International Journal of Obesity (1998) 22, 171±177 ß 1998 Stockton Press All rights reserved 0307±0565/98 $12.00 Is there a relationship between leptin and insulin sensitivity independent of obesity? A population-based study in the Indian Ocean nation of Mauritius
PZ Zimmet1, VR Collins1, MP de Courten1, AM Hodge1, GR Collier2, GK Dowse3, KGMM Alberti4, J Tuomilehto5, F Hemraj6, H Gareeboo6, P Chitson6 and D Fareed 7on behalf of Mauritius NCD Study Group
1International Diabetes Institute, Melbourne, Australia; 2Deakin University, Geelong, Australia; 3Disease Control Service, Health Department, Western Australia; 4Department of Medicine, Newcastle-upon-Tyne, UK; 5Public Health Institute, Helsinki, Finland; 6Ministry of Health, Port Louis, Mauritius; and 7WHO Of®ce, Port Louis, Mauritius
OBJECTIVE: It has been shown previously in smaller studies that fasting serum leptin and insulin concentrations are highly correlated, and insulin sensitive men have lower leptin levels than insulin resistant men matched for fat mass. We have examined the association between insulin resistance (assessed by fasting insulin) and leptin after controlling for overall and central adiposity in a population-based cohort. DESIGN: Leptin levels were compared across insulin resistance quartiles within three categories of obesity (tertiles of body mass index (BMI)). Partial correlation coef®cents and multiple linear regression models were used to assess the relationship between leptin and fasting insulin after adjusting for BMI and waist to hip ratio (WHR) or waist circumference. SUBJECTS: Subjects were normoglycemic participants of a 1987 non-communicable diseases survey conducted in the multiethnic population of Mauritius. 1227 men and 1310 women of Asian Indian, Creole and Chinese ethnicity had normal glucose tolerance and fasting serum leptin measurements. RESULTS: Mean serum leptin concentration increased across quartiles of fasting insulin in each BMI group and gender, after controlling for BMI, WHR and age. Furthermore, fasting insulin was a signi®cant determinant of serum leptin concentration, independent of BMI and WHR, in both men and women. Similar results were found if waist circumference replaced BMI and WHR in the model. CONCLUSION: These results suggest that insulin resistance=concentration may contribute to the relatively wide variation in leptin levels seen at similar levels of body mass or alternatively, leptin may play a role in the etiology of insulin resistance. Further studies will be important to determine whether the hyperleptinemia=insulin resistance relationship has a role in the natural history of obesity, Type 2 diabetes mellitus and the other metabolic abnormalities associated with insulin resistance.
Keywords: leptin; insulin sensitivity; population-based study; obesity
Introduction The effects of short and long term insulin infusions on leptin production have been studied,11 and while the results suggest that ob gene expression and leptin Leptin, the circulating product of the recently discov- 12 ered ob gene, may be a critical factor in the control production are indirectly regulated by insulin, more of energy stores. The effects of leptin suggest regula- detailed studies are needed. Certainly, a strong posi- 1 tive correlation exists between leptin and insulin tion of energy balance at the hypothalamic level, and 10±14 leptin receptors have now been demonstrated in the concentrations, and insulin sensitive men have 2 lower leptin concentrations than those with insulin choroid plexus. Leptin treatment causes drama- 15 tic reductions in food intake and body weight resistance, independent of body fat mass. This raises in rodents.3±5 However, only the obese (ob=ob) important questions about the potential role of leptin mouse 3,4 lacks circulating leptin, whereas other in the modulation of insulin sensitivity, or vice versa. animal models of obesity.5±7 and obese humans8±10 The interrelationship of leptin and insulin sensitiv- show hyperleptinemia. ity is confounded by the strong association between leptin and obesity6,8±10 and the effect of obesity on insulin sensitivity,16 indicating the need to control for Correspondence: Professor Paul Zimmet, International Diabetes the effect of obesity. In addition, much of human Institute, 260 Kooyong Road, Caul®eld South, Victoria, 3162, leptin research so far has been based on small clinical Australia. 