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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 6 2593-2596
Copyright © 2003 by The Endocrine Society

Changes in Serum Leptin in Lean and Obese Subjects with Acute Hyperglycemic Crises

Abbas E. Kitabchi and Guillermo E. Umpierrez

Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Address all correspondence and requests for reprints to: Abbas E. Kitabchi, Ph.D., M.D., Professor of Medicine and Molecular Sciences, University of Tennessee Health Science Center, 951 Court Avenue, Room 335M, Memphis, Tennessee 38163. E-mail: akitabchi{at}utmem.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We aimed to determine the effect of insulin replacement on serum leptin concentration in lean and obese patients with diabetic ketoacidosis (DKA). We compared serial leptin levels in 52 patients with DKA, 14 obese subjects with hyperglycemia, and 52 nondiabetic control subjects. Leptin levels on admission were significantly decreased in lean and obese patients with DKA and/or hyperglycemia compared with weight- and gender-matched controls. Insulin therapy resulted in a significant increase in leptin levels within 4 h, with peak stimulation at 12 h. Leptin levels on admission and at resolution of hyperglycemia were higher in obese DKA (9.7 ± 2 ng/ml and 26.5 ± 5 ng/ml, respectively; P < 0.001) and obese hyperglycemia subjects (11.9 ± 4 ng/ml vs. 24.4 ± 2 ng/ml; P < 0.001) than in lean DKA subjects (5.3 ± 0.3 ng/ml and 10.1 ± 2 ng/ml; P < 0.001).

We conclude that insulin treatment in patients with acute hyperglycemic crises is followed by rapid and significant increase in leptin concentration, and this increase is more discernible in obese subjects. The low serum leptin level on admission in subjects with hyperglycemic crises may be the result of impaired adipocyte glucose utilization due to insulin deficiency and/or to increased catecholamine levels.


   Introduction
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 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LEPTIN, A LIPOSTATIC HORMONE secreted by adipocytes, is important in the regulation of body weight and energy metabolism. Leptin secretion is modulated by various factors, including changes in the ob gene expression, gender, body weight, hypothalamic-pituitary-adrenal axis state, caloric intake, energy expenditure, and diurnal variation (1, 2, 3, 4). In humans, the most significant correlate for serum leptin concentration is the percentage of body fat (5, 6). Similar to leptin, insulin plays a pivotal role in the regulation of energy metabolism and intermediary metabolism, and insulin levels correlate with body weight (7, 8). Despite their similar effects on energy balance and intermediary metabolism, their regulatory mechanisms are elusive. Although certain studies have reported no acute effect of insulin on serum leptin concentration (9, 10), other reports have shown such an effect in diabetic subjects (11, 12). Diabetic ketoacidosis (DKA), especially in African-Americans, may occur in lean and obese patients with graded degrees of pancreatic insulin reserve (as determined by basal and stimulated C-peptide levels), which is lower than in obese patients with nonketotic hyperglycemia (13, 14). Lean and obese patients with DKA and nonketotic hyperglycemia provide unique models in whom to evaluate the relationship, both at presentation and during insulin treatment, between circulating levels of serum leptin and insulin, as well as counterregulatory hormones.

We were able to demonstrate the presence of low levels of leptin in acute hyperglycemic conditions as well as a rapid stimulatory effect of insulin infusion on serum leptin concentration. Based on our data and review of the work in the literature, a hypothesis is proposed for the initial low level of leptin in hyperglycemic crises and its prompt response to insulin.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and materials

The study population included 36 lean patients with DKA (27 males and 9 females), 16 obese patients with DKA (5 males and 11 females), 14 obese patients with hyperglycemia but without ketoacidosis (6 males and 8 females), 22 lean nondiabetic controls (11 males and 11 females), and 30 obese nondiabetic (22 males and 8 females) subjects. The diagnosis of DKA was established in the emergency department by a plasma glucose level greater than 13.8 mmol/liter (250 mg/dl), a serum bicarbonate level no greater than 15 mmol/liter, a blood pH below 7.3, and a positive serum ketone level at a dilution of at least 1:4 by the nitroprusside reaction. Obese patients with nonketotic hyperglycemia were admitted with a plasma glucose level above 400 mg/dl (22.2 mmol/liter), a blood pH above 7.3, a serum bicarbonate level above 18 mEq/liter, and a serum ketone level no greater than 1:2 dilutions.

