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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 12 4545-4548
Copyright © 1999 by The Endocrine Society

Original Studies

Changes in Plasma Leptin during the Treatment of Diabetic Ketoacidosis

Eba H. Hathout, Jeannine Sharkey, Michael Racine, David Ahn, John W. Mace and Mohammed F. Saad

Division of Pediatric Endocrinology, Loma Linda University Children’s Hospital (E.H.H., J.S., M.R., D.A., J.W.M.), Loma Linda, California 92354; and the Department of Medicine, University of California School of Medicine (M.F.S.), Los Angeles, California 90024

Address all correspondence and requests for reprints to: Eba H. Hathout, M.D., Division of Pediatric Endocrinology, Loma Linda University Children’s Hospital, 11175 Campus Street, CP-A1120R, Loma Linda, California 92354.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To test the hypothesis that insulin regulates leptin, we measured the plasma leptin concentration before and during treatment of diabetic ketoacidosis (DKA), a condition characterized by extreme insulin deficiency. The study included 17 patients with type 1 diabetes (7 males and 10 females), aged 10 ± 1 yr (mean ± SE), with a body mass index of 17.6 ± 1.9 kg/m2. Patients were treated with continuous insulin infusion and fluid and electrolyte replacement. Plasma leptin was measured every 6 h in the first 24 h, during which patients received a total insulin dose of 0.6–2.0 U/kg. Plasma leptin concentrations were also measured in a control group of 29 stable type 1 diabetic children (12 males and 17 females) and 25 healthy children (11 males and 14 females), aged 11 ± 1 yr, with a body mass index of 18.5 ± 1.1 kg/m2. Before treatment, plasma leptin concentrations were significantly lower in patients with DKA than those in diabetic and healthy controls (4.9 ± 1.2 vs. 9.0 ± 1.8 and 11.2 ± 2.1 ng/mL, respectively; P < 0.05). In the DKA patients, plasma leptin increased to 6.4 ± 1.5, 7.5 ± 1.9, 9.1 ± 2.7, and 8.9 ± 2.5 at 6, 12, 18, and 24 h, respectively, after starting treatment (P = 0.001). Thus, leptin levels increased by 38 ± 10% and 92 ± 38% within 6 and 24 h of starting treatment. There was no difference in the change in plasma leptin by 24 h between subjects who could eat (n = 7) and those who could not (n = 10). The plasma leptin increase was paralleled by a rise in insulin level and a decline in glucose and cortisol levels at 6 and 24 h. In conclusion, DKA was associated with decreased plasma leptin concentrations. Treatment resulted in a significant increase in plasma leptin, which may be due to the effect of insulin on leptin production. Our data lend support to the hypothesis that insulin is the link between caloric intake and plasma leptin.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LEPTIN, THE ob gene product, is a 16-kDa peptide that is secreted mainly by adipocytes. Leptin is thought to be a lipostatic signal that contributes to body weight regulation through modulating feeding behavior and/or energy expenditure (1, 2, 3, 4, 5). Mutations of the ob gene that lead to leptin deficiency are associated with hyperphagia, hypometabolism, and obesity in the obese ob/ob mice (1). The recent description of massive obesity in congenitally leptin-deficient children (6) as well as those with mutated leptin receptors (7) highlights its importance in weight regulation in man.

