C. D. A. Stehouwer

F Vegt de

J. C. Seidell

J. M. Dekker

JB Ruige

JM Mooy

L. M. Bouter

M. B. Snijder

MI Schmidt

R. J. Heine

Snijder, M.B.

Dekker, J.M.

Bouter, L.M.

Heine, R.J.

Stehouwer, C.D.A.

Seidell, J.C.

DSpace at VU

LETTER
Comment on: Schmidt MI, Duncan BB, Vigo A et al (2006)
Leptin and incident type 2 diabetes: risk or protection?
Diabetologia 49:2086–2096
M. B. Snijder & J. M. Dekker & L. M. Bouter &
R. J. Heine & C. D. A. Stehouwer & J. C. Seidell
Received: 21 August 2006 /Accepted: 25 August 2006 / Published online: 11 October 2006
# Springer-Verlag 2006
To the Editor: We read with great interest the recently
published paper by Schmidt et al., who prospectively
investigated the association between leptin levels and
incident diabetes in middle-aged adults in the Atheroscle-
rosis Risk in Communities (ARIC) study [1]. We were
intrigued by their results, which showed that high leptin
levels predicted a lower risk of type 2 diabetes, once
adjusted for factors purportedly associated with leptin
resistance. Their results prompted us to perform similar
analyses in the Hoorn Study. In this letter we would like to
share our results, but also express some caution regarding
the interpretation of the results.
The Hoorn Study is a population-based cohort study of
glucose tolerance, which started in 1989 and included 2,484
white men and women aged 50 to 75 years [2]. An
extensive physical examination took place and leptin was
measured by means of a radioimmunoassay [3]. From 1996
to 1998 follow-up examinations were conducted [4]. Of the
remaining 2,086 subjects who were invited, 1,513 subjects
(72.5%) participated. After exclusion of subjects with type
2 diabetes at baseline and of subjects with missing data on
leptin or covariates, prospective analyses were performed in
1,238 subjects (573 men and 665 women). The presence of
type 2 diabetes at follow-up was ascertained by an OGTT,
and defined according to the WHO 1999 criteria [5]. In
addition, to make the study more comparable to the ARIC
study, analyses were also performed using the diabetes
definition according to the American Diabetes Association
(ADA) 1997 criteria [6], which is based on fasting glucose
levels only (86% of the cases were diagnosed on the basis
of fasting glucose in the ARIC study [1]). Informed consent
was obtained from all participants and ethical approval for
the study was obtained from the local ethics committee.
The mean age at baseline was 60.1±6.9 years (60.0±
6.9 years in men and 60.2±6.8 years in women), and
median (interquartile range) leptin concentrations were 7.04
(2.99–15.16) μg/l (3.05 [1.66–5.34] μg/l in men, 13.68
[8.13–22.85] μg/l in women). After a mean follow-up of
6.4 years, 59 men and 57 women had developed type 2
diabetes according to the WHO 1999 criteria, and 51 men
and 47 women had developed the disease according to the
ADA 1997 criteria. Table 1 shows the results of logistic
regression analyses, in which odds ratios for developing
type 2 diabetes according to ADA 1997 are calculated. In
women, but not in men, a positive statistically significant
association was shown between leptin and incident diabe-
tes, after adjustment for age (model 1). After adjustment for
BMI, the difference between men and women disappeared
and no association was observed in either sex (model 2). To
study the individual influence of WHR and metabolic
variables on the associations, we adjusted this model for
these factors one by one (models 3 to 8). Finally, we added
all variables to form one regression model, similarly to the
approach of Schmidt et al. (model 9). In contrast to the
results of Schmidt et al., the negative associations were not
statistically significant and appeared more markedly in
men, not in women.
Diabetologia (2007) 50:234–236
DOI 10.1007/s00125-006-0461-7
M. B. Snijder (*) : J. C. Seidell
Institute of Health Sciences, Faculty of Earth and Life Sciences,
Vrije Universiteit Amsterdam,
Amsterdam, the Netherlands
e-mail: marieke.snijder@falw.vu.nl
M. B. Snijder : J. M. Dekker : L. M. Bouter :R. J. Heine
EMGO Institute, VU University Medical Center,
Amsterdam, the Netherlands
C. D. A. Stehouwer
Department of Internal Medicine, Academic Hospital Maastricht,
Maastricht, the Netherlands
Table 2 shows the results of logistic regression analyses
when incident diabetes was defined according to the WHO
1999 criteria. After adjustment for age, a significant
positive association between leptin and incident diabetes
was shown, particularly in women. Again, BMI largely
explained this association. In the fully adjusted model,
Table 2 Risk, for sex-specific tertiles of leptin, of developing type 2 diabetes according to the WHO 1999 criteria
2nd tertile 3rd tertile p value for trend
OR 95% CI OR 95% CI
Men
Model 1: age 1.34 0.67–2.66 1.37 0.69–2.71 0.122
Model 2: age + BMI 1.36 0.67–2.75 1.42 0.64–3.17 0.112
Model 3: age + BMI + WHR 1.18 0.58–2.41 1.11 0.49–2.53 0.385
Model 4: age + BMI + ln-insulin 1.26 0.62–2.57 1.13 0.49–2.58 0.327
Model 5: age + BMI + hypertension 1.31 0.65–2.67 1.32 0.59–2.97 0.207
Model 6: age + BMI + ln-triacylglycerol 1.20 0.59–2.46 1.18 0.52–2.68 0.171
Model 7: age + BMI + adiponectin 1.33 0.66–2.69 1.38 0.62–3.08 0.119
Model 8: age + BMI + fasting glucose 1.17 0.55–2.53 1.18 0.51–2.75 0.153
