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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 654-657
Copyright © 1997 by The Endocrine Society

Clinical Studies

UKPDS 20: Plasma Leptin, Obesity, and Plasma Insulin in Type 2 Diabetic Subjects

Adji Widjaja, Irene M. Stratton, Ruediger Horn, Rury R. Holman, Robert Turner and Georg Brabant

Departments of Diabetes Research Laboratories (A.W., I.M.S., R.R.H., R.T.), Radcliffe Infirmary, Woodstock Road, Oxford, United Kingdom; and Abt Klinische Endokrinologie (R.H., G.B.), Medizinische Hochschule, Konstanty-Gutschow Strasse, Hannover, Germany

Address all correspondence and requests for reprints to: Professor R. C. Turner, Diabetes Research Laboratories Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, United Kingdom.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We measured plasma leptin and insulin concentrations across a spectrum of obesity in 829 white Caucasian, 154 Afro-Caribbean, and 204 Asian type 2 diabetic subjects. Although the leptin concentrations covered a large range, there were no subgroups of diabetic subjects with very high or low leptin levels that would suggest mutations in the leptin gene or leptin receptor gene comparable to the obese diabetic ob/ob and db/db mice models respectively. In all three ethnic groups, leptin concentrations correlated with body mass index (BMI) in a similar manner to nondiabetic patients and were higher in females than males after adjustment for BMI, with no difference between ethnic groups. In a multivariate regression analysis, plasma leptin was associated with gender and BMI, (both P < 1 x 10-17) and with fasting plasma insulin concentrations (P = 5 x 10-9). Subjects treated with insulin had both raised insulin and leptin concentrations. When matched for different therapies, gender, and BMI, diabetic subjects with high leptin levels also had high insulin levels (P < 0.0009). High leptin concentrations may in part be influenced by hyperinsulinemia or impaired insulin sensitivity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OBESITY IN the ob/ob mouse is the result of a nonsense mutation in the ob gene resulting in impaired production of the hormone leptin from adipocytes, leading to increased food intake, obesity, and diabetes (1). Administration of leptin to ob/ob mice decreased food intake, body weight, insulin, and glucose concentrations (2), but had no effect on db/db mice (3). In man, serum leptin concentrations are increased in relation to the increased body fat content (4) (5), in part because of the increased adipose tissue mass and also because of increased expression of ob messenger RNA (mRNA) by adipocytes. The high leptin levels associated with obesity imply that the satiety center is insensitive to endogenous leptin production (4). Insulin may interact with the control of leptin concentrations, as the low insulin concentrations induced by streptozotocin-induced diabetes in rats are associated with low ob mRNA levels in epididymal fat tissue, and an infusion of insulin for 3–4 h increased the adipocyte ob mRNA levels (6, 7). The hyperinsulinemia prevalent in human obese patients may play a role in regulating adipocyte ob mRNA expression and plasma leptin levels under physiological and pathophysiological states. In this study we investigated whether there was any indication of low leptin production or very high leptin levels in obese diabetic subjects from three ethnic groups, comparable to the genetically determined ob/ob and db/db mice models, reflecting impaired leptin formation or impaired sensitivity of the satiety center respectively. We also assessed the relationship between leptin and fasting plasma insulin concentrations.


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

Type 2 diabetic subjects. We studied 1187 type 2 diabetic subjects from 3 different ethnic groups, white Caucasian, Afro-Caribbean, and Asian Indian (Table 1Go). To cover the range of obesity, a stratified sample was taken from UKPDS subjects who attended clinics between 1992 and 1995 (Table 1Go). All subjects had been fasting from 2000 h the previous evening for a blood sample taken at a morning clinic. All subjects gave informed consent in accord with the Declaration of Helsinki and with approval of local Ethics Committees.


