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Original Studies |
Concentrations in a Native Canadian Population with High Rates of Type 2 Diabetes Mellitus1
Samuel Lunenfeld Research Institute, Mount Sinai Hospital (B.Z., A.J.G.H., I.G.F.); and the Banting and Best Diabetes Center (B.Z., J.K., I.G.F.) and the Department of Public Health Sciences (A.J.G.H.), University of Toronto, Toronto, Canada M5G 1X5; and the Thames Valley Family Practice Research Unit, University of Western Ontario (S.B.H.), London, Ontario, Canada N6G 4X8
Address all correspondence and requests for reprints to: Dr. Bernard Zinman, Division of Endocrinology and Metabolism, Mount Sinai Hospital, 600 University Avenue, Suite 782, Toronto, Ontario, Canada M5G 1X5. E-mail: zinman{at}mshri.on.ca
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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(TNF) may
play an important role in obesity-associated insulin resistance and
diabetes. We studied the relationship between TNF and the
anthropometric and physiological variables associated with insulin
resistance and diabetes in an isolated Native Canadian population with
very high rates of type 2 diabetes mellitus (DM).
A stratified random sample (n = 80) of participants was
selected from a population-based survey designed to determine the
prevalence of type 2 DM and its associated risk factors. Fasting blood
samples for glucose, insulin, triglyceride, leptin, and TNF were
collected; a 75-g oral glucose tolerance test was administered, and a
second blood sample was drawn after 120 min. Insulin resistance was
estimated using the homeostasis assessment (HOMA) model. Systolic and
diastolic blood pressure (BP), height, weight, and waist and hip
circumferences were determined, and percent body fat was estimated
using biological impedance analysis. The relationship between
circulating concentrations of TNF and the other variables was
assessed using Spearman correlation coefficients, analysis of
covariance, and multiple linear regression.
The mean TNF concentration was 5.6 pg/mL (SD =
2.18) and ranged from 2.0–12.9 pg/mL, with no difference between men
and women (P = 0.67). There were moderate, but
statistically significant, correlations between TNF and fasting
insulin, HOMA insulin resistance (HOMA IR) waist circumference, fasting
triglyceride, and systolic BP (r = 0.23–0.34; all
P < 0.05); in all cases, coefficients for females
were stronger than those for males. Individuals with normal glucose
tolerance had lower log TNF concentrations than those with impaired
glucose tolerance or type 2 DM (both P = 0.03,
adjusted for age and sex), although differences were not significant
after adjustment for HOMA IR (both P > 0.25).
Regression analysis indicated that log HOMA IR and log systolic BP were
significant independent contributors to variations in log TNF
concentration (model r2 = 0.32). We conclude that in this
homogeneous Native Canadian population, circulating TNF
concentrations are positively correlated with insulin resistance across
a spectrum of glucose tolerance. The data suggest a possible role for
TNF in the pathophysiology of insulin resistance.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recent research suggests that tumor necrosis factor- (TNF), an
inflammatory cytokine produced mainly by monocytes and macrophages, may
play an important role in obesity-associated IR and diabetes (6).
In vitro studies have shown that TNF reduces
transcriptional activity of the GLUT4 gene (7) and increases IR by
inhibition of insulin receptor tyrosine kinase activity in muscle and
fat tissue (8, 9). The latter process possibly occurs via stimulation
of the p55 TNF receptor (TNFR) and sphingomyelinase activity (10, 11, 12).
In humans, adipose tissue TNF messenger ribonucleic acid (mRNA)
levels are correlated positively with percent body fat and body mass
index (BMI), and inversely with lipoprotein lipase activity (13, 14).
The elevated TNF mRNA levels in obese subjects are decreased by
weight loss, which supports a putative role in the induction of IR
(14).
Several attempts have been made to neutralize TNF in
vivo. Hotamisligil et al. (8, 15) administered a
recombinant soluble TNF receptor-IgG chimeric protein to Zucker
fatty rats and reported improvements in insulin sensitivity as well as
insulin, glucose, and fatty acid levels. In contrast, Ofei and
co-workers (16) used recombinant TNF-neutralizing antibody and
reported no effect on IR in obese subjects with noninsulin-dependent
diabetes mellitus. A recently published report demonstrated that
targeted disruption of the TNF gene in mice resulted in reduced body
adiposity and triglyceride levels in -/- nonobese animals, but the
absence of TNF was "not sufficient to substantially protect
against insulin resistance" (17). These apparently contradictory
findings have led to controversy about the role of TNF in the IR
syndrome.
