Original PDF Flash format ej6119-173..179  


Ej6119 173..179

European Journal of Endocrinology (2001) 145 173±179
ISSN 0804-4643
CLINICAL STUDY
Role of diabetes in in¯uencing leptin concentration in elderly
overweight patients
Angela Passaro, Fabio Calzoni, Pier Francesco Zamboni, Daniele Manservigi1, Lorenzo Alberti,
Edoardo Dalla Nora, Renato Fellin and Anna Solini
Department of Clinical and Experimental Medicine, Section of Internal Medicine II, University of Ferrara School of Medicine, Italy and 1Diabetes Centre,
S. Anna Hospital, Ferrara, Italy
(Correspondence should be addressed to A Solini, Department of Clinical and Experimental Medicine, Section of Internal Medicine II, University of Ferrara
School of Medicine, Via Savonarola, 9, I-44100 Ferrara, Italy; Email: a.solini@dns.unife.it)
Abstract
Background: Leptin, the product of the ob gene, could have a signi®cant role in the pathogenesis of
obesity and non-insulin-dependent diabetes mellitus. However, it is still debated whether different
degrees of glucose tolerance may affect plasma leptin concentrations in obese patients.
Objective: To investigate whether diabetes might in¯uence leptin concentrations in obese patients.
Methods: We evaluated clinical parameters, anthropometric measures, and sex hormones, fasting
plasma leptin, glucose and insulin concentrations in 100 elderly obese diabetic patients and 100
obese non-diabetic control individuals matched for age and sex.
Results: After adjustment for age and fat mass, plasma leptin concentrations did not differ between
diabetic and non-diabetic obese individuals, in both men and women. In all patients leptin was
signi®cantly related to body mass index, fat mass and the homeostasis model insulin resistance index;
moreover we observed a signi®cant relationship with fasting plasma glucose and age in diabetic obese
women, and with blood pressure values and testosterone concentrations in diabetic obese men.
Multiple regression analysis revealed age and fasting plasma glucose to be the only independent
determinants of fasting plasma leptin in diabetic obese women.
Conclusions: These data suggest that leptin concentrations do not differ between obese diabetic and
obese non-diabetic elderly patients. Among correlates of the metabolic syndrome, systolic pressure
seems to be related to leptin only in men. In the postmenopausal or andropausal status, sex hormones
are related to leptin concentrations only in diabetic men; in diabetic women, however, high glucose
seems to be relevant in maintaining the same leptin concentrations as in non-diabetic women with
similar degree of obesity.
European Journal of Endocrinology 145 173±179
Introduction
determining plasma hormone concentrations (3, 4).
Greater concentrations of leptin have been reported in
The discovery of leptin, the product of the obesity (ob) women compared with those in men, even when
gene, as a hormone secreted by adipocytes has been a individuals of similar total fat mass were considered (5,
major advance in understanding the regulation of 6), suggesting a role of sex hormones in in¯uencing its
energy balance (1). In ob/ob mice obesity is caused by concentration. Testosterone has been found to decrease
the absent or extremely reduced production of leptin by adipocyte production of leptin (7); moreover, leptin
the adipose tissues (1, 2). Administration of the ob gene concentrations have been shown to correlate with
product to these animals leads to weight loss, insulin concentration and the degree of insulin
ameliorates glucose intolerance and improves insulin sensitivity, and a role for leptin has been proposed in
sensitivity (1). In humans, leptin concentrations are the aetiology of insulin resistance and non-insulin-
directly proportional to body fat mass, suggesting that dependent diabetes mellitus (NIDDM) (8±10).
obese individuals might be resistant to the leptin signal,
Whether leptin concentrations are different in
rather than leptin de®cient, though the pathogenetic normoglycaemic individuals and patients with NIDDM
mechanism remains unknown (3). Leptin concentra- is still questioned, as previous studies have yielded
tions, however, vary widely among individuals with contrasting results (11±13). Even less is known
similar amounts of adipose tissue, indicating a possible concerning the possible different effects of metabolic
in¯uence of other inherited/environmental factors in variables on leptin in obese diabetic patients compared
q 2001 Society of the European Journal of Endocrinology
Online version via http://www.eje.org
174 A Passaro and others
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145
with those individuals with normal glucose tolerance plasma insulin (chemiluminescent sandwich assay
but a similar degree of obesity, particularly in the with no cross-reactivity with proinsulin; Access Sys-
elderly. Therefore, we compared the relationship tem, Beckman, Palo Alto, CA, USA) and leptin
between fasting leptin concentrations and other clinical concentration (radioimmunoassay; Linco Research, St
and metabolic characteristics in two groups of ageing Charles, MO, USA). Glycated haemoglobin (HbA1c) was
overweight patients with and without NIDDM.