All patients with DKA were treated with a standard low-dose insulin infusion protocol (15, 16). In brief, initial fluid therapy with normal saline (0.9% NaC1) was given at a rate of 500-1000 ml/h for the first 2 h; subsequent fluid therapy was administered as half-normal saline (0.45% NaC1) at 200–500 ml/h. Insulin was administered by an initial iv bolus of 0.1 U/kg, followed by a continuous infusion of 0.1 U/kg·h until blood glucose levels decreased to approximately 13.8 mmol/liter (250 mg/dl). At this time, iv fluids were changed to dextrose-containing solutions, and the insulin infusion rate was decreased by 50% or to 0.05 U/kg·h. Thereafter, the rate of insulin administration was adjusted to keep blood glucose concentration approximately 12 mmol/liter (200 mg/dl) until resolution of ketoacidosis. Patients with nonketotic hyperglycemia received iv hydration and insulin therapy until glucose values were below 200 mg/dl.

During treatment, blood glucose levels were determined at bedside in all subjects every 2 h using a glucose oxidase reagent strip, and blood samples were drawn every 4 h for determination of serum electrolytes, glucose, venous pH, ß-hydroxybutyrate, free fatty acids (FFA), cortisol, and leptin levels. The results from these experimental groups were compared with those obtained in lean and obese nondiabetic control subjects after an overnight fast. Total serum osmolality was calculated as: [2 x sodium ion (mmol/liter)] + [glucose (mg/dl)/18] + [blood urea nitrogen (mg/dl)/2.8], with normal values being 290 ± 5 mmol/kg of water.

Chemical analysis

Serum leptin was measured by RIA, using the reagent obtained from Linco Research, Inc. (St. Charles, MO), which has a detection limit of 0.5 ng/ml and interassay coefficient of variation of 5–7%. Serum cortisol and insulin were measured by RIA, and FFA were measured by a colorimetric method established in this laboratory by the previously described method (17). Plasma glucose was measured using the glucose oxidase method. All samples from the same patients were measured in the same assay.

Statistical analysis

Mean values and SD were calculated for all continuous variables. To compare baseline demographics and clinical characteristics between groups, ANOVA with Scheffe’s method was used for continuous variables, with log transformations when necessary. For comparison of categorical variable, {chi}2 analyses were performed. A two-tailed P value of less than 0.05 was considered significant. StatView version 5.0 (SAS Institute, Inc., Cary, NC) was the statistical software used for the analysis (18).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The admission clinical and biochemical information in study and control subjects is shown in Table 1Go. Admission serum glucose and acid-base parameters were similar between obese and lean subjects with DKA. Obese subjects with hyperglycemia had a similar glucose level on admission, but normal serum bicarbonate and venous pH. The admission C-peptide concentration in lean (0.7 ± 0.1 ng/ml) and obese (1.0 ± 0.1 ng/ml) DKA patients was lower than in obese subjects with hyperglycemia (1.4 ± 0.1 ng/ml). Levels of ß-hydroxybutyrate, FFA, and cortisol were significantly higher in lean and obese DKA subjects than in obese subjects with hyperglycemia and nondiabetic controls.