There have been few studies of TNF in the clinical setting, and none
that we are aware of in the context of population-based epidemiological
studies. It may be particularly informative to compare various
populations with differing rates of diabetes and obesity. We studied
the relationship between TNF and the anthropometric and
physiological variables associated with IR and diabetes in an isolated
Native Canadian population with very high rates of type 2 DM.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The community of Sandy Lake, Ontario, Canada, accessible only by air for most of the year, comprises approximately 1600 people and is located roughly 2000 km northwest of Toronto. Historically, the inhabitants of this area lived in small nomadic groups and were physically active; their diet was high in protein from wild meat and fish, with seasonal supplementation with berries and roots. Their lifestyle has changed dramatically over the past several decades, with a marked decrease in physical activity and an alteration in diet to one characterized by excess consumption of saturated fat and processed foods (18). This population is consequently undergoing an epidemiological transition (19), with a marked increase in morbidity related to chronic diseases, such as obesity and type 2 DM (20, 21, 22).
The methodology of the Sandy Lake Health and Diabetes Project (SLHDP)
has been described in detail in previous publications (23, 24, 25). From
July 1993 to March 1995, 728 of 1018 (72%) eligible residents of Sandy
Lake, aged 10–79 yr, volunteered to participate in a cross-sectional
survey to determine the prevalence of type 2 DM and its associated risk
factors. Signed informed consent was obtained from all participants,
and the study was approved by the Sandy Lake First Nation Band Council
and University of Toronto human subjects review committee. The present
analysis is based on a stratified random sample (n = 80) of the
SLHDP study population. Twenty individuals (10 males and 10 females)
were randomly selected from each of four glucose tolerance status (GTS)
categories: type 2 DM, impaired glucose tolerance (IGT), obese (BMI,
24) with normal glucose tolerance (NGT), and nonobese (BMI, <24)
NGT.
Metabolic and biochemical testing
Volunteers provided fasting blood samples for glucose, insulin,
lipids, leptin, and TNF after an 8- to 12-h overnight fast. A 75-g
oral glucose tolerance test was administered, and a second blood sample
for glucose determination was drawn after 120 min. Individuals were
excluded from the oral glucose tolerance test if they had
physician-diagnosed diabetes and 1) were currently receiving treatment
with insulin or oral hypoglycemic agents or 2) had a fasting blood
glucose exceeding 11.1 mmol/L. Diabetes and IGT were diagnosed
according to established criteria (26).
Fasting plasma insulin concentrations were determined by RIA. IR was estimated using the homeostasis model assessment (HOMA) approach of Matthews and colleagues (27). Plasma concentrations of total triglyceride were measured using procedures described in the Lipid Research Clinics Manual of Operations (28). Glucose level was determined using standard laboratory procedures.
The TNF concentration was measured using the quantitative sandwich
enzyme immunoassay technique (R & D Systems, Minneapolis,
MN), which has an interassay coefficient of variation of 7.5–10.4%
and a lower limit of detection of 0.5 pg/mL. Measurements were made
using specimens that had been stored at -70 C for approximately 3 yr.
Although we have no direct information on the stability of TNF over
time at this temperature, it has been suggested that other cytokines
show no loss of activity after storage at various temperatures (up to
56 C) for 1 yr (29). In addition, Thavasu and colleagues demonstrated
that there was "no effect on TNF levels after six repeat
freeze/thaw cycles" (samples frozen at -40 C) (30).
Assessment of anthropometry, blood pressure (BP), and medication use
Anthropometric measurements were performed without shoes and with the volunteer wearing either undergarments and a hospital gown or light athletic clothing. Each measurement was performed twice, and the average was used in the analysis. Height was measured to the nearest 0.1 cm using a wall-mounted stadiometer. Weight was measured to the nearest 0.1 kg using a hospital balance beam scale. BMI was defined as weight (kilograms)/height (meters)2. The waist was measured to the nearest 0.5 cm at the minimal circumference between the umbilicus and xiphoid process; the hips were measured to the nearest 0.5 cm at maximum extension of the buttocks. The waist/hip ratio (WHR) was calculated as the ratio of these two circumferences.
The percent body fat was estimated by bioelectrical impedance analysis using the Tanita TBF-201 Body Fat Analyzer (Tanita Corp., Tokyo, Japan). We have documented high reproducibility of percent fat estimates using this machine (intraclass correlation coefficient = 0.99) (31) in a sample from this population. The instrument has been validated against dual energy x-ray absorptiometry in a number of populations (32, 33, 34).
BP was measured in the right arm with the volunteer seated and the arm bared. Systolic BP was recorded to the nearest 2 mm Hg at the appearance of the first Korotkoff sound (phase I), and diastolic BP was recorded to the nearest 2 mm Hg at the appearance of the fifth Korotkoff sound (phase V). Two measurements were performed using a hand-held aneriod sphygmomanometer, and the average of the two was used in the analysis.
Current use of medications for diabetes and hypertension was determined from patient medical files and pharmaceutical log books.