determined by HPLC. Radioimmunoassay commercial
kits were used to determine total testosterone, dehydro-
epiandrosterone sulphate (DHEAs) and sex hormone-
Participants and methods
binding globulin (SHBG). Both intra-assay and interassay
Participants
coef®cients of variation in all of the above methods
were less than 5%. 17b-Oestradiol was assayed by
We consecutively recruited 100 elderly (aged more ELISA. The homeostasis model insulin resistance index
than 55 years), overweight or obese (body mass index (IRI) (HOMA index), suitable as a simple assessment of
(BMI) .27 kg/m2) patients with NIDDM and 100 non- insulin sensitivity, was calculated using the formula
diabetic obese control individuals comparable for age, [fasting plasma glucose (mmol/l) Â fasting IRI (mU/
sex and degree of obesity. All these patients attended ml)]/405) (14) and the mean indexes of the groups
the outpatient clinic for Metabolic Diseases at the were compared.
University of Ferrara. Exclusion criteria were the
coexistence of any other serious illness and high
blood pressure values (.150/90 mmHg or current Statistical analysis
antihypertensive therapy). NIDDM was de®ned as non-
ketosis-prone diabetes by medical history and current Data were stored and analysed using SPSS 7.5 package
treatment with diet or oral agents. Administration of (SPSS, Evanston, IL, USA) for Windows. Biochemical
insulin for glycaemic control was considered an parameters not normal y distributed were analysed after
exclusion criterion. In controls, diabetes was excluded being logarithmically transformed. Differences between
by an oral glucose tolerance test. The local medical groups were compared by Student's unpaired t-test, one-
ethics committee approved the study and informed way ANOVA or ANCOVA. Simple and partial correla-
consent was obtained from all participants.
tion coef®cients between the variables were determined
and multiple regression analysis was performed to
determine relationships between variables of interest.
Anthropometric measurements
Data are expressed as mean^S.D. or median (range);
After an overnight fast, all participants were admitted statistical signi®cance was accepted at P , 0X05X
to the outpatient clinic, weighed in light clothing, their
heights were recorded and their BMI calculated. Waist
circumference was measured between the lower rib and Results
the iliac crest, at the end of a normal expiration. Body Clinical and metabolic characteristics of the four groups
composition was determined by bioelectrical impedance are shown in Tables 1 and 2. Diabetic obese patients
using a BIA 109 instrument (RJL System, Detroit, MI, had waist:hip ratio, BMI and systolic blood pressure
USA) with the individual in the supine position.
values similar to those of obese non-diabetic indivi-
duals. Fasting plasma glucose and HbA1c were greater
Biochemical analysis
in diabetic obese women and in diabetic obese men
than in obese women and obese men by inclusion
A blood sample was drawn for determination of fasting criteria. Plasma insulin concentrations were similar in
plasma glucose (by the glucose oxidase method), the four groups.
Table 1 Clinical characteristics of the four study groups.
DOM
OM
DOW
OW
Characteristic
(n ˆ 49)
(n ˆ 51)
(n ˆ 48)
(n ˆ 52)
Age (years)
64^7
61^9
64^8
64^8
Diabetes duration (years)
8^6
±
7^5
±
Systolic blood pressure (mmHg)
138^11
134^14
137^13
132^15
Diastolic blood pressure (mmHg)
80^5
78^6
81^4
80^4
BMI (kg/m2)
30.4^4.5
29.2^2.4
32.7^4.4
31.4^3.5
Waist:hip ratio
1.005^0.071
0.978^0.080
0.931^0.078
0.901^0.080
Fat mass (kg)
26.6^10.6
24.6^8.4
31.1^6.4
28.7^5.9
DOM, DOW, diabetic obese men or women; OM, OW, non-diabetic obese men or women.
www.eje.org
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145
Plasma leptin in NIDDM
175
Table 2 Metabolic and hormonal parameters of the four study groups. Data are expressed as mean^S.D. or median (range).
Abbreviations as in Table 1.
