O R I G I N A L A R T I C L E

Epidemiology of Type 2 Diabetes: Risk

Factors
STEVEN M. HAFFNER, MD
A number of cross-sectional and prospective studies that compared the insulin sensitivity of
various national and ethnic populations within the U.S. to the total U.S. population were ana-
lyzed to find possible risk factors for the development of type 2 diabetes. It was found that the
risks for diabetes in African-Americans, Hispanics, and Native Americans are approximately
2, 2.5, and 5 times greater, respectively, than in Caucasians. Studies of the prevalence of type
2 diabetes in Mexican Americans and non-Hispanic whites in San Antonio showed that there
is an inverse relationship between socioeconomic status and the prevalence of diabetes. It also
appears that cultural effects lead to an increased incidence of obesity in these populations,
which may lead to insulin resistance. Genetic factors may also be a contributing factor. A 5-
year, prospective study of insulin resistance in Pima Indians showed a relationship between
impaired glucose tolerance and subsequent development of type 2 diabetes. In a 7-year study
in Mexican Americans, those subjects who had both high insulin secretion and impaired
insulin sensitivity had a 14-fold increased risk of developing type 2 diabetes. Regardless of cul-
tural and ethnic factors, the San Antonio Heart Study, which compared Mexican Americans and
non-Hispanic whites, showed that in both groups, the strongest predictors of developing type
2 diabetes are elevated fasting insulin concentrations and low insulin secretion.
Diabetes Care 21 (Suppl. 3):C3-C6,1998
C
iting the increasing incidence of type
2 diabetes in the U.S. and other devel-
oped countries, some researchers
have called diabetes a disease of affluence.
The marked variation in the incidence of
diabetes among many national and ethnic
populations, even when socioeconomic
factors are taken into account, indicates
that other risk factors may be involved.
In fact, results of recent cross-sectional
and prospective studies of insulin sensitiv-
ity in normal subjects suggest possible rea-
sons for the high incidence of type 2
diabetes among African-Americans and
Mexican Americans. Significantly, these
results also indicate that the risk factors for
disease development are the same regard-
less of whether a particular population has
a high or low risk of developing type 2 dia-
betes. Consequently, these findings open
new avenues in diabetes prevention for all
individuals at risk: the identification of risk
factors is essential to the successful imple-
mentation of primary prevention programs.
A number of cross-sectional and
prospective studies have compared insulin
sensitivity of various ethnic groups within
the U.S. population with that of the U.S.
population as a whole to determine whether
certain ethnic groups have an increased risk
of developing type 2 diabetes. This article
reviews recent epidemiological data on eth-
nicity, obesity, insulin sensitivity, and other
risk factors that may profoundly influence
the development of type 2 diabetes.
ETHNICITY Within the U.S., African-
Americans have a twofold increase in risk
of the development of type 2 diabetes com-
pared with Caucasians, and this risk is
slightly higher in women, probably as a
result of increased obesity. The risk in His-
From the Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Center, San
Antonio, Texas.
Address correspondence to Steven M. Haffner, MD, The University of Texas Health Center at San Antonio,
Department of Medicine, Division of Clinical Epidemiology, 7703 Floyd Curl Dr., San Antonio, TX 78284-7873.
Received for publication 1 October 1997 and accepted in revised form 24 April 1998.
This article is based on a presentation at a symposium sponsored by Amylin Pharmaceuticals, Inc. Its pub-
lication in a supplement to Diabetes Care is made possible by an educational grant from Amylin and Ortho-
McNeil Pharmaceutical, Inc.
panics, particularly individuals of either
Puerto Rican or Mexican origin, is approx-
imately 2.5 times greater than in Cau-
casians, whereas Native Americans show a
fivefold increase in risk (1,2).