8,9,13±15 Received 19 March 1997; revised 9 September 1997; accepted studies. This study aimed to evaluate the 26 September 1997 relationship between insulin sensitivity and leptin Leptin and insulin sensitivity PZ Zimmet et al 172 concentration independent of obesity in data from a Spearman rank correlation coef®cients were calcu- large epidemiological study of diabetes and cardio- lated between all variables using a 2-tailed test for vascular (CVD) disease in the multiethnic population signi®cance. The relationship of serum leptin concen- of Mauritius.17 tration to insulin resistance was examined within gender-speci®c tertiles of BMI. For men, the cut-off points to de®ne the tertiles were 21.0 and 24.0 kg=m2 Research design and methods and for women they were 21.1 and 25.0 kg=m2. Within each tertile of BMI, gender-speci®c distribu- Subjects. The subjects were drawn from a population- tions of fasting insulin were divided into quartiles. based non-communicable disease survey performed in Mean levels of serum leptin were calculated across Mauritius in 1987 and are described in detail else- quartiles of fasting insulin adjusting for differences in 17,18 where. Mauritius is an island nation located in the age, BMI and WHR by analysis of covariance. The southwestern Indian Ocean. The multiethnic popula- signi®cance of differences across groups was assessed tion comprises about 70% of Asian Indian origin, by the F-test. Log10transformation was used to nor- 27.9% Creole (mixed with mainly African ancestry) malize distributions of leptin, fasting glucose and and 2.1% Chinese. The survey protocol was reviewed fasting insulin, and mean values were back-trans- and approved by the Alfred Healthcare Group Ethics formed for presentation. The independent linear rela- Committee (Melbourne, Australia) and consent of the tionship between log10leptin and log10fasting insulin subjects for leptin measurement was inferred from their was assessed using all subjects after adjusting for age, voluntary participation. BMI, WHR and log10fasting glucose in multiple linear regression models calculated for men and women Survey procedure and analyses. All adults aged 25± separately. Partial correlations of fasting insulin with 74 y were eligible to attend the survey if resident in leptin were calculated as the other variables were the population clusters chosen in the representative sequentially added to the model. These models were sample.17 Subjects presented to a survey site between also used to calculate the overall R2 and signi®cance 08:00 and 10:00 h after an overnight fast. All subjects of changes in R2 as the independent variables were not using oral hypoglycaemic tablets or insulin, under- added. Similar linear regression models using waist went an oral glucose tolerance test (75 g dextrose circumference instead of BMI and WHR were also monohydrate). Fasting and 2 h blood samples were calculated. In an alternative analysis, insulin sensitiv- collected and plasma glucose was measured on site ity computed using the Homeostasis Model Assess- using a glucose analyser (YSI, Yellow Springs, OH). ment (HOMA) model24 was used instead of fasting Glucose tolerance status was classi®ed according to insulin. WHO recommendations.19 Body mass index (BMI) was calculated as kg=m2 and waist and hip girth were measured in duplicate to calculate waist to hip ratio (WHR) from the means of Results measurements as previously described.18 Eligibility for the present study was limited to 1227 Table 1 shows the mean levels of selected variables in men and 1310 women who had normal glucose the study subjects. Men were leaner (according to tolerance19 in 1987, and who also attended a follow- BMI), but had higher mean WHR and waist circum- up survey in 1992. Serum leptin levels were only ference than women. All subjects had normal glucose available for those who participated in both surveys. tolerance (by selection), although mean fasting glu- Leptin measurements on sera frozen since 1987 cose levels were higher in men than women. Women (720C), were performed in 1996, using radioimmu- had higher fasting insulin concentration and also were noassay kits (Linco, St Louis, MO). Insulin values for more insulin resistant on the basis of HOMA than the same subjects were measured in 1987 on frozen men. Mean serum leptin levels were about 3-fold sera using an in-house assay.20,21 Interassay and higher in women than men (10.2 vs 3.4 ng=ml). intraassay coef®cients of variation were 6% and 4%, To assess associations between the variables used in respectively. Cross-reactivity with intact proinsulin later multivariate analyses, Table 2 shows Spearman and 32,33-split proinsulin was 27% and 16%, respec- correlation coef®cients between the anthropometric