Model 9: all previous 0.99 0.45–2.16 0.77 0.31–1.89 0.659
Women
Model 1: age 1.42 0.64–3.14 2.63 1.27–5.44 0.010
Model 2: age + BMI 1.10 0.48–2.51 1.50 0.64–3.56 0.460
Model 3: age + BMI + WHR 0.92 0.40–2.13 1.30 0.54–3.14 0.484
Model 4: age + BMI + ln-insulin 1.06 0.46–2.41 1.32 0.55–3.20 0.725
Model 5: age + BMI + hypertension 1.09 0.48–2.49 1.46 0.61–3.48 0.602
Model 6: age + BMI + ln-triacylglycerol 0.91 0.39–2.12 1.28 0.54–3.06 0.465
Model 7: age + BMI + adiponectin 0.97 0.42–2.23 1.28 0.53–3.11 0.999
Model 8: age + BMI + fasting glucose 1.28 0.54–3.03 1.49 0.58–3.82 0.612
Model 9: all previous 0.94 0.38–2.32 1.20 0.45–3.19 0.864
The first leptin tertile is the reference category. Values are odds ratios (ORs) with 95% CIs.
Table 1 Risk, for sex-specific tertiles of leptin, of developing type 2 diabetes according to the ADA 1997 criteria
2nd tertile 3rd tertile p value for trend
OR 95% CI OR 95% CI
Men
Model 1: age 1.06 0.52–2.17 1.11 0.55–2.26 0.101
Model 2: age + BMI 1.07 0.51–2.23 1.12 0.48–2.60 0.076
Model 3: age + BMI + WHR 0.91 0.43–1.92 0.85 0.36–2.01 0.287
Model 4: age + BMI + ln-insulin 0.99 0.47–2.09 0.90 0.38–2.14 0.202
Model 5: age + BMI + hypertension 1.04 0.50–2.18 1.06 0.45–2.46 0.124
Model 6: age + BMI + ln-triacylglycerol 0.93 0.44–1.96 0.91 0.39–2.15 0.110
Model 7: age + BMI + adiponectin 1.04 0.50–2.17 1.08 0.47–2.50 0.078
Model 8: age + BMI + fasting glucose 0.84 0.37–1.91 0.90 0.37–2.19 0.088
Model 9: all previous 0.69 0.30–1.61 0.59 0.23–1.55 0.304
Women
Model 1: age 1.04 0.45–2.43 2.05 0.97–4.35 0.025
Model 2: age + BMI 0.80 0.34–1.93 1.14 0.46–2.83 0.541
Model 3: age + BMI + WHR 0.65 0.27–1.58 0.94 0.37–2.41 0.582
Model 4: age + BMI + ln-insulin 0.78 0.32–1.87 1.03 0.41–2.60 0.741
Model 5: age + BMI + hypertension 0.79 0.33–1.91 1.10 0.44–2.74 0.724
Model 6: age + BMI + ln-triacylglycerol 0.67 0.27–1.63 0.98 0.39–2.43 0.547
Model 7: age + BMI + adiponectin 0.73 0.30–1.76 1.01 0.40–2.54 0.939
Model 8: age + BMI + fasting glucose 0.93 0.37–2.36 1.11 0.40–3.05 0.702
Model 9: all previous 0.71 0.27–1.89 0.93 0.32–2.66 0.835
The first leptin tertile is the reference category. Values are odds ratios (ORs) with 95% CIs.
Diabetologia (2007) 50:234–236 235
higher leptin levels were associated with a slightly lower
risk of type 2 diabetes in men, but not in women.
In the Hoorn Study, therefore, we were able to
replicate—in men, but not in women—the findings of
Schmidt et al. from the ARIC Study, when type 2 diabetes
was defined on the basis of fasting glucose levels only.
However, if incident type 2 diabetes was defined according
to the WHO 1999 criteria, which also includes post-load
glucose levels and is considered the gold standard for
diagnosis of type 2 diabetes, there was no longer a strong
negative association in men.
Schmidt et al. discuss the possibility of over-adjustment
when adjusting for baseline glucose levels, because glucose
may mediate part of the association, while other variables are
considered to be true confounders. We argue, however, that
controlling for other metabolic factors may also result in over-
adjustment, because they also may well be mediators in the
causal pathway by which high leptin leads to type 2 diabetes.
The interpretation of the regression model that includes all
these factors implies that a person with high leptin per BMI
who does not develop insulin resistance, hypertension and
metabolic abnormalities has advantages with respect to
diabetes risk. It should, however, be realised that unfortunate-
ly most obese people do in fact develop these adiposity-
related abnormalities. In addition, the results of the Hoorn
Study, using data from the OGTT, suggest that the seemingly
beneficial effect of high leptin after adjustment could also be
an artefact due to imprecise measurement of diabetes.
In conclusion, we were not able to confirm the negative
associations between leptin and incident diabetes when
diabetes diagnosis was based on both fasting and post-load
glucose levels (gold standard), and after adjusting for
measures of obesity and metabolic factors. Although a
weak negative association in men cannot be excluded, the
adjustments for obesity and metabolic factors probably
represent over-adjustment as a result of adjusting for
mediating factors.
References
1. Schmidt MI, Duncan BB, Vigo A et al (2006) Leptin and incident
type 2 diabetes: risk or protection? Diabetologia 49:2086–2096
2. Mooy JM, Grootenhuis PA, de Vries H et al (1995) Prevalence and
determinants of glucose intolerance in a Dutch caucasian popula-
tion. The Hoorn Study. Diabetes Care 18: 1270–1273
3. Ruige JB, Dekker JM, Blum WF et al (1999) Leptin and variables
of body adiposity, energy balance, and insulin resistance in a
population-based study. The Hoorn Study. Diabetes Care 22:
1097–1104
4. de Vegt F, Dekker JM, Jager A et al (2001) Relation of
impaired fasting and postload glucose with incident type 2
diabetes in a Dutch population: The Hoorn Study. JAMA 285:
2109–2113
5. World Health Organisation (1999) World Health Organisation:
Definition, diagnosis and classification of diabetes mellitus and its
complications. Report of a WHO consultation
6. No authors listed (1997) Report of the Expert Committee on the
diagnosis and classification of diabetes mellitus. Diabetes Care
20:1183–1197
236 Diabetologia (2007) 50:234–236