DOM
OM
DOW
OW
Parameter
(n ˆ 49)
(n ˆ 51)
(n ˆ 48)
(n ˆ 52)
Plasma glucose (mmol/l)
9.77^3.1***
5.55^0.5
9.88^2.9***
5.38^0.5
Plasma insulin (mU/ml)
7.55 (2.7±20.0)
7.0 (3.2±34.0)
7.0 (2.0±45.0)
7.2 (3.0±87.0)
HbAlc (%)
8.6^1.2***
5.4^0.8
8.5^1.5***
5.3^0.9
HOMA index
3.2 (1.35±15.01)***
1.61 (0.7±6.97)
3.48 (0.91±13.29)*
1.72 (0.64±18.69)
17b-Oestradiol (pg/ml)
±
±
4.7^10.1
9.6^17.0
Testosterone (ng/ml)
3.34^1.27
3.71^1.14
±
±
SHBG (nmol/l)
36.2^24.5
35.3^24.2
41.5^23.0
54.9^33.6
DHEAS (mg/dl)
116.2^80.0
148.8^88.0
87.7^78.9
75.5^56.6
*P , 0X05 compared with group OW; ***P , 0X001 compared with non-diabetic group of same sex.
Biochemical and hormonal parameters of the four women leptin was associated with fasting plasma
study groups are reported in Table 2. We did not glucose, but not with HbA1c. Some of these correlations
observe differences in plasma hormone concentrations in diabetic patients are depicted in Fig. 1.
between obese and diabetic obese patients, either in
To address further the possible differences in the
men or in women.
relationship between serum leptin concentration and
Analysis of covariance for age, fat mass, glucose and other variables among the study groups, multiple
insulin, oestradiol or testosterone, revealed that both regression analysis was applied. Using this analysis
leptin concentrations …22X6 ^ 1X5 ngaml in diabetic (Table 4), we observed a strong effect of age and fasting
obese women, 20X2 ^ 1X3 ngaml in non-diabetic obese plasma glucose on serum leptin …P , 0X001 and
women, 8X5 ^ 0X5 ngaml in diabetic obese men and P ˆ 0X023Y respectively) in diabetic obese women,
8X9 ^ 0X8 ngaml in non-diabetic obese men; all whereas in men BMI and fat mass were the only
P ˆ NS) and leptin:fat mass ratio …0X741 ^ 0X05 in parameters signi®cantly contributing to leptin concen-
diabetic obese women, 0X691 ^ 0X06 in non-diabetic trations.
obese women, 0X315 ^ 0X02 in non-diabetic obese men
and 0X307 ^ 0X03 in diabetic obese men; all P ˆ NS)
were signi®cantly greater in women than in men; no Discussion
difference was observed between diabetic and non- The main result of the present study is that, even
diabetic patients of either sex.
though leptin concentrations do not differ between
Univariate analysis (Table 3) revealed that leptin obese and diabetic obese patients in either men or
concentrations were positively related to BMI, fat mass, women, some correlates of the so-called metabolic
insulin and HOMA index in all groups. In women, no syndrome are associated with this parameter in the two
relationship was apparent with any hormonal para- clinical conditions. The intrinsic nature of a cross-
meter, whereas in diabetic obese men a negative sectional study like this one, however, does not allow
relationship with testosterone was observed. No rela- one to draw conclusions on the causal relationship
tion was observed between DHEAS and leptin in any of between leptin and other variables; the relatively small
the groups. Moreover, in men we observed an interest- sample size also prevents such conclusions.
ing direct relationship between leptin and both systolic
In our study population, diabetic obese individuals
and diastolic blood pressures, irrespective of the had a slightly, but not signi®cantly, greater fat mass
presence of diabetes, whereas in diabetic obese compared with non-diabetic obese participants; no
Table 3 Spearman's coef®cients of the relationship between leptin (log-transformed values) and other variables in
the four study groups. Numbers within parentheses are P values; those in bold are statistically signi®cant.