tively. There was < 5% difference between results and metabolic variables. Insulin sensitivity calculated obtained with this assay and a highly speci®c enzyme- from the HOMA model was very strongly correlated linked immunosorbent assay. Fasting insulin was used with fasting insulin in both men and women. Leptin as a marker of insulin sensitivity. It has previously was signi®cantly correlated with each of the anthrop- been shown that in non-diabetic subjects fasting metric variables, although the relationship with WHR insulin is closely correlated with more direct measures was not as strong as with BMI or waist circumference. of insulin resistance.22 Strong correlations were also observed between leptin and the metabolic variables, except fasting glucose. Statistical analysis. All analyses were performed Figure 1 depicts age-, BMI- and WHR-adjusted using the Statistical Package for the Social Sciences.23 geometric mean leptin according to quartiles of fast- Leptin and insulin sensitivity PZ Zimmet et al 173 Table 1 Mean (95% con®dence intervals) levels of selected characteristics of Mauritians in the study
Characteristics Men Women
n 1227 1310 Age (y) 39.9 (39.2±40.5) 40.5 (39.8±41.1) BMI (kg=m2) 22.7 (22.5±22.9) 23.5 (23.3±23.8) WHR 0.88 (0.88±0.89) 0.80 (0.79±0.80) Waist (cm) 77.0 (76.6±77.5) 72.6 (72.0±73.1) Fasting plasma glucose (mmo1=1)a 5.17 (5.15±5.20) 5.04 (5.02±5.07) Fasting serum insulin (mU=ml)a 4.16 (3.92±4.41) 5.44 (5.19±5.69) HOMAS (%)a 85.2 (81.1±89.5) 69.1 (66.3±72.0) Serum leptin (ng=ml)a 3.36 (3.24±3.47) 10.17 (9.78±10.58)
a Geometric mean. BMI body mass index; WHR waist to hip ratio, HOMAS insulin sensitivity from the HOMA model. ing insulin within categories of obesity. At each level reduced to about half by adjustment for BMI. Further of obesity, and in both men and women, there was a adjustment for age, fasting glucose and WHR did not highly signi®cant increase in mean leptin levels with alter the magnitude of the partial correlation coef®- increasing insulin resistance (P < 0.001 for each com- cient. The models shown in Table 3 explained 43% parison). It can also be seen from Figure 1, that leptin and 53% of the variation in leptin in men and women, levels increase across BMI categories (note the dif- respectively. If BMI and WHR were replaced with ference in the magnitude of the scales of the leptin waist circumference 44% and 48% of this variation axes between BMI groups). This analysis was was explained. A BMI by fasting insulin interaction repeated for each ethnic group separately (data not term was also tested, but was not signi®cant in either shown) and the relationship between fasting insulin gender. Models using insulin resistance from the and leptin was consistent for each of Indians, Creoles HOMA model rather than fasting insulin concentra- and Chinese, although differences across fasting insu- tion showed very similar results. lin were not statistically signi®cant in Chinese, due to small numbers. To assess the linear relationship between leptin and Discussion fasting insulin across the entire range of obesity, multiple linear regressions were performed with leptin (log10) as the dependent variable, on men and This study, in a large population-based cohort, con- women separately (Table 3). Partial correlation coef- ®rms results of clinic-based investigations14,15 and our ®cients for insulin, adjusting for the other independent ®ndings in another population,10 that insulin resis- variables are presented along with R2 for the models. tance (as indicated by fasting insulin concentration) is The partial correlation coef®cient for fasting insulin associated with elevated leptin concentrations inde- alone was about 0.5 in both men and women but was pendent of adiposity and fat distribution. More insulin
Table 2 Spearman correlations of anthropometric and metabolic variables used in analyses
Fasting Fasting BMI Age Waist WHR Leptin insulin glucose
Men BMI Age 0.024ns Waist 0.866*** 0.143*** WHR 0.594*** 0.271*** 0.762*** Leptin 0.633*** 0.106*** 0.635*** 0.433*** Fasting insulin 0.561*** 7 0.064* 0.572*** 0.379*** 0.540*** Fasting glucose 0.102*** 0.161*** 0.142*** 0.138*** 0.051ns 0.177*** HOMAS 7 0.561*** 0.056* 7 0.573*** 7 0.381*** 7 0.537*** 7 0.999*** 7 0.216***
Women BMI Age 0.135*** Waist 0.863*** 0.234*** WHR 0.478*** 0.315*** 0.747*** Leptin 0.708*** 0.011ns 0.636*** 0.336*** Fasting insulin 0.479*** 7 0.053ns 0.480*** 0.310*** 0.506*** Fasting glucose 0.138*** 0.304*** 0.174*** 0.165*** 0.068* 0.179*** HOMAS 7 0.499*** 0.040ns 7 0.487*** 7 0.314*** 7 0.504*** 7 0.999*** 7 0.219***