Comment on: Schmidt MI, Duncan BB, Vigo A et al. Leptin and incident type 2 diabetes: risk or protection?

Snijder, M B

Dekker, J M

Bouter, L M

Heine, Robert J

Stehouwer, Coen D A

Seidell, J C

VU Research Portal

VU Research PortalComment onSnijder, M B; Dekker, J M; Bouter, L M; Heine, Robert J; Stehouwer, Coen D A; Seidell, JCpublished inDiabetologia2007DOI (link to publisher)10.1007/s00125-006-0461-7document versionPublisher's PDF, also known as Version of recordLink to publication in VU Research Portalcitation for published version (APA)Snijder, M. B., Dekker, J. M., Bouter, L. M., Heine, R. J., Stehouwer, C. D. A., & Seidell, J. C. (2007). Commenton: Schmidt MI, Duncan BB, Vigo A et al (2006) Leptin and incident type 2 diabetes: risk or protection?Diabetologia 49:2086-2096. Diabetologia, 50(1), 234-6; author reply 237-8; discussion 239-40.https://doi.org/10.1007/s00125-006-0461-7General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying the publication in the public portal ?Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.E-mail address:vuresearchportal.ub@vu.nlDownload date: 22. May. 2021LETTERComment on: Schmidt MI, Duncan BB, Vigo A et al (2006)Leptin and incident type 2 diabetes: risk or protection?Diabetologia 49:2086–2096M. B. Snijder & J. M. Dekker & L. M. Bouter &R. J. Heine & C. D. A. Stehouwer & J. C. SeidellReceived: 21 August 2006 /Accepted: 25 August 2006 / Published online: 11 October 2006# Springer-Verlag 2006To the Editor: We read with great interest the recentlypublished paper by Schmidt et al., who prospectivelyinvestigated the association between leptin levels andincident diabetes in middle-aged adults in the Atheroscle-rosis Risk in Communities (ARIC) study [1]. We wereintrigued by their results, which showed that high leptinlevels predicted a lower risk of type 2 diabetes, onceadjusted for factors purportedly associated with leptinresistance. Their results prompted us to perform similaranalyses in the Hoorn Study. In this letter we would like toshare our results, but also express some caution regardingthe interpretation of the results.The Hoorn Study is a population-based cohort study ofglucose tolerance, which started in 1989 and included 2,484white men and women aged 50 to 75 years [2]. Anextensive physical examination took place and leptin wasmeasured by means of a radioimmunoassay [3]. From 1996to 1998 follow-up examinations were conducted [4]. Of theremaining 2,086 subjects who were invited, 1,513 subjects(72.5%) participated. After exclusion of subjects with type2 diabetes at baseline and of subjects with missing data onleptin or covariates, prospective analyses were performed in1,238 subjects (573 men and 665 women). The presence oftype 2 diabetes at follow-up was ascertained by an OGTT,and defined according to the WHO 1999 criteria [5]. Inaddition, to make the study more comparable to the ARICstudy, analyses were also performed using the diabetesdefinition according to the American Diabetes Association(ADA) 1997 criteria [6], which is based on fasting glucoselevels only (86% of the cases were diagnosed on the basisof fasting glucose in the ARIC study [1]). Informed consentwas obtained from all participants and ethical approval forthe study was obtained from the local ethics committee.The mean age at baseline was 60.1±6.9 years (60.0±6.9 years in men and 60.2±6.8 years in women), andmedian (interquartile range) leptin concentrations were 7.04(2.99–15.16) μg/l (3.05 [1.66–5.34] μg/l in men, 13.68[8.13–22.85] μg/l in women). After a mean follow-up of6.4 years, 59 men and 57 women had developed type 2diabetes according to the WHO 1999 criteria, and 51 menand 47 women had developed the disease according to theADA 1997 criteria. Table 1 shows the results of logisticregression