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  		Table 1. Demographic details of subjects with NIDDM according to ethnic group and gender, with plasma leptin and insulin concentrations

 
Radioimmunoassay for plasma leptin

Leptin was measured in EDTA plasma samples from type 2 diabetic patients, after storage at -20 C, by radioimmunoassay with rabbit antihuman leptin peptide (amino acids 126–140) antibody and I125 leptin 126–140 (8). Dilution curves of endogenous leptin measured in serum samples of 4 obese patients demonstrated parallelism to the standard curve. When 20 mL of pooled serum were fractionated by Sephadex G-50 chromatography (Pharmacia, Freiburg, Germany), a single fraction was recognized by the antibody. The minimum detectable concentration of the assay was 6 pmol/L; intraassay variation in serum was 4.8% at 100 pmol/L and interassay variation 8.3% at 100 pmol/L. Leptin concentrations in 12 plasma specimens were analyzed in parallel by a radioimmunoassay (Linco Research, Inc, St Louis, MO) using a polyclonal antibody raised in rabbits against recombinant human leptin and the assay described above. The measurements using leptin pep-tide 126–140 antibody and standards are 8-fold lower than those obtained with the same assay using human recombinant leptin antibody and standards, as binding of the leptin 126–140 antibody to the endogenous molecule is lower than to the peptide 126–140. However, the correlation between the assays’ results was good, rs = 0.96, so the overall results of the study were unaffected by the choice of assays.

Other analyses

Plasma glucose and urate were measured in the clinical centers with measurement monitored by a quality control scheme administered by the UKPDS coordinating laboratory. All other samples were transported at 4 C, overnight, to the coordinating laboratory. Insulin was measured by a double antibody radioimmunoassay (PhRIA 100; Pharmacia Ltd, Milton Keynes, Bucks, UK); normal fasting range 2.9–15.5 mU/L. HbA1c was measured by high performance liquid chromatography with a Bio-Rad DIAMAT, normal range 4.5–6.2%. Total HDL and LDL cholesterol and triglyceride were measured by an enzymatic colorimetric method with a Cobas FARA centrifugal analyzer (Roche Diagnostic Systems, Welwyn Garden City, Hertfordshire, UK).

Statistical analysis

The plasma leptin results were assessed in relation to obesity, calculated by body mass index (BMI). Plasma leptin and insulin were analyzed after log transformation. Multiple regression analysis was performed to evaluate the relation of other variables to the serum leptin concentration after adjustment for the BMI, gender, ethnic group, age, and current diabetic therapy.

A case control analysis identified 66 type 2 diabetic subjects with the highest leptin concentrations in relation to obesity, placing them in the top 10th percentiles of Studentized residuals after adjustment for gender, ethnic group, and BMI. These cases were then matched with control subjects from the lower half of the distribution of Studentized residuals, one control group for each case, for gender, ethnic group, age within 5 yr, BMI within 3 kg·m2, and the same diabetic therapy. The data describing the patients studied are expressed as mean ± 1 SD or geometric mean (SD range), and the results of analysis are described as mean ± 1 standard error of the mean (SEM) or geometric mean (SEM) range. All P-values were two-tailed and conducted with SAS software (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows the leptin concentrations in the different ethnic groups by gender, and Fig. 1Go shows the leptin concentrations relative to the BMI. In each ethnic group, the leptin levels were higher in obese diabetic than in normal weight diabetic subjects (Spearman rank correlation coefficient P < 0.001 in each case). The regression lines for log leptin vs. BMI were significantly different between male and female diabetic subjects in each of the three ethnic groups (each P < 0.0001), but not between ethnic groups. No subpopulation of diabetic subjects with distinctly high or low leptin levels, separate from the majority of the subjects, could be discerned.



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  		Figure 1. Relationship of log plasma leptin concentrations to BMI in male and female diabetic subjects from different ethnic groups.

 
Table 2Go shows the results of stepwise multivariate regression analysis of log leptin concentrations against the variables in Table 1Go. It confirmed the major association with both gender and BMI (each P < 1 x 10-17) and also an association with log fasting insulin concentrations (P < 5 x 10-9). Age and height were also significantly associated with leptin levels, whereas there was no association of log leptin with ethnic group, waist-hip ratio, hemoglobin A1c, or other variables.


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  		Table 2. Stepwise multiple regression analysis of log plasma leptin concentrations against other variables

 
The fasting insulin levels were significantly higher in patients treated with insulin, after adjustment for gender, ethnic group, and obesity (P < 0.0001). The leptin concentrations were also significantly higher in those on insulin therapy than on other therapies (P < 0.01; Table 3Go).