* P < 0.05; ** P < 0.01; *** P < 0.001; ns not statistically signi®cant. BMI body mass index; WHR waist to hip ratio, HOMAS insulin sensitivity from the HOMA model. Leptin and insulin sensitivity PZ Zimmet et al 174 contributing to variations in leptin. This observation may also be important in explaining male=female differences in leptin levels which persist after adjust- ing for body fat in some studies, and do not appear to be explained by levels of female reproductive hor- mones.26±30 The HOMA model has been suggested as a useful tool for assessing insulin sensitivity in large epide- miological studies, where it is prohibitive, both eco- nomically and practically, to undertake more complex assessments of insulin sensitivity.31,32 HOMA esti- mates of insulin resistance have been shown to corre- late well with more direct methods.33 However, when HOMA derived insulin sensitivity is strongly corre- lated with fasting insulin, as observed in this popula- tion, it is not adding any extra information. Haffner and colleagues34,35 have reported similar high correla- tion coef®cients for HOMA insulin sensitivity and fasting insulin in the Mexico City Diabetes Study and San Antonio Heart Study populations, concluding that the HOMA model may be most useful for estimating b-cell function. Thus it is not surprising that similar results were obtained, whether HOMA insulin sensi- tivity or fasting insulin were used. To account for the confounding effect of obesity on leptin and insulin sensitivity, Segal et al15 assessed the relationship speci®cally in 18 lean insulin sensitive and resistant men matched closely for body fat mass. Insulin sensitivity was classi®ed using an intravenous glucose tolerance test and minimal model analysis. Leptin was signi®cantly lower in the lean insulin sensitive subjects than in those who were relatively insulin resistant. Our study uses indirect estimates of both insulin resistance and fat mass but given the magnitude of the observed difference, it seems unli- kely that this effect would be lost if more direct measures were used. Moreover, the association of Figure 1 Age-, BMI- and WHR-adjusted mean leptin levels insulin sensitivity and leptin, independent of BMI according to quartiles of fasting insulin within obesity groups and WHR or waist circumference, was seen over the (BMI tertiles) in Mauritian men and women. ***P < 0.001 across entire population range of BMI (not just in lean insulin resistance quartiles. subjects), and in both men and women. There is a possibility that the contribution of adipose tissue to leptin levels was not being fully resistant subjects had leptin levels consistently higher accounted for by adjusting for BMI and WHR. In fact, than insulin sensitive subjects regardless of gender or there was a trend for increasing waist circumference level of obesity, and this was true in each ethnic with insulin resistance, after correcting for BMI (data group. Linear regression models con®rmed the asso- not shown), although it was not possible to adjust for ciations observed within BMI tertiles. Consistent with both BMI and WHR when assessing waist circumfer- earlier reports,8±10 mean leptin concentration was ence, due to collinearity. However, Segal's study substantially higher in obese than lean Mauritian assessing the effect of adipose tissue mass with subjects, and women had leptin levels at least three more sophisticated methods such as densitometry times higher than men. Moreover, the large variation con®rms the independence of the relationship of in leptin at similar levels of BMI suggests that factors leptin with measures of insulin resistance.15 besides obesity are important in regulating serum A number of other studies have examined the leptin.8±10 Insulin sensitivity appears to be one such relationship between leptin and insulin resistance or factor. insulin concentration independent of obesity with Testosterone levels or the ratio of androgen- con¯icting results. Havel et al36 found that leptin =estrogen have recently been observed to correlate was correlated with fasting insulin in women over a negatively with leptin concentrations in men indepen- range of BMI, but after adjusting for BMI or percent dent of BMI,25 suggesting another possible factor body fat this relationship was no longer signi®cant. In Leptin and insulin sensitivity PZ Zimmet et al 175 Table 3 Partial correlation coef®cients for log10 fasting insulin with log10 leptin as the dependent variable, after controlling for the other variables which were added to the linear regression model in order of listing.