analyses, in which odds ratios for developingtype 2 diabetes according to ADA 1997 are calculated. Inwomen, but not in men, a positive statistically significantassociation was shown between leptin and incident diabe-tes, after adjustment for age (model 1). After adjustment forBMI, the difference between men and women disappearedand no association was observed in either sex (model 2). Tostudy the individual influence of WHR and metabolicvariables on the associations, we adjusted this model forthese factors one by one (models 3 to 8). Finally, we addedall variables to form one regression model, similarly to theapproach of Schmidt et al. (model 9). In contrast to theresults of Schmidt et al., the negative associations were notstatistically significant and appeared more markedly inmen, not in women.Diabetologia (2007) 50:234–236DOI 10.1007/s00125-006-0461-7M. B. Snijder (*) : J. C. SeidellInstitute of Health Sciences, Faculty of Earth and Life Sciences,Vrije Universiteit Amsterdam,Amsterdam, the Netherlandse-mail: marieke.snijder@falw.vu.nlM. B. Snijder : J. M. Dekker : L. M. Bouter :R. J. HeineEMGO Institute, VU University Medical Center,Amsterdam, the NetherlandsC. D. A. StehouwerDepartment of Internal Medicine, Academic Hospital Maastricht,Maastricht, the NetherlandsTable 2 shows the results of logistic regression analyseswhen incident diabetes was defined according to the WHO1999 criteria. After adjustment for age, a significantpositive association between leptin and incident diabeteswas shown, particularly in women. Again, BMI largelyexplained this association. In the fully adjusted model,Table 2 Risk, for sex-specific tertiles of leptin, of developing type 2 diabetes according to the WHO 1999 criteria2nd tertile 3rd tertile p value for trendOR 95% CI OR 95% CIMenModel 1: age 1.34 0.67–2.66 1.37 0.69–2.71 0.122Model 2: age + BMI 1.36 0.67–2.75 1.42 0.64–3.17 0.112Model 3: age + BMI + WHR 1.18 0.58–2.41 1.11 0.49–2.53 0.385Model 4: age + BMI + ln-insulin 1.26 0.62–2.57 1.13 0.49–2.58 0.327Model 5: age + BMI + hypertension 1.31 0.65–2.67 1.32 0.59–2.97 0.207Model 6: age + BMI + ln-triacylglycerol 1.20 0.59–2.46 1.18 0.52–2.68 0.171Model 7: age + BMI + adiponectin 1.33 0.66–2.69 1.38 0.62–3.08 0.119Model 8: age + BMI + fasting glucose 1.17 0.55–2.53 1.18 0.51–2.75 0.153Model 9: all previous 0.99 0.45–2.16 0.77 0.31–1.89 0.659WomenModel 1: age 1.42 0.64–3.14 2.63 1.27–5.44 0.010Model 2: age + BMI 1.10 0.48–2.51 1.50 0.64–3.56 0.460Model 3: age + BMI + WHR 0.92 0.40–2.13 1.30 0.54–3.14 0.484Model 4: age + BMI + ln-insulin 1.06 0.46–2.41 1.32 0.55–3.20 0.725Model 5: age + BMI + hypertension 1.09 0.48–2.49 1.46 0.61–3.48 0.602Model 6: age + BMI + ln-triacylglycerol 0.91 0.39–2.12 1.28 0.54–3.06 0.465Model 7: age + BMI + adiponectin 0.97 0.42–2.23 1.28 0.53–3.11 0.999Model 8: age + BMI + fasting glucose 1.28 0.54–3.03 1.49 0.58–3.82 0.612Model 9: all previous 0.94 0.38–2.32 1.20 0.45–3.19 0.864The first leptin tertile is the reference category. Values are odds ratios (ORs) with 95% CIs.Table 1 Risk, for sex-specific tertiles of leptin, of developing type 2 diabetes according to the ADA 1997 criteria2nd tertile 3rd tertile p value for trendOR 95% CI OR 95% CIMenModel 1: age 1.06 0.52–2.17 1.11 0.55–2.26 0.101Model 2: age + BMI 1.07 0.51–2.23 1.12 0.48–2.60 0.076Model 3: age + BMI + WHR 0.91 0.43–1.92 0.85 0.36–2.01 0.287Model 4: age + BMI + ln-insulin 0.99 0.47–2.09 0.90 0.38–2.14 0.202Model 5: age + BMI + hypertension 1.04 0.50–2.18 1.06 0.45–2.46 0.124Model 6: age + BMI + ln-triacylglycerol 0.93 0.44–1.96 0.91 0.39–2.15 0.110Model 7: age + BMI + adiponectin 1.04 0.50–2.17 1.08 0.47–2.50 0.078Model 8: age + BMI + fasting glucose 0.84 0.37–1.91 0.90 0.37–2.19 0.088Model 9: all previous 0.69 0.30–1.61 0.59 0.23–1.55 