Statistical analysis
All statistical analyses were conducted using SAS version 6.09 in the VMS environment (35). Data are presented as means, SDs, medians, and ranges. Relationships between continuous variables were assessed using Spearman correlation coefficients. Distributions of continuous variables were tested for normality, and, if appropriate, the natural log transformations of skewed variables were used in subsequent analyses. t tests were employed to assess differences between groups, and analysis of covariance was used to test for differences between groups while adjusting for other factors.
Multiple linear regression models were constructed to examine factors
that were associated with variations in TNF concentration. The log
transformation of serum TNF was used as the dependent variable.
Independent variables were included in the initial models according to
the strength of their univariate relationships with serum TNF and
their biological importance based on the scientific evidence available
at the time the analysis was conducted. Terms for interaction effects
between gender and other independent variables were initially added to
the full regression model as a global test for interactions. None of
these interactions was statistically significant (all P
> 0.05; data not shown), and thus subsequent modelling was performed
with the genders pooled. In addition to the full regression model
approach, a backward stepwise elimination procedure was employed to
assist in the construction of models that best predicted TNF
concentration in this sample (36).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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concentration was 5.6 pg/mL (SD =
2.18) and ranged from 2.0–12.9 pg/mL. There were no differences
between males and females in terms of age, TNF, fasting insulin,
glucose (fasting and 2 h post-challenge), fasting
triglycerides, and waist circumference (Table 1
). The percent body fat and leptin
levels were significantly higher among females (P <
0.001), whereas males had significantly elevated WHRs and BP levels
(both systolic and diastolic) relative to females (P <
0.05; Table 1).
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and fasting insulin, HOMA IR, waist
circumference, fasting triglyceride, and systolic BP; in all cases,
coefficients for females were higher than those for males (Table 2 and Figs. 1 and 2).
The associations between TNF and BMI, WHR, fasting glucose, and 2-h
PC glucose were of borderline significance, with higher sex-specific
coefficients among males for the latter three variables (Table 2). The
relationships between TNF and age, percent body fat, diastolic BP,
and leptin were generally weak, although the positive correlation with
leptin among females was notable (Table 2). When individuals with
diabetes were excluded from the correlation analysis, coefficients were
stronger for all variables among women and weaker for all variables
among men (data not shown). With the sexes pooled, correlations were
slightly stronger for all factors except fasting and 2-h PC glucose
(data not shown).
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concentrations than those with
IGT or type 2 DM. These differences were statistically significant,
both unadjusted as well as adjusted for age and sex. When these
comparisons were further controlled for log HOMA IR, however,
differences were no longer significant (both P > 0.25;
Fig. 3).
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concentration. Independent
variables that were considered included age, WHR, percent body fat, and
diastolic BP; the log transformations of triglyceride concentration,
HOMA IR, leptin concentration, and systolic BP; and indicator variables
for gender, IGT, diabetes, and use of hypertension medication. Waist
circumference and BMI were not included in the same multivariate model
due to very strong colinearity between these two variables.
Backward stepwise elimination was used to assist in the construction of
a regression model that best predicted the TNF concentration in this
sample. Using an inclusion criterion of P = 0.05, log
HOMA IR and log systolic BP were determined to be significant
independent factors by this procedure (model F = 11.45;
P < 0.0001; model r2 = 0.23; log HOMA IR:
b = 0.16, t = 3.23, P =
0.0018; log systolic BP: b = 1.03, t =
3.44, P = 0.0009). The full linear regression model is
presented in Table 3. Log HOMA IR and log
systolic BP were independently related to log TNF; none of the other
factors in the model was significantly associated in the presence of
other variables (model r2 = 0.28).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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in the pathogenesis of IR in humans is
controversial. In this study of an isolated Native Canadian community,
we found that in subjects with varying degrees of obesity and glucose
intolerance there was a significant correlation of circulating TNF
concentrations with fasting insulin as well as with HOMA IR, a measure
of IR. TNF was also significantly correlated with waist
circumference, WHR, fasting triglycerides, and systolic blood pressure,
parameters previously demonstrated to be positively associated with IR.
Multiple linear regression analysis along with backward stepwise
elimination revealed that only HOMA IR and systolic blood pressure
remained significant and independent predictors of TNF.
Studies in rodents support a role for TNF as a mediator of IR (8, 15, 37). In human subjects, elevated adipose tissue TNF mRNA content
and fasting insulin are correlated, and both decrease with weight loss
(13, 14). Although circulating TNF concentrations are elevated in
obese rodents (15), this has been difficult to substantiate in human
subjects (6, 13, 37). This is due in part to the low circulating levels
and previous lack of ultrasensitive assays. Furthermore, elevated local
production of TNF in adipose tissue may not always be reflected in
peripheral blood, as the cytokine is synthesized and secreted by other
tissues, notably monocytes/macrophages (38), and may not always be
released into the circulation by the adipose tissue (39). A local
autocrine/paracrine action may also explain in part the inability to
reverse the IR with anti-TNF antibody administration in human
subjects (16).