Stepwise linear regression Partial correlations model
Partial correlation Significance Significance of Variable entered coefficient (PCC) of PCC Adjusted R2 change in R2
Men Fasting insulina 0.498 < 0.001 0.25 < 0.001 BMI 0.251 < 0.001 0.42 < 0.001 Age 0.264 < 0.001 0.43 < 0.001 Fasting glucosea 0.273 < 0.001 0.43 0.007 WHR 0.269 < 0.001 0.43 0.106
Women Fasting insulina 0.507 < 0.001 0.26 < 0.001 BMI 0.260 < 0.001 0.52 < 0.001 Age 0.250 < 0.001 0.52 0.007 Fasting glucosea 0.256 < 0.001 0.53 0.029 WHR 0.255 < 0.001 0.53 0.759
a log transformed. BMI body mass index; WHR waist to hip ratio.
African-American women, leptin was not correlated shown to be a potent regulator of leptin gene expres- with insulin sensitivity (by intravenous glucose toler- sion in cultured human adipocytes and to induce ance test) after adjusting for body fat mass by dual- increased leptin production.12 Clinical studies of the energy X-ray absorbtiometry (DEXA).37 Studies by effects of insulin on leptin also show mixed results. Larsson et al,38 Kohrt et al39 and Turpeinen et al 40 In some studies, no short-term effect was also found that insulin or insulin sensitivity did not observed,11,13,14 although Kolaczynski et al11 demon- correlate with leptin, independent of obesity, mea- strated that in the long-term (48±72 h) insulin may sured by impedance, DEXA or infra-red densitometric regulate ob gene expression and leptin production assay, respectively, in subjects with normal or indirectly, possibly via a trophic effect on adipocytes. impaired glucose tolerance. More rapid, although not acute, responses of leptin to However, in support of our ®ndings, leptin was insulin have also been observed. In normal and Type 2 independently related to insulin sensitivity (hyperin- diabetic subjects, leptin levels were increased by 8.5 h sulinaemic, euglycaemic clamp) after adjusting for of hyperinsulinemic clamp,43 and leptin levels were body fat percentage in Danish men and women,30 increased after only 4 h of supraphysiological hyper- and in a large epidemiological study, leptin levels insulinaemia in lean normal subjects.44 However, the were related to fasting insulin independently of lack of acute effects of insulin on leptin implies that BMI.41 None of the positive results discussed so far post-prandial satiety is not regulated by leptin,44 have indicated the relative strength of the relation- although insulin may be important in long-term ships between leptin and insulin concentration or leptin regulation.11,43,44 insulin sensitivity. As these two parameters are clo- On the other hand, ®ndings from a study using sely correlated in most populations, it is dif®cult to human liver cells have suggested that leptin when differentiate between them. Both fasting insulin and administered in concentrations similar to that found in insulin sensitivity (hyperinsulinaemic, euglycaemic obesity, antagonizes insulin signaling.45 This led the clamp) were correlated with leptin independently of authors to conclude that secretion of leptin by adipose BMI in middle-aged Finnish men, but no attempt was tissue may be a mechanism whereby adiposity causes made to assess which was more important.42 In sub- insulin resistance. In the Israeli Sand rat (Psammomys jects with Type 2 diabetes mellitus, the association obesus), a model of Type 2 diabetes, leptin has been between insulin concentration and resistance is not as reported to inhibit insulin binding to adipocyte insulin close, and in two studies making use of this phenom- receptors, offering another mechanism whereby enon, leptin was found to be more closely correlated hyperleptinaemia could contribute to insulin resis- with insulin concentration than with insulin resistance. tance in obesity.46 These inconsistent results indicate the need to stan- At the genetic level, the leptin receptor and acute dardize the approach to investigations into leptin, insulin response loci appear to be closely co-localised insulin and obesity. on chromosome 1, as demonstrated in Pima Indians.47 