0.304WomenModel 1: age 1.04 0.45–2.43 2.05 0.97–4.35 0.025Model 2: age + BMI 0.80 0.34–1.93 1.14 0.46–2.83 0.541Model 3: age + BMI + WHR 0.65 0.27–1.58 0.94 0.37–2.41 0.582Model 4: age + BMI + ln-insulin 0.78 0.32–1.87 1.03 0.41–2.60 0.741Model 5: age + BMI + hypertension 0.79 0.33–1.91 1.10 0.44–2.74 0.724Model 6: age + BMI + ln-triacylglycerol 0.67 0.27–1.63 0.98 0.39–2.43 0.547Model 7: age + BMI + adiponectin 0.73 0.30–1.76 1.01 0.40–2.54 0.939Model 8: age + BMI + fasting glucose 0.93 0.37–2.36 1.11 0.40–3.05 0.702Model 9: all previous 0.71 0.27–1.89 0.93 0.32–2.66 0.835The first leptin tertile is the reference category. Values are odds ratios (ORs) with 95% CIs.Diabetologia (2007) 50:234–236 235higher leptin levels were associated with a slightly lowerrisk of type 2 diabetes in men, but not in women.In the Hoorn Study, therefore, we were able toreplicate—in men, but not in women—the findings ofSchmidt et al. from the ARIC Study, when type 2 diabeteswas defined on the basis of fasting glucose levels only.However, if incident type 2 diabetes was defined accordingto the WHO 1999 criteria, which also includes post-loadglucose levels and is considered the gold standard fordiagnosis of type 2 diabetes, there was no longer a strongnegative association in men.Schmidt et al. discuss the possibility of over-adjustmentwhen adjusting for baseline glucose levels, because glucosemay mediate part of the association, while other variables areconsidered to be true confounders. We argue, however, thatcontrolling for other metabolic factors may also result in over-adjustment, because they also may well be mediators in thecausal pathway by which high leptin leads to type 2 diabetes.The interpretation of the regression model that includes allthese factors implies that a person with high leptin per BMIwho does not develop insulin resistance, hypertension andmetabolic abnormalities has advantages with respect todiabetes risk. It should, however, be realised that unfortunate-ly most obese people do in fact develop these adiposity-related abnormalities. In addition, the results of the HoornStudy, using data from the OGTT, suggest that the seeminglybeneficial effect of high leptin after adjustment could also bean artefact due to imprecise measurement of diabetes.In conclusion, we were not able to confirm the negativeassociations between leptin and incident diabetes whendiabetes diagnosis was based on both fasting and post-loadglucose levels (gold standard), and after adjusting formeasures of obesity and metabolic factors. Although aweak negative association in men cannot be excluded, theadjustments for obesity and metabolic factors probablyrepresent over-adjustment as a result of adjusting formediating factors.References1. Schmidt MI, Duncan BB, Vigo A et al (2006) Leptin and incidenttype 2 diabetes: risk or protection? Diabetologia 49:2086–20962. Mooy JM, Grootenhuis PA, de Vries H et al (1995) Prevalence anddeterminants of glucose intolerance in a Dutch caucasian popula-tion. The Hoorn Study. Diabetes Care 18: 1270–12733. Ruige JB, Dekker JM, Blum WF et al (1999) Leptin and variablesof body adiposity, energy balance, and insulin resistance in apopulation-based study. The Hoorn Study. Diabetes Care 22:1097–11044. de Vegt F, Dekker JM, Jager A et al (2001) Relation ofimpaired fasting and postload glucose with incident type 2diabetes in a Dutch population: The Hoorn Study. JAMA 285:2109–21135. World Health Organisation (1999) World Health Organisation:Definition, diagnosis and classification of diabetes mellitus and itscomplications. Report of a WHO consultation6. No authors listed (1997) Report of the Expert Committee on thediagnosis and classification of diabetes mellitus. Diabetes Care20:1183–1197236 Diabetologia (2007) 50:234–236