When assessing risk factors for the
development of diabetes in these various
ethnic groups, it is important to ascertain
whether the risk is due to the relative
poverty of these populations or whether
other, possibly greater, risk factors are
involved. Studies of the prevalence of type
2 diabetes in Mexican Americans and non-
Hispanic whites in San Antonio have
shown that there is indeed an inverse rela-
tionship between socioeconomic status and
the prevalence of diabetes (2). This rela-
tionship has been observed in all developed
countries, and it also includes a trend
toward increased prevalence in urban areas
compared with rural communities. How-
ever, within the same neighborhood, Mex-
ican Americans have a higher prevalence of
type 2 diabetes than do non-Hispanic
whites, indicating that there may also be
some genetic factors involved in the devel-
opment of diabetes within this population.
OBESITY A number of investigators
have explored the apparent relationship
between obesity and the development of
type 2 diabetes within Mexican-American
and African-American populations (3,4).
A study comparing insulin concentrations
with the waist-to-hip ratios of Mexican-
American and non-Hispanic white men
found that within the same quartile for
waist-to-hip ratio, Mexican Americans had
higher insulin concentrations. These results
suggest that Mexican Americans may have
a greater level of insulin resistance than
non-Hispanic whites (5).
The role of insulin sensitivity and its
relation to obesity was investigated directly
in the Insulin Resistance Atherosclerosis
Study (6). This study included approxi-
mately 1,100 healthy subjects drawn from
three ethnic groups: Mexican Americans,
non-Hispanic whites, and African-Ameri-
cans. Compared with those for non-His-
panic whites, the cumulative frequency
curves for 2-h insulin response were shifted
slightly to the right for both African-Amer-
icans and Mexican Americans, which sug-
DIABETES CARE, VOLUME 21, SUPPLEMENT 3, DECEMBER 1998 C3

Risk factors of type 2 diabetes
CO
18
14
O5
-i- 10
o
Q_
Si
o
u
O
0.10 0.14 0.18 0.23 0.27 0.31
Intra-abdominal/Total adipose tissue
Figure 1Correlation of the proportion of intra-abdominal to total adipose tissue and insulin-medi-
ated glucose disposal (per kilogram lean body mass) during an insulin infusion of 1 mU kg~
l
min~
l
in African-American men. From Banerji et al. (8).
gests that these populations are more
insulin resistant.
In addition, studies of insulin sensitiv-
ity showed that African-Americans had a
lower sensitivity than non-Hispanic whites,
whereas a smaller reduction in insulin sen-
sitivity was seen among Mexican Ameri-
cans. The differences in insulin sensitivity
between African-Americans and non-His-
panic whites remained even when the data
were corrected for such variables as BMI,
waist-to-hip ratio, and differences in phys-
ical activity and diet. However, these cor-
rections did abolish the differences in
insulin sensitivity between the Mexican
Americans and non-Hispanic whites. Fur-
ther analysis of the data from the Mexican-
American population demonstrated that
subjects drawn from the urbanized area of
San Antonio, where Mexican Americans
tend to be very obese, did show evidence of
reduced insulin sensitivity.
Results of a 1992 study by Banerji and
Lebovitz (7) suggest that approximately 40%
of African-Americans are insulin sensitive.
More recently, a 1995 study of 22 African-
American men with type 2 diabetes, who
had a mean BMI of approximately 26.5
kg/m
2
, found that there was a strong corre-
lation (r = - 0. 78, P < 0.001) between
insulin resistance and visceral fat (Fig. 1);
but there was little or no correlation between
BMI and insulin resistance (r = 0.5, NS) in
this population (8). These studies, there-
fore, highlight the importance of visceral fat
as a determinant of insulin resistance in
African-American subjects. This is an impor-
tant observation, because there have been
some differences in the literature with
respect to the predictive value of BMI for
insulin resistance in this population. For
example, one study suggested that waist-to-
hip ratio is not a reliable predictor of insulin
sensitivity in African-Americans (9), and
Conway et al. (10) showed that, for a given
30-i
20-
10-
waist-to-hip ratio, African-American sub-
jects may have less visceral fat than Cau-
casian subjects.
