vivo experimental set-up to assess the effect of insulin on leptin. Therefore, the aim of this study was to test the hypothesis that leptin levels are low in newly diagnosed patients with type 1 diabetes and increase after institution of insulin therapy.

	Subjects and Methods

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Subjects

Nineteen children (14 boys and 5 girls), aged 9.8 ± 1.0 yr, admitted to Children’s Hospital of Pittsburgh with new-onset type 1 diabetes were studied. All subjects had abrupt onset with classical symptoms. Fifteen presented with ketosis and/or ketoacidosis. Three patients required iv insulin infusion (0.1 U/kg·h) as the initial therapy; the remaining subjects were started on short acting sc insulin injections every 4–6 h for the first 24 h. After the first 24 h, all patients were started on a split-mix regimen of intermediate and short acting insulin sc. The nondiabetic control group consisted of 19 healthy children (3). The clinical characteristics of patients and controls are depicted in Table 1.

Blood samples for leptin assay were collected at presentation before insulin therapy was initiated (day 0), 1 day after insulin therapy (day 1), 3–5 days after insulin therapy (days 3–5), and at 3 months of follow-up (3 months). All leptin samples were obtained after overnight fasting in control subjects and patients, except on day 0 when the samples were obtained at initial presentation so as not to delay institution of insulin treatment. Written informed consent was obtained from all participants and their guardians. The serum leptin level was measured by the RIA method (Linco Research, Inc., St. Louis, MO) (3). Serial samples of patients were all measured in the same assay.

Statistical analysis was performed using the Mann-Whitney U test for the comparison between patients and controls, and Wilcoxon test and Page’s test, which was suitable to within-subjects comparison, in nonparametric distribution. P < 0.05 was the criterion for significance. Data are presented as the mean ± SE.

	Results

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Before insulin therapy (day 0) leptin levels were lower in patients with new-onset type 1 diabetes compared with those in controls (3.3 ± 0.2 vs. 6.2 ± 0.9 ng/mL; P < 0.005; Table 1). Leptin levels before insulin therapy did not correlate with body weight, body mass index (BMI), or glycosylated hemoglobin. After insulin therapy, leptin levels increased by day 1 (P < 0.005; Fig. 1) without statistically significant changes in weight. Page’s test showed a significant increasing trend for leptin over time (Fig. 1). By days 3–5, leptin levels were not significantly different from control values. Leptin levels on days 3–5 correlated with the insulin dose in units per kg/day (r = 0.43; P = 0.03), but not with weight or the change in weight. Leptin levels correlated with BMI at 3 months only (r = 0.52; P < 0.05). Furthermore, the increase in leptin levels between days 3–5 and 3 months correlated with the increase in BMI during the same period (r = 0.44; P = 0.03).

View larger version (17K): [in this window] [in a new window]   Figure 1. Leptin levels before insulin therapy and after (day 1, days 3–5, and month 3) in children with new-onset type 1 diabetes (open bars) compared with those in control subjects (cross-hatched bar). *, P < 0.005; **, P < 0.05; ***, P < 0.005.

	Discussion

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Several studies have investigated the role of insulin on leptin in vivo. Most of these were insulin-glucose clamp experiments. The results were not uniform. Although some of the studies showed elevations in leptin level after insulinemia (4, 5, 6), others reported no change (7, 8, 9). The discrepancy in the findings could be related to the different rates of insulin infusion and the different durations of insulin administration. In vitro studies also revealed a stimulatory role of insulin on leptin production in human and rat adipocytes (6, 11, 12). In primary cultures of human abdominal adipocytes, insulin increased leptin gene expression at 72 h, followed by elevations in leptin concentrations in the culture medium (6). In human mammary fat cells, insulin stimulated a dose-dependent increase in leptin, whereas removal of insulin was followed by a rapid decrease in leptin expression (11). In rat adipocytes, insulin increased both the secretion and the production of leptin (12).

In type 2 diabetes, hyperinsulinemia was associated with elevated leptin levels independent of body fat mass (15). In adults with type 1 diabetes of long duration, leptin levels were higher than control values (16). This is most likely due to peripheral hyperinsulinemia resulting from present day unphysiological insulin replacement modalities. In our previous study of normal children, insulin levels correlated with leptin independently of fat mass (3). Such indirect findings are in further support of a potential independent role of insulin on leptin.

In conclusion, leptin levels are low in newly diagnosed children with type 1 diabetes. After institution of insulin therapy, circulating levels increase and within 3–5 days become comparable to levels found in healthy control subjects. It remains to be determined whether this is solely due to insulinization or is also the result of nutritional replenishment and changes in fat cell metabolism.

	Acknowledgments

 
We thank the nurses of General Clinical Research Center for their invaluable assistance with these studies. We are thankful to Pat Antonio for her excellent secretarial assistance.

	Footnotes

 
¹ This work was supported by NIH Grant HD-27503 and USPHS Grant MO1-RR-00084 (to the General Clinical Research Center) and by the Renziehausen Trust Fund. Presented at the 80th Annual Meeting of The Endocrine Society, New Orleans, LA, June 1998.

Received September 29, 1998.

Revised January 11, 1999.

Accepted January 25, 1999.

	References

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