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Comment on:Schmidt MI, Duncan BB, Vigo A et al (2006) Leptin and incident type 2 diabetes: risk or protection? Diabetologia 49:2086-2096

Maastricht University Research Portal

Comment on: Schmidt MI, Duncan BB, Vigo A et al (2006) Leptin and incident type 2 diabetes: risk or protection?

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Comment on: Schmidt MI, Duncan BB, Vigo A et al (2006) Leptin and incident type 2 diabetes: risk or protection? Diabetologia 49:2086-2096

VU Research PortalComment on: Schmidt MI, Duncan BB, Vigo A et al. Leptin and incident type 2diabetes: risk or protection?Snijder, M.B.; Dekker, J.M.; Bouter, L.M.; Heine, R.J.; Stehouwer, C.D.A.; Seidell, J.C.published inDiabetologia2006DOI (link to publisher)10.1007/s00125-006-0351-zdocument versionPublisher's PDF, also known as Version of recordLink to publication in VU Research Portalcitation for published version (APA)Snijder, M. B., Dekker, J. M., Bouter, L. M., Heine, R. J., Stehouwer, C. D. A., & Seidell, J. C. (2006). Commenton: Schmidt MI, Duncan BB, Vigo A et al. Leptin and incident type 2 diabetes: risk or protection? Diabetologia,49, 2086-2096. https://doi.org/10.1007/s00125-006-0351-zGeneral rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying the publication in the public portal ?Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.E-mail address:vuresearchportal.ub@vu.nlDownload date: 22. May. 2021LETTERComment on: Schmidt MI, Duncan BB, Vigo A et al (2006)Leptin and incident type 2 diabetes: risk or protection?Diabetologia 49:2086–2096M. B. Snijder & J. M. Dekker & L. M. Bouter &R. J. Heine & C. D. A. Stehouwer & J. C. SeidellReceived: 21 August 2006 /Accepted: 25 August 2006 / Published online: 11 October 2006# Springer-Verlag 2006To the Editor: We read with great interest the recentlypublished paper by Schmidt et al., who prospectivelyinvestigated the association between leptin levels andincident diabetes in middle-aged adults in the Atheroscle-rosis Risk in Communities (ARIC) study [1]. We wereintrigued by their results, which showed that high leptinlevels predicted a lower risk of type 2 diabetes, onceadjusted for factors purportedly associated with leptinresistance. Their results prompted us to perform similaranalyses in the Hoorn Study. In this letter we would like toshare our results, but also express some caution regardingthe interpretation of the results.The Hoorn Study is a population-based cohort study ofglucose tolerance, which started in 1989 and included 2,484white men and women aged 50 to 75 years [2]. Anextensive physical examination took place and leptin wasmeasured by means of a radioimmunoassay [3]. From 1996to 1998 follow-up examinations were conducted [4]. Of theremaining 2,086 subjects who were invited, 1,513 subjects(72.5%) participated. After exclusion of subjects with type2 diabetes at baseline and of subjects with missing data onleptin or covariates, prospective analyses were performed in1,238 subjects (573 men and 665 women). The presence oftype 2 diabetes at follow-up was ascertained by an OGTT,and defined according to the WHO 1999 criteria [5]. Inaddition, to make the study more comparable to the ARICstudy, analyses were also performed using the diabetesdefinition according to the American Diabetes Association(ADA) 1997 criteria [6], which is based on fasting glucoselevels only (86% of the cases were diagnosed on the basisof fasting glucose in the ARIC study [1]). Informed consentwas obtained from all participants and ethical approval forthe study was obtained from the local ethics committee.The mean age at baseline was 60.1±6.9 years (60.0±6.9 years in men and 60.2±6.8 years in women), andmedian (interquartile range) leptin concentrations were 7.04(2.99–15.16) μg/l (3.05 [1.66–5.34] μg/l in men, 13.68[8.13–22.85] μg/l in women). After a mean follow-up of6.4 years, 59 men and 57 women had developed type 2diabetes according to the WHO 1999 criteria, and 51 menand 