DOM
OM
DOW
OW
Variable
(n ˆ 49)
(n ˆ 51)
(n ˆ 48)
(n ˆ 52)
Age
20.117 (0.243)
20.223 (0.165)
0.414 (0.007)
20.053 (0.403)
BMI
0.711 (0.000)
0.527 (0.007)
0.412 (0.007)
0.410 (0.023)
Fat mass
0.766 (0.000)
0.399 (0.037)
0.421 (0.006)
0.616 (0.001)
Plasma insulin²
0.350 (0.016)
0.515 (0.008)
0.331 (0.026)
0.406 (0.024)
HOMA index²
0.321 (0.049)
0.519 (0.008)
0.207 (0.116)
0.389 (0.030)
DHEAS
20.148 (0.188)
20.090 (0.353)
20.010 (0.476)
20.127 (0.215)
SHBG
20.232 (0.081)
0.242 (0.152)
20.180 (0.150)
20.196 (0.277)
²Log-transformed values.
www.eje.org
176 A Passaro and others
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145
Figure 1 Plots of plasma leptin concentrations and some correlates of the metabolic syndrome in diabetic patients: (A) testosterone
in men; (B) systolic blood pressure in men; (C) diastolic blood pressure in men; (D) fasting plasma glucose in women.
Table 4 Multiple regression analysis of the relation between leptin concentrations and variables of interest.
Diabetic obese individuals
Non-diabetic obese individuals
Standard coef®cient
P value
Standard coef®cient
P value
Men
Age
0.028
0.795
20.007
0.978
Systolic blood pressure
20.065
0.610
0.013
0.962
Diastolic blood pressure
0.088
0.472
20.030
0.899
BMI
0.497
0.010
0.374
0.315
Fat mass
0.374
0.035
0.294
0.369
HOMA model
0.033
0.760
0.389
0.052
Testosterone
20.070
0.504
20.149
0.558
Regression coef®cient
R2 0.729; P , 0X001
R2 0.696; P , 0X02
Women
Age
0.668
,0.001
20.019
0.403
BMI
0.195
0.251
20.347
0.306
Fat mass
0.213
0.198
0.867
0.013
Plasma glucose
20.347
0.007
20.240
0.203
HOMA model
0.409
0.008
0.332
0.058
Regression coef®cient
R2 0.634; P , 0X001
R2 0.554; P , 0X0016
www.eje.org
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145
Plasma leptin in NIDDM
177
signi®cant difference was detected, however, when concentrations in both humans and animal models
mean values of fasting leptin concentration were (29, 30). The relationship between the two hormones
compared, even after adjustment for confounding seems to be reciprocal: Seufert et al. (10) recently
factors. This partially con®rms the ®ndings of previous reported that the application of leptin to freshly
studies in populations of different ethnicity (11, 13). obtained human islets resulted in a marked suppression
However, in women we con®rmed the presence of of both insulin secretion and the expression of
greater leptin concentrations in women, independent of proinsulin mRNA within the islets, emphasising the
body fat mass (5, 6) and waist circumference, an index presence of a negative feed-back loop between pan-
of truncal obesity.
creatic b-cell insulin secretion and adipocyte leptin
Many reasons have been invoked to explain this synthesis, which could be involved in the pathogenesis
discrepancy between the sexes. Increased leptin pro- of the so-called adipogenic NIDDM (31, 32). However,
duction has been reported in peripheral-subcutaneous studies performed in humans have yielded contrasting
than in abdominal-visceral fat depots (15); as women results concerning the existence of an inhibitory effect
have a predominantly subcutaneous distribution of fat, of leptin on insulin synthesis and secretion, at least in
the presence of a fat depot that produces more leptin non-diabetic individuals (33). We did not observe
mRNA than adipose cells from other sites (16) has been differences in either leptin or plasma insulin concen-
proposed. Alternatively, the difference could be due to trations between obese and diabetic obese patients of
the steroid milieu, as proposed by several authors (17, either sex; the obese condition was probably not able to
18). Increasing evidence suggests that testosterone reveal any reciprocal regulatory effect of the two
decreases the circulating concentrations of leptin, hormones, at least for fasting insulin concentrations
probably by direct inhibition of leptin expression in within the normal range, even though a direct
the adipocyte (19); in contrast, the relationship relationship between insulin and leptin was con®rmed
between circulating oestrogens and leptin remains in our four groups of patients. It is possible, however,
inconclusive. Some studies have not shown an in¯u- that measurement of post-prandial insulinaemia, not
ence of oestrogens (18, 20), whereas others did so (21, available in the present study, would have reinforced
22). A recent report by Elbers et al. (23) described a this relationship, which is much more in¯uenced by the
slight but signi®cant increase in serum leptin concen- day-long insulin response to meals, as shown in
trations after a 2-month period of oestrogen replace- previous studies performed in non-diabetic individuals
ment therapy in healthy postmenopausal women, (34).