Results from a cross-sectional study such as this do It has been suggested therefore, that the leptin recep- not reveal the direction of the association between tor gene could play a secondary role in regulation of leptin and insulin resistance. However, recent studies the acute insulin response (AIR), with high leptin have shed some light on the possible effects of insulin levels down-regulating the receptor gene and dimin- and=or insulin resistance on leptin. Insulin has been ishing AIR, which may in turn have implications for Leptin and insulin sensitivity PZ Zimmet et al 176 insulinaemia and insulin sensitivity. However, if Reduced sensitivity compared with lean animals. Diabetes leptin and insulin are acting as part of a feed-back 1996; 45: 1446±1450. 6 Frederich RC, Hamann A, Anderson S, LoÈllman B, Lowell loop controlling adipose tissue mass, each could BB, Flier JS. Leptin levels re¯ect body lipid content in mice: modulate the other simultaneously. Direct effects of Evidence for diet-induced resistance to leptin action. Nature leptin on insulin sensitivity at the insulin receptor Medicine 1995; 1: 1311±1314. have yet to be examined in humans. Only studies 7 Collier G, Walder K, Lewandowski P, Sanigorski A, Lee investigating the effect of leptin administration, once S, Zimmet P. Development of obesity and hyperleptinemia in Psammomys obesus. Diabetologia 1996; 39 (Suppl 1): leptin is available for human use, on insulin concen- A146. trations or insulin sensitivity, will help to clarify these 8 Maffei M, Halaas J, Ravussin E, Prateley RE, Lee GH, Zhang associations. Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, In conclusion, our ®ndings in a large population- Friedman JM. Leptin levels in human and rodent: Measure- based sample are consistent with a biological link ment of plasma leptin and ob RNA in obese and weight- reduced subjects. Nature Medicine 1995; 1: 1155±1161. between leptin and insulin. They also suggest that 9 Considine RV, Sinha MK, Heiman ML, Kriauciunas A, there are determinants of serum leptin concentration Stephens TW, Nyce MR, Ohannesian JP, Marco CC, Mckee beside body fat. Insulin resistance or insulin concen- LJ, Bauer TL, Caro JF. Serum immunoreactive-leptin concen- tration per se, or via determinants including genetic, trations in normal-weight and obese humans. N Engl J Med biological and environmental factors16,31 may modu- 1996; 334: 292±295. 10 Zimmet P, Hodge A, Nicolson M, Staten M, de Courten M, late leptin concentration. Alternatively, leptin itself Moore J, Morawiecki A, Lubina J, Collier G, Alberti G, may have an important role in the determination of Dowse G. Serum leptin concentration, obesity, and insulin insulin resistance in the liver,45 or through interactions resistance in Western Samoans: cross sectional study. BMJ with the insulin receptor.46 Our ®ndings of a strong 1996; 313: 965±969. association between leptin and a marker for insulin 11 Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF. Acute and sensitivity independent of obesity suggest an impor- chronic effects of insulin on leptin production in humans. tant role for leptin in human metabolism. Further Studies in vivo and in vitro. Diabetes 1996; 45: 699±701. studies on the dynamics of the relationship between 12 Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Eng- leptin, insulin and adipose tissue are required to laro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner clarify the underlying importance of leptin. Prospec- H. Insulin and cortisol promote leptin production in cultured human fat cells. Diabetes 1996; 45: 1435±1438. tive epidemiological studies will also be required to 13 Gabriel M, Jinagouda S, Boyadjian R, Kades W, Ayad M, assess the possible role of leptin in the natural history Saad M. Is leptin the link between obesity and insulin of obesity and glucose intolerance. resistance? Diabetes 1996; 45 (Suppl 2): 51A. 14 Dagogo-Jack S, Fanelli C, Paramore D, Brothers J, Landt M. Plasma leptin and insulin relationships in obese