47 women had developed the disease according to theADA 1997 criteria. Table 1 shows the results of logisticregression analyses, in which odds ratios for developingtype 2 diabetes according to ADA 1997 are calculated. Inwomen, but not in men, a positive statistically significantassociation was shown between leptin and incident diabe-tes, after adjustment for age (model 1). After adjustment forBMI, the difference between men and women disappearedand no association was observed in either sex (model 2). Tostudy the individual influence of WHR and metabolicvariables on the associations, we adjusted this model forthese factors one by one (models 3 to 8). Finally, we addedall variables to form one regression model, similarly to theapproach of Schmidt et al. (model 9). In contrast to theresults of Schmidt et al., the negative associations were notstatistically significant and appeared more markedly inmen, not in women.Diabetologia (2007) 50:234–236DOI 10.1007/s00125-006-0461-7M. B. Snijder (*) : J. C. SeidellInstitute of Health Sciences, Faculty of Earth and Life Sciences,Vrije Universiteit Amsterdam,Amsterdam, the Netherlandse-mail: marieke.snijder@falw.vu.nlM. B. Snijder : J. M. Dekker : L. M. Bouter :R. J. HeineEMGO Institute, VU University Medical Center,Amsterdam, the NetherlandsC. D. A. StehouwerDepartment of Internal Medicine, Academic Hospital Maastricht,Maastricht, the NetherlandsTable 2 shows the results of logistic regression analyseswhen incident diabetes was defined according to the WHO1999 criteria. After adjustment for age, a significantpositive association between leptin and incident diabeteswas shown, particularly in women. Again, BMI largelyexplained this association. In the fully adjusted model,Table 2 Risk, for sex-specific tertiles of leptin, of developing type 2 diabetes according to the WHO 1999 criteria2nd tertile 3rd tertile p value for trendOR 95% CI OR 95% CIMenModel 1: age 1.34 0.67–2.66 1.37 0.69–2.71 0.122Model 2: age + BMI 1.36 0.67–2.75 1.42 0.64–3.17 0.112Model 3: age + BMI + WHR 1.18 0.58–2.41 1.11 0.49–2.53 0.385Model 4: age + BMI + ln-insulin 1.26 0.62–2.57 1.13 0.49–2.58 0.327Model 5: age + BMI + hypertension 1.31 0.65–2.67 1.32 0.59–2.97 0.207Model 6: age + BMI + ln-triacylglycerol 1.20 0.59–2.46 1.18 0.52–2.68 0.171Model 7: age + BMI + adiponectin 1.33 0.66–2.69 1.38 0.62–3.08 0.119Model 8: age + BMI + fasting glucose 1.17 0.55–2.53 1.18 0.51–2.75 0.153Model 9: all previous 0.99 0.45–2.16 0.77 0.31–1.89 0.659WomenModel 1: age 1.42 0.64–3.14 2.63 1.27–5.44 0.010Model 2: age + BMI 1.10 0.48–2.51 1.50 0.64–3.56 0.460Model 3: age + BMI + WHR 0.92 0.40–2.13 1.30 0.54–3.14 0.484Model 4: age + BMI + ln-insulin 1.06 0.46–2.41 1.32 0.55–3.20 0.725Model 5: age + BMI + hypertension 1.09 0.48–2.49 1.46 0.61–3.48 0.602Model 6: age + BMI + ln-triacylglycerol 0.91 0.39–2.12 1.28 0.54–3.06 0.465Model 7: age + BMI + adiponectin 0.97 0.42–2.23 1.28 0.53–3.11 0.999Model 8: age + BMI + fasting glucose 1.28 0.54–3.03 1.49 0.58–3.82 0.612Model 9: all previous 0.94 0.38–2.32 1.20 0.45–3.19 0.864The first leptin tertile is the reference category. Values are odds ratios (ORs) with 95% CIs.Table 1 Risk, for sex-specific tertiles of leptin, of developing type 2 diabetes according to the ADA 1997 criteria2nd tertile 3rd tertile p value for trendOR 95% CI OR 95% CIMenModel 1: age 1.06 0.52–2.17 1.11 0.55–2.26 0.101Model 2: age + BMI 1.07 0.51–2.23 1.12 0.48–2.60 0.076Model 3: age + BMI + WHR 0.91 0.43–1.92 0.85 0.36–2.01 0.287Model 4: age + BMI + ln-insulin 0.99 0.47–2.09 0.90 0.38–2.14 0.202Model 5: age + BMI + hypertension 1.04 0.50–2.18 1.06 0.45–2.46 0.124Model 6: age + BMI + ln-triacylglycerol 0.93 0.44–1.96 0.91 0.39–2.15 0.110Model 7: age + BMI + adiponectin 1.04 0.50–2.17 1.08 0.47–2.50 0.078Model 8: age + BMI + fasting glucose 0.84 0.37–1.91 0.90 0.37–2.19 0.088Model 9: all previous 0.69 0.30–1.61 0.59 0.23–1.55 0.304WomenModel 1: age 1.04 0.45–2.43 2.05 0.97–4.35 0.025Model 2: age + BMI 0.80 0.34–1.93 1.14 0.46–2.83 