The value of body fat distribution as a
predictor of type 2 diabetes in Mexican
Americans was also investigated, and it was
found that waist circumference is a better
predictor of type 2 diabetes in women than
either waist-to-hip ratio or BMI. Similarly,
waist circumference is the best predictor of
type 2 diabetes in men, whereas BMI is a
better predictor than waist-to-hip ratio (11).
INSULIN SENSITIVITY AND
GLUCOSE TOLERANCEInsulin
sensitivity and impaired glucose tolerance
are other factors that have been investigated
as possible predictors of the development of
type 2 diabetes. Results of a 5-year prospec-
tive study of insulin resistance in Pima Indi-
ans showed a clear relationship between
impaired glucose tolerance and the subse-
quent development of type 2 diabetes (12).
Furthermore, analysis of 2-h insulin profiles
showed that there was a nearly linear rela-
tionship between insulin concentration and
the development of type 2 diabetes; a simi-
lar relationship was seen with fasting insulin
concentrations (Fig. 2). According to this
report, low insulin response and increased
insulin resistance are both predictors of type
2 diabetes, and each variable acts as an
independent risk factor (12).
A 7-year study in Mexican Americans
found that there was a step-wise increase in
the incidence of type 2 diabetes within the
quartiles for fasting insulin concentration (a
1 2 3 4
Plasma glucose (2-hour) quintile
301
20-
8 "5 10-
1 2 3 4
Plasma glucose (fasting) quintile
30-1
20-
10-
B
1 2 3
Serum insulin (2-hour
4
quintile
301
20-
10-
1 2 3 4
Serum insulin (fasting) quintile
Figure 2Within a population of Pima Indians, the 5-year incidence of type 2 diabetes was related
to the quintilesfor insulin resistance as measured by 2-h plasma glucose (A), 2-h serum insulin (B), fast-
ing plasma glucose (C), and fasting serum insulin concentrations (D). Adapted from Lillioja et al. (12).
C4 DIABETES CARE, VOLUME 21, SUPPLEMENT 3, DECEMBER 1998

Haffner
15 T
13.9
Fasting insulin
AI / AG
p value for trend: < 0.001
123
high
low
Figure 3The risk of developing type 2 diabetes by fasting insulin concentration and insulin secre-
tion (change in insulin concentration divided by change in glucose concentrations over the first 30 min
of an oral glucose tolerance test [AI
3O
/AG
3O
]). Adapted from Haffner et al. (13).
surrogate for insulin resistance) at baseline.
However, there was an inverse relationship
between insulin secretionas assessed by
insulin response (30-min insulin minus fast-
ing insulin) divided by glucose response (30-
min glucose minus fasting glucose) following
a standard oral glucose tolerance testat
baseline and the subsequent development of
diabetes (13). When these two factors were
combined, it was shown that they have an
approximate additive effect. Thus, people
who had either low insulin secretion but
normal sensitivity or normal insulin secre-
tion but impaired sensitivity at baseline had
an approximately fivefold increase in risk of
developing type 2 diabetes compared with
subjects who had values within the normal
range for both insulin secretion and sensitiv-
ity. Furthermore, those subjects who had
both high insulin secretion and impaired
insulin sensitivity had a 14-fold increase in
their risk of developing type 2 diabetes (Fig.
3). Finally, a multivariate analysis of risk fac-
tors for the development of type 2 diabetes in
Mexican Americans showed that predictors
for disease development include age, fasting
insulin concentration, low insulin secretion,
waist-to-hip ratio, and impaired glucose tol-
erance (13). It may be concluded, therefore,
that low insulin secretion and increased
insulin resistance predict the development of
type 2 diabetes in Mexican Americans, a
population that is a characterized by hyper-
insulinemia and insulin resistance.
ARE THE RISK FACTORS FOR
TYPE 2 DIABETES THE SAME I N
DIFFERENT POPULATIONS?