It has been suggested that TNF interaction with its cell surface
receptor results in proteolytic cleavage of the extracellular binding
domain, releasing a substantial amount of soluble receptor (40, 41, 42, 43, 44).
One study found that circulating levels of soluble TNFR2, the soluble
portion of the larger 80-kDa TNFR, but not TNFR1 (55 or 60 kDa), were
elevated in obese subjects and correlated with IR (45), whereas another
study reported that circulating levels of the smaller p55 TNFR
correlated with insulin levels, BMI, and serum leptin concentrations
(46). Although it has been proposed that the longer circulating
t1/2 of the soluble receptors may provide a more accurate
reflection of TNF action (42, 43, 44), further studies are required to
determine whether this is the case for obesity and IR, and which form
of receptor best reflects the cytokine action in adipose tissue.
In another study elevated circulating TNF levels were found in
Caucasian men (but not in women) with type 2 DM compared with levels in
nondiabetic men (47). In our study, TNF levels were also higher in
type 2 DM as well as in IGT compared to NGT subjects in both genders.
Notably, adjustment for HOMA IR eliminated these differences,
supporting the concept that the association of elevated TNF
concentrations with abnormalities in glucose metabolism is related to
the IR. The stronger correlation of TNF with HOMA-IR in women in our
study may be due to their greater degree and range of obesity, as
adipose tissue is probably the major source of excess TNF in these
subjects.
IR precedes the development of glucose intolerance in the offspring of
type 2 DM subjects (1, 2, 3, 4). Kellerer et al. reported a
significant negative correlation between circulating TNF levels and
glucose disposal rate determined by the euglycemic hyperinsulinemic
clamp technique in both German and Finnish nondiabetic offspring of
type 2 DM parents (48). In that study multiple linear regression
analysis revealed a significant correlation of TNF with the
percentage of desirable body weight. These data are consistent with the
increased synthesis and secretion of TNF in adipose tissue of obese
subjects, but did not show that TNF was directly related to the IR.
It should be noted that lean subjects with type 2 DM are also insulin
resistant (3, 4, 5). Thus, the etiology of IR as well as that of type 2 DM
appear to be multifactorial and heterogeneous among different
populations (2, 3, 4, 5). Our study is unique, in that a genetically
homogeneous isolated Native Canadian population was examined.
Another approach to substantiate a role for TNF in human obesity is
genetic analysis. Studies of the TNF gene-coding sequence and
promoter region in both Caucasians and Pima Indians did not find any
polymorphisms associated with type 2 DM or obesity (49, 50). However, a
marker located 10 kb from the TNF gene was associated with BMI in
the Pima study (50). In another study, the NcoI restriction
site of the TNF promoter was associated with increased percent body
fat, leptin levels, and IR (51). However, circulating TNF levels
were not different. These data do not prove but suggest that the
up-regulation of TNF is, in general, an acquired accompaniment of
the obese state.
The explanation of the independent predictive value of systolic BP on
TNF concentration is not known. However, recent studies in the
spontaneously hypertensive rat (SHR) model found that TNF synthesis
and secretion are increased in response to lipopolysaccharide
stimulation compared with those in nonhypertensive control rats (52, 53); interestingly, this is most marked in adipose tissue (54).
Furthermore, TNF has been reported to stimulate angiotensinogen gene
expression in liver (55). These data raise the possibility of TNF
contributing to the elevated BP. On the other hand, Ferreri et
al. found that TNF production by the thick ascending tubule of
the renal medulla was elevated in angiotensin II-dependent hypertensive
rats and that neutralization with anti-TNF antiserum exacerbated the
hypertension (56). Thus, the mechanism of the relationship between BP
and TNF and its pathophysiological significance in hypertensive
human subjects remains to be determined.
In summary, this study demonstrates that in a genetically homogeneous
Native Canadian population there is a significant and independent
association between the circulating TNF concentration and IR.
Systolic BP, well documented to be associated with IR and obesity (4),
also showed a significant independent association. Furthermore,
elevated levels of TNF in subjects with abnormal glucose tolerance
and overt diabetes could be accounted for by their degrees of IR. Thus,
our data support a significant contribution of TNF to the
pathogenesis of obesity-related IR and glucose intolerance in this
population.
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Acknowledgments |
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Footnotes |
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Received June 5, 1998.
Revised September 17, 1998.
Accepted October 2, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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N. Paquot, M. J. Castillo, P. J. Lefèbvre, and A. J. Scheen No Increased Insulin Sensitivity after a Single Intravenous Administration of a Recombinant Human Tumor Necrosis Factor Receptor: Fc Fusion Protein in Obese Insulin-Resistant Patients J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1316 - 1319. [Abstract] [Full Text]
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