whereas this effect was not evident in a placebo
A recent report by Panarotto et al. (35) has described
group. In our ageing women, low concentrations of lower leptin concentrations in women with diabetes or
17b-oestradiol were unable to affect leptin concentra- impaired glucose tolerance, compared with those in
tions signi®cantly; with regard to testosterone, even controls. Our data only appear to be in contrast with
though we did not observe signi®cant differences these ®ndings; our patients had, actually, a greater
between diabetic and non-diabetic obese men, con®rm- degree of obesity than those studied by Panarotto's
ing previous observations of a blunted effect of group, and greater fasting plasma glucose concentra-
testosterone as a major determinant of serum leptin tions. It is interesting to note that, in both studies,
in men (24, 25), an inverse relationship of testosterone leptin was inversely related to the degree of hyper-
and serum leptin was observed in diabetic men only. glycaemia in diabetic women, irrespective of plasma
Previous authors have described this relationship (23, hormone concentrations. These ®ndings suggest that,
26); our data offer a further contribution to the in women with NIDDM, the synthesis of leptin by
connection between diabetes and obesity, showing adipose tissue is susceptible to in vivo regulation by both
that, in men with the same degree of obesity and the glucose and insulin, raising the possibility that a
same blood pressure values, testosterone is related to relative de®ciency of leptin could be associated with
leptin only in diabetic patients. In none of the groups an increased adiposity and a worse metabolic control in
were we able to observe a relationship with DHEAS, obese individuals with NIDDM. Our two subgroups of
excluding an effect of this hormone on leptin concen- diabetic patients had absolutely superimposable HbA1c
tration in elderly individuals also, as already pointed values, and so we could not detect this difference in our
out in obese children and adolescents (23).
study, but it has been shown that poorly controlled
Both plasma insulin concentrations and indexes of NIDDM was accompanied by a signi®cant reduction in
insulin resistance have been associated with serum leptin concentrations in morbidly obese individuals
leptin independently of variance in total or percentage (13). The results of our multiple regression analysis,
body fat mass (27); there is, however, evidence that showing glucose as independent predictor of leptin in
plasma leptin concentrations vary much more as a these patients, con®rm its regulatory role of hormone
function of the circulating insulin concentrations than concentrations in NIDDM.
of the degree of insulin resistance itself (28). Long-term
An association between systolic blood pressure and
exogenous hyperinsulinaemia leads to an increase in ob serum leptin concentrations in hypertensive men has
gene expression and, consecutively, in plasma leptin been described (36). Among other mechanisms, sex
www.eje.org
178 A Passaro and others
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145
hormones probably have a role in mediating these sex
6 Kennedy A, Gettys TW, Watson P, Wallace P, Ganaway E, Pan Q
differences: in spontaneously hypertensive rats, it has
et al. The metabolic signi®cance of leptin in humans: gender-
been shown that early treatment with a testosterone
based differences in relationship to adiposity, insulin sensitivity
and energy expenditure. Journal of Clinical Endocrinology and
antagonist attenuates the development of high blood
Metabolism 1997 82 1293±1300.
pressure (37); moreover, there is a large nocturnal
7 De Pergola G. The adipose tissue metabolism: role of testosterone
increase in circulating leptin concentrations, and an
and dehydroepiandrosterone. International Journal of Obesity and
in¯uence of sex on the relationship between nocturnal
Related Metabolic Disorders 2000 24 S59±S63.
leptin increment and blood pressure regulation may be
8 Segal KR, Landt M & Klein S. Relationship between insulin
sensitivity and plasma leptin concentration in lean and obese
supposed. Our observations con®rm this link between
men. Diabetes 1996 45 988±991.
leptin and blood pressure values in normotensive
9 Cohen B, Novick D & Rubinstein M. Modulation of insulin
patients also; interestingly, the correlation is main-
activities by leptin. Science 1996 274 1185±1188.
tained in diabetic patients despite the presence of
10 Seufert J, Kieffer TJ, Leech CA, Holz GG, Moritz W, Ricordi C et al.
insulin concentrations similar to those in non-diabetic
Leptin suppression of insulin secretion and gene expression in
human pancreatic islets: implications for the development of
individuals, suggesting that other elements besides the
adipogenic diabetes mellitus. Journal of Clinical Endocrinology and
sympathetic effect of insulin could link leptin to blood
Metabolism 1999 84 670±676.
pressure regulation in NIDDM. A recent report by
11 Haffner SM, Stern MP, Miettinen H, Wei M & Gingerich RL.
Schorr et al. (38) supports the hypothesis that adipose
Leptin concentrations in diabetic and nondiabetic Mexican-
mass is an important determinant of blood pressure in
Americans. Diabetes 1996 45 822±824.