and nonobese Acknowledgements humans. Diabetes 1996; 45: 695±698. This study was a collaborative project with invaluable 15 Segal KR, Landt M, Klein S. Relationship between insulin support provided by the Government and Health sensitivity and plasma leptin concentration in lean and obese men. Diabetes 1996; 45: 988±991. Department of Mauritius, and the World Health Orga- 16 Kolaczynski JW, Caro JF. Molecular mechanism of insulin nization. The work was supported by Grant DK-25446 resistance in human obesity. Current Opinion in Endocrinol- from the National Institute of Diabetes and Digestive ogy and Diabetes 1996; 3: 36±43. and Kidney Diseases. We are grateful to the whole 17 Dowse G, Gareeboo H, Zimmet P, Alberti K, Tuomilehto J, survey team, especially Mr Ray Spark and Ms Linda Fareed D, Brissonnette L, Finch C. High prevalence of NIDDM and impaired glucose tolerance in Indian, Creole Ashworth for technical assistance, and to the British and Chinese Mauritians. Diabetes 1990; 39: 390±396. Diabetic Association for laboratory support. 18 Dowse G, Zimmet P, Gareeboo H, Alberti K, Tuomilehto J, Finch C, Chitson P, Tulsidas H. Abdominal obesity and physical inactivity as risk factors for NIDDM and impaired References glucose tolerance in Indian, Creole and Chinese Mauritians. 1 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Diab Care 1991; 14: 271±282. Friedman J. Positional cloning of the mouse obese gene and 19 World Health Organization. Diabetes Mellitus: Report of a its human homolgue. Nature 1994; 372: 425±432. WHO Study Group. WHO, Geneva: 1985. 2 Tartaglia L, Dembski M, Weng X, Deng N, Culepper J, Devos 20 Soeldner J, Slone D. Critical variables in radioimmunoassay of R, Richards G, Camp®eld L, Clark F, Deeds J, Muir C, Sanker serum insulin using the double antibody technique. Diabetes S, Moriarty A, Moore K, Smutko J, Mays G, Woolf E, Monroe 1965; 14: 771±779. C, Tepper R. Identi®cation and expression cloning of a leptin 21 Dowse G, Zimmet P, Alberti K, Brigham L, Carlin J, Tuomi- receptor, OB-R. Cell 1995; 85: 1265±1271. lehto J, Knight L, Gareeboo H. Serum insulin distributions and 3 Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, reproducibility of the relationship between 2-hour insulin and Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight- plasma glucose levels in Asian Indian, Creole and Chinese reducing effects of the plasma protein encoded by the obese Mauritians. Metabolism 1993; 42: 1232±1241. gene. Science 1995; 269: 543±546. 22 Laakso M. How good a marker is insulin level for insulin 4 Pelleymounter M, Cullen M, Baker M, Hecht R, Winters D, resistance? Amer Epidemiol 1993; 137: 959±965. Boone T, Collins F. Effects of the obese gene product on 23 SPSS PC 4.0 for the IBM PC=XT=AT and PS=2 [program]. body weight regulation in ob=ob mice. Science 1995; 269: SPSS Inc., Chicago: 1990. 540±543. 24 Rudenski A, Matthews D, Levy J, Turner R. Understanding 5 Cusin I, Rohner-Jeanrenaud F, Stricker-Krongrad A, Jeanre- `Insulin Resistance': Both glucose resistance and insulin naud B. The weight-reducing effect of an intracerebro-ventri- resistance are required to model human diabetes. Metabolism cular bolus injection of leptin in genetically obese fa=fa rats. 1991; 40: 908±917. Leptin and insulin sensitivity PZ Zimmet et al 177 25 JockenhoÈvel F, Blum W, Vogel E, Englaro P, MuÈller-Wieland 36 Havel P, Kasim-Karakas S, Mueller W, Johnson P, Gingerich D, Dankwart R, Rascher W, Krone W. Testosterone substitu- R, Stern J. Relationship of plasma leptin to plasma insulin and tion normalizes elevated serum leptin levels in hypogonadal adiposity in normal weight and overweight women: Effects of men. Clin Endocrinol and Metab 1997; 82: 2510±2513. dietary fat content and sustained weight loss. J Clin Endocri- 26 Masuzaki H, Hosoda K, Ogawa Y, Miyawaki T, Hiraoka J, nol Metab 1996; 81: 4406±4413. Hanaoka I, Yasuno A, Natsui K, Sugawara A, Arii S, Yoshima 37 Dua A, Hennes M, Hoffman R, Maas D, Krakower G, Y, Nishi S, Yamori Y, Nakao K. Glucocorticoid and gender Sonnenberg G, Kissebah A. Leptin: A signi®cant indicator regulate plasma leptin levels in humans. Diabetologia 1997; of total body fat but not of visceral fat and insulin insensitivity 40 (Suppl. 