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  		Table 3. Relationship of fasting plasma leptin and insulin concentrations to current therapy, with adjustment for gender, BMI, and ethnic group

 
The case control analysis showed that subjects with leptin in the top 10th percentile after adjusting for BMI had significantly raised fasting plasma insulin levels 19(20 to 32) and 14(8 to 25) mU/l respectively (P = 0.0009), compared with diabetic subjects matched 1:1 by ethnic group, gender, BMI ± 3 kg·mL, age ± 5 yr, and current therapy. The cases and controls had no difference in their waist-hip ratios (mean difference 0.01 with SD 1.0) or for any of the other variables included in the stepwise analysis in Table 2Go. The relationship of plasma insulin and leptin concentrations was also apparent when patients with high leptin levels were compared with matched diabetic subjects on each therapy, i.e. on diet geometric mean 18 vs. 14 mU/L; insulin therapy 27 vs. 19 mU/L; chlorpropamide 18 vs. 12 mU/L; glibenclamide 17 vs. 13 mU/L; metformin and sulphonylurea 21 vs. 14 mU/L, respectively. There was no difference between the therapeutic doses in each comparison group, although there was a trend for a higher insulin dose in the subjects with high leptin levels treated with insulin compared with the matched diabetic subjects (geometric mean 49, 32 U/day respectively).

Clinical data at diagnosis of diabetic subjects with high leptin level adjusted for gender, ethnic group, and BMI were evaluated to determine whether they had different characteristics from matched diabetic subjects. The high leptin subjects had presented at an older age (52.3 yr vs. 49.1 yr, P < 0.01) but otherwise were not different in terms of height, waist-hip ratio, hemoglobin A1c, plasma cholesterol, low density lipid and high density lipid cholesterol, or triglyceride.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Fasting plasma leptin concentrations in white Caucasian, Afro-Caribbean and Asian diabetic subjects have been shown to be higher in obese than in normal weight subjects with noninsulin dependent diabetes mellitus and higher in females than in males, similar to that reported in nondiabetic subjects (4, 8). The difference in leptin levels between genders persisted after adjustment for BMI, and probably reflected the gender difference in distribution of body fat. We found no difference between the three ethnic groups. None of the obese diabetic patients had the characteristics that might be anticipated if their pathology was the same as in the obese diabetic mouse models, with either low leptin concentrations comparable to the ob/ob diabetic mouse (1) or very high leptin concentrations as in the db/db diabetic mouse, which has a splicing site mutation (9, 10, 11) and is insensitive to leptin (3, 12). In diabetic as well as nondiabetic humans (5), there is a large range of plasma leptin concentrations at each BMI, and a contribution of mutations in the leptin gene or leptin receptor genes to the variability cannot be excluded.

Type 2 diabetic subjects with high leptin levels had raised fasting insulin concentrations after adjusting for BMI, gender, ethnic group, age, and current therapy. This does not completely exclude a contribution of adiposity not measured by the BMI, such as central adiposity, to the raised insulin levels (13, 14), but this seems unlikely since the waist/hip ratio was not increased in those with high leptin levels. In addition to the association of raised plasma insulin with raised leptin levels, the diabetic subjects treated with insulin had both higher leptin and insulin concentrations than subjects treated with other therapies, suggesting that insulin may have a role in the regulation of leptin concentrations. These data are compatible with the suggestion that increased insulin levels may stimulate production of leptin from adipocytes (15, 16, 17, 18, 19), and that low ob-messenger RNA levels following streptozotocin-induced insulin deficiency may be the result of a lack of stimulatory effect of insulin on adipocyte leptin production (6, 7). The low leptin levels in obese C57BLKS-fat/fat mice might be the result of their low insulin levels accompanying hyperproinsulinemia secondary to a defect in carboxypeptidase E (17). On the other hand, impaired insulin sensitivity may both induce increased insulin levels and lead to raised leptin levels by down-regulation of the hypothalamic leptin receptors or the subsequent satiety response to leptin (20). Whether this might contribute to the weight gain induced by insulin therapy is uncertain (21).

In summary, we show that leptin plasma levels in a large group of subjects with noninsulin dependent diabetes mellitus are correlated to BMI independent of gender, age, and ethnic group. Increased leptin levels are associated with increased insulin levels, and whether this is caused by insulin stimulating leptin secretion or whether insulin resistance increases both insulin and leptin levels, is unknown.