Leptin appears to also play a role in short term energy homeostasis, as its plasma level decreases with short term fasting (8, 9) and increases with acute overfeeding (10). The nature of the regulatory signal mediating the effect of caloric intake on leptin is uncertain. Insulin is a prime candidate because it is the major regulator of energy utilization and adipose tissue metabolism. Furthermore, its plasma level changes in the same direction, albeit faster, as leptin during acute fasting and overfeeding. Several human studies showed, however, that postprandial insulin release (11, 12) and short term insulin infusions (13, 14, 15, 16, 17, 18, 19, 20, 21, 22) had no effect on plasma leptin, while 24- to 72-h infusions caused a significant increase (21, 22). It was suggested, therefore, that insulin has only a slow indirect effect on leptin through a trophic effect on adipocytes (23). Nonetheless, plasma levels were shown to be decreased, and acutely increased by insulin, in streptozotocin-induced diabetes independent of body weight (24, 25). We have shown that plasma leptin falls progressively when fasting insulin is held constant and remains stable or rises with physiological increases in insulinemia (26). To examine this issue further, we measured plasma leptin levels before and during insulin treatment of diabetic ketoacidosis (DKA) which is characterized by extreme insulin deficiency.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The study included 17 children with type 1 diabetes (7 boys and 10 girls), aged 10 ± 1 (mean ± SE) yr, and a body mass index of 17.6 ± 1.9 kg/m2. Patients were admitted to the Loma Linda University Children’s Hospital with DKA, as evidenced by an arterial pH less than 7.2, plasma glucose more than 16 mmol/L, and ketonuria. All but 1 subject had new-onset diabetes. Lack of insulin therapy was the precipitating factor for DKA in all patients; none had any evidence of infection. Patients were treated with iv fluids and continuous insulin infusion according to a standard protocol. The total insulin dose ranged from 0.6–2.0 U/kg over the first 24 h. Blood was collected for measurement of plasma leptin, glucose, insulin, and cortisol before and 6, 12, 18, and 24 h after starting treatment. Seven patients received food 9–12 h after the start of treatment. Patient food intake documentation was prospectively outlined to nurses. The nurse to patient ratio was 1:1, and the nurses were instructed to document times and percent consumption of meals and snacks. The other 10 patients were not able to ingest any food or drink during the first 24 h. For comparison, fasting plasma leptin concentrations were measured between the hours of 0800–1000 h in a control group of 29 ketone-negative children with type 1 diabetes (12 boys and 17 girls) and 25 healthy children (11 boys and 14 girls), aged 11 ± 1 yr, with a body mass index of 18.5 ± 1.1 kg/m2.

Biochemical analysis

Plasma leptin was measured by RIA with reagents from Linco Research, Inc. (St. Louis, MO), with a detection limit of 0.5 ng/mL and an interassay coefficient of variation of 5–7%. Plasma cortisol and insulin levels were measured by RIA. Plasma glucose was measured using the glucose oxidase method. All samples from a single patient were measured in the same assay.

Statistical analysis

Data are expressed as the mean ± SE. Statistical analyses were performed using programs from SPSS, Inc. (Chicago, IL) (27). Between-group comparisons were made with ANOVA. Intrasubject comparisons were performed using repeated measures ANOVA. The effects of pubertal stage, gender, body mass index, weight-adjusted insulin dose, and food were tested by including each variable in the repeated measures ANOVA model.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Before treatment, plasma leptin concentrations in the patients with DKA were significantly lower than those in a control group of diabetic and healthy children of comparable age, gender distribution, and body mass index (4.9 ± 1.2 vs. 9.0 ± 1.8 vs. 11.2 ± 2.1 ng/mL; P < 0.05). Plasma leptin level in the patients increased to 6.4 ± 1.5, 7.5 ± 1.9, 9.1 ± 2.7, and 8.9 ± 2.5 at 6, 12, 18, and 24 h, respectively, after starting treatment (P = 0.001; Fig. 1Go). Thus, leptin levels increased by 38 ± 10% and 92 ± 38% within 6 and 24 h of starting treatment. Leptin levels at 24 h were significantly less than those in healthy controls, but not significantly different from those in diabetic controls. Leptin levels were significantly higher in girls than in boys at admission (6.0 ± 2 vs. 3.3 ± 1.6 ng/mL; P = 0.017) and throughout the treatment period after adjusting for age and body mass index. Analysis of food as a variable (Fig. 2Go), showed a mean of leptin at baseline and 24 h of 5.7 ± 2.0 vs. 11.5 ± 4.0 for the fasting group, and 3.8 ± 0.4 vs. 6.6 ± 1.6 for the group that could eat, which contained more younger and prepubertal patients. The increase in leptin was paralleled by an increase in insulin level and a decline in glucose and cortisol levels at 6 and 24 h (Fig. 3Go). However, there was no significant correlation between the weight-adjusted insulin dose and the proportional increase in leptin over 24 h.