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  		Table 1. Clinical characteristics on admission

 
Leptin levels on admission and at resolution of DKA or hyperglycemia in lean and obese diabetic subjects and controls are shown in Fig. 1Go. On presentation, the mean serum leptin levels in lean DKA (5.3 ± 0.3 ng/ml) and obese DKA subjects (9.7 ± 2 ng/ml) and with hyperglycemia (11.9 ± 4 ng/ml) were significantly lower than their pair-match nondiabetic control subjects (lean, 12 ± 3 ng/ml; obese, 24 ± 3 ng/ml; all, P < 0.01). Serum leptin levels in obese women with hyperglycemia were higher than in male subjects (22.6 ng/ml vs. 12.1 ng/ml, respectively; P < 0.01); however, we observed no significant gender differences in serum leptin concentration in lean DKA (female, 6.4 ± 0.5 ng/ml, vs. male, 4.9 ± 0.3 ng/ml; P = not significant) and obese DKA (female, 12.1 ± 4 ng/ml, vs. male, 8.9 ± 1 ng/ml; P = not significant) subjects. In nondiabetic control subjects, serum leptin correlated with body mass index (BMI), and obese women had 3-fold higher leptin levels than lean subjects (female, 31.9 ± 3.3 ng/ml, vs. male, 8.5 ± 2 ng/ml; P < 0.01). We found no correlation between admission serum leptin and glucose levels, acid-base parameters, cortisol, FFA, or concentration of ketone bodies.



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  		Figure 1. Leptin levels before and after therapy in lean and obese DKA, obese hyperglycemia, and control subjects.

 
Insulin administration resulted in a rapid and significant increase in serum leptin levels in lean and obese subjects with DKA and hyperglycemia. As shown in Fig. 2Go, the leptin response to insulin administration was greater in obese DKA subjects than in lean DKA subjects. Serum leptin levels in obese DKA subjects increased by 2-fold at 4 h and by 4-fold at 12 h of insulin therapy. Lean DKA patients demonstrated lower leptin levels on admission and a lower stimulatory effect during insulin infusion than obese DKA patients (P < 0.01), and levels during treatment in lean DKA patients did not reach significant difference until 12 h into insulin effusion (Fig. 2Go). In obese subjects with hyperglycemia, the stimulatory effect of insulin therapy was intermediate between obese and lean DKA, with an increase in serum leptin levels from 11.5 ng/ml to 36 and 24.4 ng/ml at 12 and 24 h, respectively (P < 0.01). In all groups, leptin values at resolution were significantly greater than at baseline, and levels were similar in value to those observed in weight-matched control nondiabetic subjects.



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  		Figure 2. Serum leptin levels in lean and obese patients during treatment of DKA.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our study indicates that serum leptin levels are markedly decreased in lean and obese patients with DKA and/or hyperglycemia, and that leptin levels increase rapidly during insulin infusion to reach levels similar to those observed in pair-weight nondiabetic controls at resolution of ketoacidosis and/or hyperglycemia.

All counterregulatory hormones (glucagon, cortisol, GH, catecholamines), as well as FFA, are known to be increased to various degrees in patients with hyperglycemic crises (15). Of these hormones, cortisol is the most potent known stimulator for leptin secretion in vivo as well in vitro in human subjects (19, 20). In contrast, catecholamines through ß-adrenergic receptor activation, inhibit leptin secretion (3, 4, 21). The question then arises as to why, in the presence of high levels of cortisol, leptin levels are decreased in patients with hyperglycemic crises. There are at least three possible explanations for such an observation. First, because hyperglycemic crises metabolically resemble the state of caloric deprivation, fasting and starvation may independently lower serum leptin level. A period of 72-h fasting is known to inhibit serum leptin concentration, which could be reversed by feeding or glucose infusion (22, 23). Second, fasting plasma glucose concentrations are negatively associated with leptin levels, independent of BMI, waist circumference, or insulin (24). Moreover, leptin secretion may be dependent on adipocyte glucose utilization, which is clearly attenuated during hyperglycemic crises (25). In hyperglycemic crises in which admission glucose is consistently above 250 mg/dl, such a level could conceivably contribute to a lower level of leptin. Third, while glucocorticoids stimulate leptin synthesis and release, their effect is nullified in the presence of ß-adrenergic agonists (26). Thus, these two counterregulatory hormones may exert opposite effects and could possibly neutralize each other. This situation, in the presence of absolute or relative reduction of insulin concentration, may bring about significant diminution of leptin level. There is also the possibility of the modulating effect of N-acetyl glucosamine pathway on leptin, a recently described phenomenon (27) that may or may not be affected in patients with hyperglycemic crises.

