Asia Pacific J Clin Nutr (1995) 4: 343-344
Asia Pacific J Clin Nutr (1995) 4: 343-344
Insulin resistance and low metabolic
rate: do they cause obesity?
Boyd Swinburn, MD, ChB, FRACP
Department of Community Health, University
of Auckland, Auckland, New Zealand
a symposium organised by the Australasian Clinical Nutrition Society
(New Zealand Division) held at the School of Medicine, University
of Aukland on 8-9 December 1994. Presented on pages 337-370.
Insulin resistance and obesity have genetic determinants
which are separate and probably polygenic. Under certain environmental
conditions, both probably offer selective advantages for survival.
Under modern environmental conditions, a genetic predisposition
to both would result in marked insulin resistance and be a major
risk for the development of NIDDM. A low relative metabolic rate
and a high insulin sensitivity have been shown to predict weight
gain. However, upon the weight gain these "metabolic risks"
appear to normalise thus raising doubts about whether these factors
are truly aetiological. The thrifty genotype hypothesis remains
a valid construct to explain the presence of common, genetically-determined
factors which are currently detrimental to health, however, the
original mechanisms proposed by Neel of an "efficient"
metabolism or hyperinsulinaemia need considerable rethinking in
light of 30 years of evidence.
Among the major predictors for the development of
non-insulin dependent diabetes mellitus (NIDDM) are race, family history,
obesity, and insulin resistance1. Race and, to some extent,
family history reflect the genetic basis for NIDDM. Part of this genetic
transmission may be through the genetic determinants of obesity2,3
and insulin resistance4. How is the triad of NIDDM, obesity,
and insulin resistance linked and how do these relationships bring
us closer to understanding reasons for a high frequency of a NIDDM
genotype in populations? Also, is the NIDDM or obesity genotype due
to a "thrifty" or "efficient" metabolism as Neel
Relationship between obesity, insulin resistance,
In cross-sectional studies, obesity is associated
with insulin resistance, although the relationship is not as tight
as commonly believed (r values of about 0.3-0.4) with a considerable
spread at all levels of body fatness5. From weight gain
and weight loss studies, it is well recognised that weight gain cause
increases insulin resistance and weight loss decreases it6.
NIDDM, especially in non-European races, is almost
invariably associated with both insulin resistance and obesity1.
Could insulin resistance, therefore, be the common denominator causing
both obesity and NIDDM? If this were the case, the genetic dete 1000
rminants of insulin resistance could be the "thrifty" genotype.
Insulin resistance attenuates weight gain
Three longitudinal studies have shown that insulin
resistance attenuates, rather than accelerates, weight gain. The first
study in Pima Indians measured insulin action directly using the hyperinsulinaemic,
euglycaemic clamp technique and showed that the cumulative incidence
of gaining 10 kg of body weight was 3.8 (95% CI 1.7-8.6) times greater
in insulin sensitive subjects (90th percentile of insulin action)
than in insulin resistant subjects (10th percentile of insulin action).
Two further studies, both in Hispanics and Caucasians, confirmed these
findings by showing that low fasting insulin levels predicted weight
gain7,8. Therefore, insulin resistance is unlikely to be
the common precursor genotype which explains both NIDDM and obesity.
Selective advantages of insulin resistance
Insulin resistance is common, it appears to be partly
genetically determined, and it is implicated in the development of
NIDDM, hypertension, dyslipidaemia and atherosclerosis. One could
then ask Neels question: Was there once a selective advantage
for insulin resistance? The answer to that must be "yes"
if one looks at the physiological role of insulin resistance. Puberty
is a period of marked insulin resistance9 which appears
to be related to the growth factor role of insulin. Normal pregnancy
is associated with a fall in insulin sensitivity to about 30-50% of
the non-pregnant state10 resulting in a re-direction of
glucose away from maternal skeletal muscle and towards the fetus which
would be advantageous for fetal growth (unless there was too much
glucose as in gestational diabetes). Insulin resistance also develops
during starvation and major trauma and sepsis11, and this
serves to re-allocate the fuel supplies of glucose, fatty acids and
protein during these stresses. There are undoubtedly a variety of
mechanisms by which insulin resistance is produced under these conditions
(for example, starvation is hypoinsulinaemic and pregnancy is hyperinsulinaemic).
Obesity: Metabolic rate and other predictors of
Metabolic rate is usually conceptualised as total
calories burned in 24 hours in the same way that calorie intake is
characterised as total calories per 24 hours. Under these absolute
terms, obesity is clearly associated with high metabolic rates (and
high energy intake). Researchers in the energy metabolism field, however,
usually adjust the metabolic rate to body size (eg kcal/kg fat-free
mass/24 hours). This is a different concept. It means that a person
can be described as having a high or low metabolic rate relative to
what one would predict given the persons body size (mainly fat-free
No population with a high prevalence of obesity or
NIDDM has been shown to have lower metabolic rates (absolute or relative)
compared to Caucasians. What has been shown is that individuals with
a low relative metabolic rate have a higher rate of weight gain than
those with a metabolic rate greater than predicted12. However,
upon gaining that weight, the "abnormally low"
relative metabolic rate appears to self correct. This
has been seen in other metabolic predictors of weight gain, suggesting
that these factors are better viewed as modulators of weight change
(preventing large swings in weight) than as causes of obesity13.
Metabolic predictors of weight gain identified among Pima Indians
include a low relative metabolic rate, low ratio of fat: carbohydrate
oxidation, high insulin sensitivity, low "fidgeting" activity,
low core temperature, and a reduced insulin secretion14.
The differences in prevalence of obesity between populations
are probably explained by environmental differences (such as the national
diet) and not metabolic differences. Indeed, the search for a metabolic
cause of obesity in certain populations has largely been fruitless.
However, within a particular environment, the genetic makeup of some
individuals means that they will gain more weight than others. A degree
of relative energy "efficiency" or "thriftiness"
may explain some of these individual differences in response to a
modern environment, but there are likely to be many metabolic determinants
of energy or fat balance which also may contribute.
- Knowler WC, Pettitt DJ, Saad MF, Bennett PH. Diabetes
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- Stunkard AJ, Sorensen TIA, Hanis C, et al. An adoption
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- Lillioja S, Mott D, Zawadzski J, et al. In vivo
insulin action is familial characteristic in non-diabetic Pima Indians.
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- Swinburn BA, Nyomba BL, Saad MF, et al. Insulin
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- Sims EAH. Experimental obesity, dietary induced
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- Valdez R, Mitchell BD, Haffner SM, et al. Predictors
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- Hoag S, Marshall JA, Jones RH, Hamman RF. High
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JM, Preece MA. Insulin and growth factors adaptation to normal puberty.
Horm Res 1992; 37(suppl 3):70-73.
- Buchanan TA, Metzger BE, Freinkel N, Bergman RN.
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late pregnancy in lean and moderately obese women with normal glucose
tolerance or mild gestational diabetes. Am J Obstet Gynecol 1990;
- Zenni GC, McLane MP, Law WR, Raymond RM. Hepatic
insulin resistance during chronic hyperdynamic sepsis. Circ Shock
- Ravussin E, Lillioja S, Knowler WC, et al. Reduced
rate of energy expenditure as a risk factor for body weight gain.
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- Ravussin E, Swinburn BA. Metabolic predictors of
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- Schwartz MW, Boyko EJ, Kahn SE, Ravussin E, Bogardus
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Copyright © 1995 [Asia Pacific Journal of Clinical
Nutrition]. All rights reserved.
January 19, 1999