   Acknowledgments
 
We are grateful to Ivy Samuel and Caroline Wood for assistance with the manuscript, to Pauline Sutton for the insulin assays, and to Dr. Sue Manley for arranging assay of specific samples for leptin.

Received June 21, 1996.

Revised September 10, 1996.

Accepted October 18, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. 1994 Positional cloning of the mouse obese gene and its human homologue. Nature. 372:425–432.[CrossRef][Medline]
  2. Pelleymonter MA, Cullen MJ, Baker MB, et al. 1995 Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 269:540–543.[Abstract/Free Full Text]
  3. Halaas JL, Gajiwala KS, Maffei M, et al. 1995 Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 269:543–546.[Abstract/Free Full Text]
  4. Considine RV, Sinha MK, Heiman ML, et al. 1996 Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 334:294–295.
  5. Maffei M, Halaas J, Ravussin E, et al. 1995 Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med. 1:1155–1161.[CrossRef][Medline]
  6. Becker DJ, Ongemba LN, Brichard V, Henquin JC, Brichard SM. 1995 Diet- and diabetes-induced changes of ob gene expression in rat adipose tissue. FEBS Lett. 371:324–328.[CrossRef][Medline]
  7. MacDougald OA, Hwang CS, Fan H, Lane MD. 1995 Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3–L1 adipocytes. Proc Natl Acad Sci USA. 92:9034–9037.[Abstract/Free Full Text]
  8. Horn R, Geldszus R, Pötter E, von zur Mühlen A, Brabant G. 1996 Radioimmunoassay for the detection of leptin in human serum. Exp Clin Endocrinol Diabetes. In press.
  9. Tartaglia LA, Dembski M, Weng X, et al. 1995 Identification and expression cloning of a leptin receptor, OB-R. Cell. 83:1263–1271.[CrossRef][Medline]
  10. Chen H, Charlat O, Tartaglia LA, et al. 1996 Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 84:491–495.[CrossRef][Medline]
  11. Lee GH, Proenca R, Montez JM, et al. 1996 Abnormal splicing of the leptin receptor in diabetic mice. Nature. 379:632–635.[CrossRef][Medline]
  12. Coleman DL. 1973 Effects of parabiosis of obese with diabetes and normal mice. Diabetologia. 9:294–298.[CrossRef][Medline]
  13. Hannan WJ, Wrate RM, Cowen SJ, Freeman CP. 1995 Body mass index as an estimate of body fat. Int J Eat Disord. 18:91–97.[Medline]
  14. Fletcher C, Peto R, Tinker C, Speizer FE. 1976 The natural history of chronic bronchitis and emphysema. Oxford: Oxford University Press.
  15. Sainsbury A, Cusin I, Doyle P, Rohner-Jeanrenaud F, Jeanrenaud B. 1996 Intracerebroventricular administration of neuropeptide Y to normal rats increases obese gene expression in white adipose tissue. Diabetologia. 39:353–356.[Medline]
  16. Saladin R, Vos Pd, Guerre-Millo M, et al. 1995 Transient increase in obese gene expression after food intake or insulin administration. Nature. 377:527–529.[CrossRef][Medline]
  17. Zheng D, Jones JP, Usala SJ, Dohm GL. 1996 Differential expression of ob mRNA in rat adipose tissue in response to insulin. Biochem Biophys Res Commun. 218:434–437.[CrossRef][Medline]
  18. Cusin I, Sainsbury A, Doyle P, Rohner-Jeanrenaud F, Jeanrenaud B. 1995 The ob gene and insulin: a relationship leading to clues to the understanding of obesity. Diabetes. 44:1467–1470.[Abstract]
  19. Schwartz MW, Marks JL, Sipols AJ, et al. 1991 Central insulin administration reduces NPY mRNA expression in the arcuate nucleus of food deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats. Endocrinology. 128:2645–2647.[Abstract]
  20. Jeanrenaud B. 1994 Central nervous system and peripheral abnormalities: clues to the understanding of obesity and NIDDM. Diabetologia. 37(Suppl 2):S170–S178.
  21. UKPDS Group. 1995 UK Prospective Diabetes Study 16: overview of six years’ therapy of type 2 diabetes - a progressive disease. Diabetes. 44:1249–1258.[Abstract]



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