0.541Model 3: age + BMI + WHR 0.65 0.27–1.58 0.94 0.37–2.41 0.582Model 4: age + BMI + ln-insulin 0.78 0.32–1.87 1.03 0.41–2.60 0.741Model 5: age + BMI + hypertension 0.79 0.33–1.91 1.10 0.44–2.74 0.724Model 6: age + BMI + ln-triacylglycerol 0.67 0.27–1.63 0.98 0.39–2.43 0.547Model 7: age + BMI + adiponectin 0.73 0.30–1.76 1.01 0.40–2.54 0.939Model 8: age + BMI + fasting glucose 0.93 0.37–2.36 1.11 0.40–3.05 0.702Model 9: all previous 0.71 0.27–1.89 0.93 0.32–2.66 0.835The first leptin tertile is the reference category. Values are odds ratios (ORs) with 95% CIs.Diabetologia (2007) 50:234–236 235higher leptin levels were associated with a slightly lowerrisk of type 2 diabetes in men, but not in women.In the Hoorn Study, therefore, we were able toreplicate—in men, but not in women—the findings ofSchmidt et al. from the ARIC Study, when type 2 diabeteswas defined on the basis of fasting glucose levels only.However, if incident type 2 diabetes was defined accordingto the WHO 1999 criteria, which also includes post-loadglucose levels and is considered the gold standard fordiagnosis of type 2 diabetes, there was no longer a strongnegative association in men.Schmidt et al. discuss the possibility of over-adjustmentwhen adjusting for baseline glucose levels, because glucosemay mediate part of the association, while other variables areconsidered to be true confounders. We argue, however, thatcontrolling for other metabolic factors may also result in over-adjustment, because they also may well be mediators in thecausal pathway by which high leptin leads to type 2 diabetes.The interpretation of the regression model that includes allthese factors implies that a person with high leptin per BMIwho does not develop insulin resistance, hypertension andmetabolic abnormalities has advantages with respect todiabetes risk. It should, however, be realised that unfortunate-ly most obese people do in fact develop these adiposity-related abnormalities. In addition, the results of the HoornStudy, using data from the OGTT, suggest that the seeminglybeneficial effect of high leptin after adjustment could also bean artefact due to imprecise measurement of diabetes.In conclusion, we were not able to confirm the negativeassociations between leptin and incident diabetes whendiabetes diagnosis was based on both fasting and post-loadglucose levels (gold standard), and after adjusting formeasures of obesity and metabolic factors. Although aweak negative association in men cannot be excluded, theadjustments for obesity and metabolic factors probablyrepresent over-adjustment as a result of adjusting formediating factors.References1. Schmidt MI, Duncan BB, Vigo A et al (2006) Leptin and incidenttype 2 diabetes: risk or protection? Diabetologia 49:2086–20962. Mooy JM, Grootenhuis PA, de Vries H et al (1995) Prevalence anddeterminants of glucose intolerance in a Dutch caucasian popula-tion. The Hoorn Study. Diabetes Care 18: 1270–12733. Ruige JB, Dekker JM, Blum WF et al (1999) Leptin and variablesof body adiposity, energy balance, and insulin resistance in apopulation-based study. The Hoorn Study. Diabetes Care 22:1097–11044. de Vegt F, Dekker JM, Jager A et al (2001) Relation ofimpaired fasting and postload glucose with incident type 2diabetes in a Dutch population: The Hoorn Study. JAMA 285:2109–21135. World Health Organisation (1999) World Health Organisation:Definition, diagnosis and classification of diabetes mellitus and itscomplications. Report of a WHO consultation6. No authors listed (1997) Report of the Expert Committee on thediagnosis and classification of diabetes mellitus. Diabetes Care20:1183–1197236 Diabetologia (2007) 50:234–236

Comment on: Schmidt MI, Duncan BB, Vigo A et al (2006) - Leptin and incident type 2 diabetes: Risk or protection? Diabetologia 49 : 2086-2096

Comment on: Schmidt MI, Duncan BB, Vigo A et al (2006) - Leptin and incident type 2 diabetes: Risk or protection? Diabetologia 49 : 2086-2096

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