12 Widjaja A, Stratton IM, Horn R, Holman RR, Turner R &
young normotensive non-obese men; our results show
Brabant G. UKPDS 20: plasma leptin, obesity, and plasma insulin
for the ®rst time that this relation holds also for older
in type 2 diabetic subjects. Journal of Clinical Endocrinology and
and obese individuals, further underlining the physio-
Metabolism 1997 82 654±657.
logical connection between leptin and other well-
13 Clement K, Lahlou N, Hager J, Bougneres P, Basdevant A, Guy-
established correlates of the insulin resistance syndrome.
Grand B et al. Association of poorly controlled diabetes with low
serum leptin in morbid obesity. International Journal of Obesity and
In summary, the results of the present study suggest
Related Metabolic Disorders 1997 21 556±561.
that, in overweight to morbidly obese individuals, the
14 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF &
presence of diabetes does not in¯uence fasting leptin
Turner RC. Homeostasis model assessment: insulin resistance
concentrations. Women have increased plasma leptin
and b-cell function from fasting plasma glucose and insulin
concentrations compared with fat-mass-matched men,
concentrations in man. Diabetologia 1985 28 412±419.
15 Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto M
and this was true in both diabetic patients and normal
et al. Human obese gene expression: adipocyte-speci®c expression
individuals; hyperglycaemia, however, seems to have a
and regional differences in the adipose tissue. Diabetes 1995 44
major role in in¯uencing leptin concentrations in
855±858.
diabetic patients. Whether these differences might
16 Montague CT, Prins JB, Sanders L, Digby JE & O'Rahilly S. Depot-
play a part in maintaining obesity or even in the
and sex-speci®c differences in human leptin mRNA expression:
implications for the control of regional fat distribution. Diabetes
pathogenesis of NIDDM requires further investigation.
1997 46 342±347.
17 Kennedy A, Gettys TW, Watson P, Wallace P, Ganaway E, Pan Q
et al. The metabolic signi®cance of leptin in humans: gender-
Acknowledgements
based differences in relationship to adiposity, insulin sensitivity,
and energy expenditure. Journal of Clinical Endocrinology and
We dedicate this paper to the memory of Marcello
Metabolism 1997 82 1293±1300.
Carantoni, remembering his great enthusiasm in start-
18 Saad MF, Damani S, Gingerich RL, Riad-Gabriel MG, Khan A,
ing any project. We thank Lorella Chiccoli for the skilful
Boyadjian R et al. Sexual dimorphism in plasma leptin
assistance in performing hormonal determinations.
concentration. Journal of Clinical Endocrinology and Metabolism
1997 82 579±584.
19 Wabitsch M, Blum WF, Muche R, Braun M, Hube F, Rascher W
et al. Contribution of androgens to the gender difference in leptin
References
production in obese children and adolescents. Journal of Clinical
Investigation 1997 100 808±813.
1 Friedman JM & Halaas JL. Leptin and the regulation of body
20 Nader S, Riad-Gabriel MG & Saad MF. The effect of a desogestrel-
weight in mammals. Nature 1998 395 763±770.
containing oral contraceptive on glucose tolerance and leptin
2 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L &
concentrations in hyperandrogenic women. Journal of Clinical
Friedman JM. Positional cloning of the mouse obese gene and
Endocrinology and Metabolism 1997 82 3074±3077.
its human homologue. Nature 1995 372 425±432.
21 Mannucci E, Ognibene A, Becorpi A, Cremasco F, Pellegrini S,
3 Lonnqvist F, Arner P, Nordfors L & Schalling M. Overexpression of
Ottanelli S et al. Relationship between leptin and oestrogens in
the obese (ob) gene in adipose tissue of human obese subjects.
healthy women. European Journal of Endocrinology 1998 139
Nature Medicine 1995 1 950±953.
198±201.
4 Considine RV, Sinha MK, Heiman ML, Kriauciunas A,
22 Hardie L, Trayhurn P, Abramovich D & Fowler P. Circulating
Stephens TW, Nyce MR et al. Serum immunoreactive-leptin
leptin in women: a longitudinal study in the menstrual cycle
concentration in normal weight and obese humans. New England
and during pregnancy. Clinical Endocrinology 1997 47 101±
Journal of Medicine 1996 334 292±295.