1): A175. in African-American women. Diabetes 1996; 45: 1635±1637. 27 Havel PJ, Kasim-Karak S, Dubuc GR, Muhler W, Phinney SD. 38 Larsson H, ElmstaÊhl S, AhreÂn B. Plasma leptin levels correlate Gender differences in plasma leptin concentrations. Nature to islet function independently of body fat in postmenopausal Medicine 2: 949±950 (Letter). women. Diabetes 1996; 45: 1580±1584. 28 Kennedy A, Gettys T, Watson P, Wallace P, Ganaway E, Pan 39 Kohrt W, Landt M, Birge Jr S. Serum leptin levels are reduced Q, Garvey W. The metabolic signi®cance of leptin in humans: in response to exercise training, but not hormone replacement Gender-based differences in relationship to adiposity, insulin therapy, in older women. J Clin Endocrinol Metab 1996; 81: sensitivity, and energy expenditure. J Clin Endocrinol Metab 3980±3985. 1997; 82: 1293±1300. 40 Turpeinen A, Haffner S, Louheranta A, Niskanen L, Miettinen 29 Rosenbaum M, Nocolson M, Hirsch J, Heyms®eld S, Galla- H, Uusitupa M. Serum leptin in subjects with impaired glucose gher D, Chu F, Leibel R. Effects of gender, body composition, tolerance in relation to insulin sensitivity and ®rst-phase and menopause on plasma concentrations of leptin. J Clin insulin response. Int J Obes 1997; 21: 284±287. Endocrinol Metab 1996; 81: 3424±3427. 41 Stolk R, Janssen J, Pols H, Englaro P, Blum W, Attanasio A, 30 Nyholm B, Fisker S, Lund S, Mùller N, Schmitz O. Increased Grobbee D, Lamberts S. Insulin and leptin are related inde- circulating leptin concentrations in insulin-resistant ®rst- pendently from body mass index. Diabetologia 1997; 40: degree relatives of patients with non-insulin-dependent dia- A262. betes mellitus: relationship to body composition and insulin 42 Haffner S, Miettinen H, MykkaÈnen L, KarhapaÈaÈ P, Rainwater sensitivity but not to family history of non-insulin-dependent D, Laakso M. Leptin concentrations and insulin sensitivity in diabetes mellitus. Eur J Endocrinol 1997; 136: 173±179. normoglycemic men. Int J Obes 1997; 21: 393±399. 31 Dowse G, Qin H, Collins V, Zimmet P, Alberti K, Gareeboo 43 MalmstroÈm R, Taskinen M-R, Karonen S-L, Yki-JaÈvinen H. H. Determinants of estimated insulin resistance and B-cell Insulin increases plasma leptin concentrations in normal sub- function in Indian, Creole and Chinese Mauritians. Diab Res jects and patients with NIDDM. Diabetologia 1996; 39: 993± Clin Prac 1990; 10: 265±279. 996. 32 Multi-Centre S. UK prospective diabetes study. v. Character- 44 Utriainen T, MalmstroÈmR,MaÈkimattila S, Yki-JaÈrvinen H. istics of newly presenting type 2 diabetic patients: estimated Supraphysiological hyperinsuliemia increases plasma leptin insulin sensitivity and islet B-cell function. Diab Med 1988; 5: concentrations after 4 h in normal subjects. Diabetes 1996; 444±448. 45: 1364±1366. 33 Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, 45 Cohen B, Novick D, Rubinstein M. Modulation of insulin Turner R. Homeostasis model assessment: insulin resistance activities by leptin. Science 1996; 274: 1185±1188. and B-cell function from fasting plasma glucose and insulin 46 Walder K, Filippis A, Clark S, Zimmet P, Collier G. Leptin concentrations in man. Diabetologia 1985; 28: 412±419. inhibits insulin binding in isolated rat adipocytes. Diabetolo- 34 Haffner S, Gonzalez C, Miettinen H, Kennedy E, Stern M. A gia 1997; 40:A 176. prospective analysis of the HOMA model: The Mexico City 47 Norman R, Leibel R, Chung W, Power-Kehoe L, Chua SJ, Diabetes Study. Diabetes Care 1996; 19: 1138±1141. Knowler W, Thompson D, Bogardus C, Ravussin E. Absence 35 Haffner S, Miettinen H, Stern M. The homeostatis model in of linkage of obesity and energy metabolism to markers the San Antonio Heart Study. Diabetes Care 1997; 20: 1087± ¯anking homologues of rodent obesity genes in Prima Indians. 1092. Diabetes 1996; 45: 1229±1232.