Previous studies on the effect of insulin in the regulation of leptin production have shown controversial results. Some studies have reported no acute effect of insulin on leptin release in normal or type 2 patients with diabetes; however, its stimulatory effect is universally seen with prolonged exposure of insulin in vitro and in vivo (9, 10). More recently, several studies have reported an acute stimulatory effect at physiological insulinemia in a dose-dependent fashion (11, 12, 28), as diurnal variation for the level of leptin is taken into consideration (29, 30).

Studies on the stimulatory effect of insulin on leptin in patients with DKA are limited to two previous reports. One study was conducted on a group of adolescent children in whom the low basal leptin level was demonstrated and was stimulated with low-dose insulin as early as 6 h during the insulin therapy (31). The second study consisted of 11 middle-aged Japanese patients in whom leptin levels were elevated on admission compared with control values, and levels were further increased during insulin therapy (32). The reason for the differences in basal levels of leptin in the two studies above is not clear. In none of these studies was the effect of severe hyperglycemia without ketoacidosis in obese subjects or the effect of insulin on gender evaluated. Our study differs from the two reports above in that we studied lean and obese subjects with and without ketoacidosis and separated the results in regard to gender to evaluate the role of each component. In agreement with Hathout et al. (31), we observed that serum leptin concentration was markedly decreased in patients with DKA, and that leptin concentration rapidly increased during insulin therapy. The leptin response to insulin administration was significantly greater and much earlier in obese DKA subjects than in lean DKA subjects. Although leptin levels in obese DKA subjects increased by 2- and 4-fold at 4 h and 12 h of insulin therapy, respectively, leptin levels in lean DKA did not reach significance until 12 h into insulin effusion.

Although the mechanisms for acute stimulatory effects of insulin on leptin in patients with DKA and/or severe hyperglycemia are not clear, it is possible that the insulin effect on adipocytes is modulated through inhibition of ß-adrenergic receptors. Insulin, in effect, can unmask the ability of glucocorticoid to stimulate leptin secretion. Furthermore, insulin, by correcting low glucose utilization in adipocytes, which can stimulate leptin secretion (25), may also stimulate leptin during recovery from DKA. A recent study on human adipose tissue reported that the stimulatory effect of dexamethasone on leptin is reduced by isoproterenol, which is reversed in the presence of 0.1 mM concentration of insulin in this primary culture preparation (26). The inhibitory effect of isoproterenol has also been demonstrated in human studies in which the infusion of 24 ng/kg·min of isoproterenol reduced serum leptin by 20–27% (33). Thus insulin stimulation of leptin may best be seen in the presence of a low, rather than high, concentration of catecholamines, when it is high enough to induce lipolysis (34).

Multiple factors and processes that are seen during severe metabolic decompensation of hyperglycemic crises, including elevated levels of counterregulatory hormones, ketone bodies, hyperglycemia, decreased caloric intake, and reduction in fat mass, are likely involved in reducing leptin levels (34, 35). The improvement in leptin concentration during treatment may be a direct effect of insulin on leptin production or an indirect insulin effect through inhibition of ß-adrenergic receptors in adipocytes.


   Acknowledgments
 
We thank Drs. Samuel Dagogo-Jack and John N. Fain for critical review of this manuscript. We gratefully acknowledge the technical assistance of John Crisler for the assay of hormones and metabolites.


   Footnotes
 
This work was supported in part by a clinical research grant from the American Diabetes Association (to A.E.K.).

Abbreviations: BMI, Body mass index; DKA, diabetic ketoacidosis; FFA, free fatty acids.

Received December 16, 2002.

Accepted February 20, 2003.


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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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