A recent study directly compared the pre-
dictive factors for the development of type 2
diabetes in two populations, one of which
has a low risk and the other a high risk of
developing the disease (14). The San Anto-
nio Heart Study followed 914 Mexican
Americans (high risk) and 362 non-His-
panic whites (low risk) for 8 years. At the
end of that time, 107 (11.7%) of the Mexi-
can Americans and 18 (4.9%) of the non-
Hispanic whites had developed type 2
diabetes, representing a 2.4% higher preva-
lence of diabetes in the Mexican Americans
(P < 0.001). Multivariate analysis showed
that within both populations, age >45 years
at the start of the study, BMI >27.7 kg/m
2
,
waist-to-hip ratio >0.825 for women or
0.938 for men, impaired glucose tolerance,
elevated fasting insulin concentrations, and
low insulin sensitivity were all independent
predictors for the development of type 2 dia-
betes (Table 1). Of these, fasting insulin con-
centrations and insulin secretion were the
strongest independent risk factors. Interest-
ingly, data from studies in Pima Indians sug-
gest that insulin sensitivity is a more
powerful risk factor than insulin secretion,
but this finding may reflect differences in the
way that insulin sensitivity was assessed in
different studies. However, even allowing
for all these factors, ethnic origin remained a
powerful independent predictor, accounting
for an excess risk of approximately 15% in
the Mexican-American population (P <
0.001). Furthermore, although a number of
studies have suggested that women have a
higher risk than men of developing type 2
diabetes, this study found that the risk was
equal for both sexes.
Examined collectively, the data from
epidemiological studies in Mexican Amer-
icans suggest that a combination of genetic
and cultural effects results in obesity and an
unfavorable body fat distribution, which
lead to insulin resistance. In addition, direct
genetic influences may also predispose this
population to insulin resistance. In
response to insulin resistance, the pancre-
atic islets initiate a prolonged period of
insulin hypersecretion, which produces (3-
cell exhaustion and ultimately results in
type 2 diabetes.
CONCLUSIONS There is substan-
tial evidence from a number of cross-sec-
tional and prospective studies that certain
ethnic groups, particularly Mexican Amer-
icans and African-Americans, have an
increased risk of developing of type 2 dia-
betes when compared with the U.S. popu-
lation as a whole. Furthermore, there is
some evidence that cultural influences may
be one factor that increases the risk of dis-
ease development. For example, there is an
Table 1Multiple logistic regression analyses of risk factors for type 2 diabetes with the
development of type 2 diabetes as a dependent variable
Variable
Age (years)
Sex (M/F)
Ethnicity (MA/NHW)
BMI (kg/m
2
)
Waist-to-hip ratio
Fasting insulin concentration
AI30/AG30
IGT (yes/no)
Odds ratio
1.24
1.56
1.48
1.05
1.48
3.29
0.322
3.00
95% CI
1.002-1.535
0.909-2.677
1.12-3.76
1.007-1.096
1.09-1.99
2.35-4.63
0.219-0.476
1.85-4.88
P value
0.048
0.107
0.019
0.022
0.011
<0.001
<0.001
<0.001
MA, Mexican American; NHW, non-Hispanic white; AI
3O
/AG3
O
, change in insulin concentration to change
in glucose concentration over the first 30 min of an oral glucose tolerance test; IGT, impaired glucose tol-
erance. Adapted from Haffner et al. (14).
DIABETES CARE, VOLUME 21, SUPPLEMENT 3, DECEMBER 1998 C5

Risk factors of type 2 diabetes
increased incidence of obesity in these pop-
ulations, which may, in turn, lead to insulin
resistance. It appears, however, that genetic
factors are also important, as demonstrated
by recent analyses that adjusted for factors
such as BM1 and found that the risk of
developing type 2 diabetes is still elevated
in Mexican Americans. Nevertheless, even
when the effects of ethnicity and obesity are
recognized, the strongest predictors of type
2 diabetes are elevated fasting insulin con-
centrations and low insulin secretion.
These findings may enhance efforts to iden-
tify susceptible individuals of any ethnic
group or national population and may
allow the development of targeted primary
prevention programs for type 2 diabetes.
Acknowledgments This work was pre-
sented at The Worldwide Burden of Diabetes
Workshop, 5-7 December 1996, Phoenix, Ari-
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