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  		Figure 1. Changes in plasma leptin during treatment of diabetic ketoacidosis (solid circles). The leptin level in the healthy control group is shown (open circle). The leptin level in the diabetic control group is also shown (large solid circle).

 


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  		Figure 2. Changes in plasma leptin during treatment of DKA in fasting subjects (solid squares) and in those who could eat (open circles).

 


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  		Figure 3. Changes in plasma glucose (top line), insulin, cortisol, and leptin (bottom line) during insulin treatment of DKA.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our data show that plasma leptin concentration was significantly lower in children with DKA than in a comparable group of similar age, gender, puberty stage, and body mass index, and that treatment with insulin and fluids promptly increased plasma leptin. The low plasma leptin in DKA can be ascribed to several factors, including decreased food intake, insulin deficiency, accumulation of ketone bodies, and increased stress hormone levels. Lack of food intake, which is common in patients with DKA, could possibly explain the decreased leptin levels. Fasting (8, 9) and refeeding (10) were found to decrease and increase plasma leptin, respectively, in normal volunteers. Our data indicate, however, that food had no direct effect, as the changes in plasma leptin by 24 h were similar in subjects who were fed and those who were not. Furthermore, plasma leptin started to increase in the first 6 h, during which none of the patients consumed any food.

It is more plausible that the low leptin levels in DKA were due to insulin deficiency and that the increase in leptin with treatment resulted from insulin replacement. Lack of correlation between insulin dose and the proportional increase in leptin may be due to intersubject variations in endogenous insulin production. Destruction of ß-cells with streptozotocin has been shown to lower plasma leptin in rodents, an effect that could be reversed with insulin administration (28). In humans, Kiess and colleagues (29) found that patients with newly diagnosed untreated type 1 diabetes had significantly lower leptin levels than healthy controls, whereas insulin-treated patients had higher levels controlling for age, sex, and body mass index (the reverse was suggested by our data, but other variables, such as the duration and degree of diabetes control, may be operative). Low plasma leptin has also been described in morbidly obese patients with poorly controlled type 2 diabetes who were insulin deficient (30). Although some human studies could not demonstrate an acute effect of insulin on leptin (13, 14, 15, 16, 17, 18, 19, 20, 21, 22), we have recently shown that leptin levels decline progressively when fasting insulinemia is kept constant and that insulin infusions at physiological concentrations increased plasma leptin (26). Two other studies found high- and supraphysiological insulin infusions to increase plasma leptin in man (31, 32). More recently, acute insulin withdrawal was associated with a rapid decline in plasma leptin in children with type 1 diabetes (33).

In addition to insulin deficiency, DKA is associated with several metabolic and hormonal disturbances, some of which could contribute to the observed changes in plasma leptin. Increased concentrations of plasma glucose, free fatty acids, and ketone bodies occur in DKA, but none is a likely culprit. Hyperglycemia was shown not to have a direct effect on plasma leptin (22). Neither lipids (34) nor ß-hydroxybutyrate (9) infusions were found to impact leptinemia. Conversely, catecholamines, interleukins, and corticosteroids, which are often elevated in DKA, were found to affect leptin levels, but in different directions. Although catecholamines and sympathetic stimulation were shown to lower plasma leptin (35), interleukins and corticosteroids increased leptin production (36, 37). It is possible that interleukins played a role in the changes in plasma leptin, but cortisol levels were not consistent with a glucocorticoid-mediated increase in leptin. The plasma cortisol decline, although expected with DKA treatment, also raises the possibility of insulin being the link between glucocorticoid administration and increased leptin levels.

In conclusion, DKA was associated with a decreased plasma leptin concentration. Treatment resulted in a significant increase in plasma leptin, which can be attributed to the effect of insulin on leptin production. Feeding did not have an independent effect on plasma leptin. Hence, our data lend support to the hypothesis that insulin is the link between caloric intake and plasma leptin.


   Acknowledgments
 
We thank the nurses and the staff of the Pediatric Intensive Care Unit of Loma Linda University Children’s Hospital for their help during the study.

Received January 28, 1999.

Revised June 17, 1999.

Accepted August 18, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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