106.
5 Ostlund RE, Yang JW, Klein S & Gingerich R. Relation between
23 Elbers JMH, deValk GW, Popp-Snijders C, Merkus AN,
plasma leptin concentration and body fat, gender, diet, age and
Westerveen E, Joenje BW et al. Effects of administration of 17b-
metabolic covariates. Journal of Clinical Endocrinology and
oestradiol on serum leptin levels in healthy postmenopausal
Metabolism 1996 81 3909±3913.
women. Clinical Endocrinology 1999 51 449±454.
www.eje.org
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145
Plasma leptin in NIDDM
179
24 Van den Saffele JK, Goemaere S, De Bacquer D & Kaufman JM.
32 Seufert J, Kieffer TJ & Habener J. Leptin inhibits insulin gene
Serum leptin levels in healthy ageing men: are decreased serum
transcription and reverses hyperinsulinemia in leptin-de®cient
testosterone and increased adiposity in elderly men the
ob/ob mice. PNAS 1999 96 674±679.
consequence of leptin de®ciency? Clinical Endocrinology 1999
33 Larsson H, ElmstaÊhl S & AhreÁn B. Plasma leptin levels correlate
51 81±88.
to islet function independently of body fat in postmenopausal
25 Haffner SM, Miettinen H, Karhapaa P, Mykkanen L & Laakso M.
women. Diabetes 1996 45 1580±1584.
Leptin concentrations, sex hormones and cortisol in non-diabetic
34 Carantoni M, Abbasi F, Azhar S, Schaaf P & Reaven GM. Can
men. Journal of Clinical Endocrinology and Metabolism 1997 82
changes in plasma insulin concentration explain the variability
1807±1809.
in leptin response to weight loss in obese women with normal
26 Vettor R, De Pergola G, Pagano C, Englaro P, Laudadio E,
glucose tolerance? Journal of Clinical Endocrinology and Metabolism
Giorgino F et al. Gender differences in serum leptin in obese
1998 84 869±872.
people: relationships with testosterone, body fat distribution and
35 Panarotto D, Ardilouze JL, Tessier D & Maheux P. The degree of
insulin sensitivity. European Journal of Clinical Investigation 1997
hyperinsulinemia and impaired glucose tolerance predicts
27 1016±1024.
plasma leptin concentrations in women only: a new exploratory
27 Segal KR, Landt M & Klein S. Relationship between insulin
paradigm. Metabolism 2000 49 1055±1062.
sensitivity and plasma leptin concentration in lean and obese
36 Sheu WHH, Lee WJ & Chen YT. High plasma leptin concentra-
men. Diabetes 1996 45 988±991.
tions in hypertensive men but not in hypertensive women.
28 Mohamed-AlõÁ V, Pinkney JH, Panahloo A, Goodrick S,
Journal of Hypertension 1999 7 1289±1295.
Coppack SW & Yudkin JS. Relationships between plasma leptin
and insulin concentrations, but not insulin resistance, in non-
37 Ganten U, Schroder G, Witt M, Zimmerman F, Ganten D &
insulin-dependent (type 2) diabetes mellitus. Diabetic Medicine
Stock G. Sexual dimorphism of blood pressure in spontaneously
1997 14 376±380.
hypertensive rats: effects of anti-androgen treatment. Journal of
29 Leroy P, Dessolin S, Villageois P, Moon BC, Friedman JM,
Hypertension 1989 7 721±726.
Ailhaud G et al. Expression of ob gene in adipose cells: regulation
38 Schorr U, Blaschke K, Turan S, Distler A & Sharma AM.
by insulin. Journal of Biological Chemistry 1996 271 2365±2368.
Relationship between angiotensinogen, leptin and blood pressure
30 Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ,
levels in young normotensive men. Journal of Hypertension 1998
Henry R et al. Acute and chronic effect of insulin on leptin
16 1475±1480.
production in humans: studies in vivo and in vitro. Diabetes 1996
45 699±701.
31 Ookuma M, Ookuma K & York DA. Effects of leptin on insulin
secretion from isolated rat pancreatic islets. Diabetes 1998 47
Received 12 January 2001
219±223.
Accepted 13 April 2001
www.eje.org