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Obesity, Hypertension, and Insulin
Resistance
ZACHARY T. BLOOMGARDEN, MD
1
T
his article summarizes material
presented at the meeting of the
American Society of Hypertension
(ASH) in New York, New York, May,
2002, as well as presentations at the
American Diabetes Association (ADA)
Annual Meeting in San Francisco, Califor-
nia, June, 2002.
At a symposium addressing the relation-
ships between obesity, hypertension, and
cardiovascular disease at the ASH, Roger
Unger (Dallas, TX) discussed lipotoxicity
and the metabolic syndrome. He pointed
out that over that past 50 years there has
been a great change in the food environ-
ment, so that the “mechanism for preload-
ing calories, storing them for when a
famine occurred,” has led to “hypertro-
phy and hyperplasia of those adipocytes
[. . . ]. Famines were eliminated and re-
placed by a never-ending stream of high-
quantity, high-fat, high-carbohydrate
foods at the same time that physical exer-
tion dropped to an all-time low.” This has
led to a progressive increase in obesity,
particularly over the past two decades.
“As long as the excess fat remains in the
adipocyte,” he stated, “health is not dele-
teriously affected,” but an “increase in ec-
topic deposition of lipids” causes the
insulin-resistant state, with insulin resis-
tance per se characterized by Unger as
“not the proximal cause of the syndrome.”
Unger examined monogenic disorders of
lack of leptin action to understand “the
mechanism of the disorder.” These syn-
dromes, which lead to components of the
metabolic syndrome, suggest that leptin
resistance or deficiency may be a more
central cause than insulin resistance.
The normal actions of leptin can be
seen in animal models of obesity, with
overfeeding leading to hyperleptinemia,
which may cause fat to deposit primarily
in the adipocyte. Normal islets, as an ex-
ample, “fill up with triglycerides” when
incubated with fatty acids, but this can be
prevented by administration of leptin.
When leptin action is insufficient, as seen
in the fatty/fatty (fa/fa) rat with loss-of-
function mutation of the leptin receptor
or the leptin-deficient ob/ob rat, there is a
marked increase in tissue fat. fa/fa rats
show both heart and muscle “loaded with
triglyceride,” suggesting that “leptin in-
creases tolerance for fat just as insulin in-
creases tolerance for glucose.”
Obesity in the fa/fa animal leads to an
increase in cardiac output to maintain the
needs of excess body tissue. Cardiac func-
tion deteriorates, with initial cardiac hy-
pertrophy leading to a pattern resembling
that seen in dilated cardiomyopathy. In-
creased cardiomyocyte apoptosis, as
shown by DNA laddering, can be seen in
this setting. Levels of the sphingomyelin
derivative ceramide increase with obesity
and may mediate these effects, and block-
ers of serine palmityl transferase (which
condenses palmityl CoA with serine to
form ceramide) can prevent this process.
Ceramide precursors lead to more rapid
ceramide synthesis and increase insulin
resistance in these animal obesity models.
In the islets, after diabetes has occurred in
these models, extensive mitochondrial
damage is seen in -cell remnants, a pro-
cess prevented by troglitazone adminis-
tration. High levels of fatty acids suppress
anti-apoptotic processes, while a trans-
genic fa/fa model overexpressing leptin
receptors in the islets is protected from
this fat-induced apoptosis.
Aspects of these processes appear to
occur in human obesity. Tissue triglycer-
ide may be synthesized from glucose as
well as from circulating free fatty acids
(FFAs), or may derive from VLDL triglyc-
eride, suggesting multiple potential
sources of lipotoxicity. Myocyte fat levels,
measured using magnetic resonance
scanning, show correlation with the de-
gree of adiposity and obesity may be as-
sociated with increased myocardial fat in
humans. Unger suggested that the condi-
tion of “fatty heart,” originally noted by
William Harvey and subsequently stud-
ied by early cardiologists, should be more
of a concern.
Gerard Ailhaud (Nice, France) dis-
cussed the differing metabolic character-
istics of visceral and subcutaneous (SC)
fat. Adipose tissue plays a role in energy
regulation and can be considered a secre-
tory organ supplying energy needs during
exercise via FFAs. “The problem is the
management of levels” of FFAs. In vitro
studies suggest that the smaller visceral
adipocytes undergo more lipolysis, with
more -adrenergic receptors leading to
greater activity of hormone-sensitive
lipase, while insulin has a stronger antili-
polytic effect on the larger SC adipocytes,
which have greater ␣-2 adrenergic recep-
tor levels. Thus, the ␣-2 adrenergic re-
sponse leads to accumulation of fat, but in
a fashion of potential benefit in terms of
sequestration of fatty acids in the adipo-
cyte, with similarity to the effects of thia-
zolidinedione administration. Local
production of cortisol may be greater in
visceral fat, while tumor necrosis factor
(TNF)-␣ and leptin are produced to a
greater extent in SC fat. Exercise pro-
motes mobilization of lipid from SC adi-
pocyte tissue in nonobese individuals, but
this process is decreased in obesity and
can be restored by administration of the
␣-2 adrenoreceptor antagonist phentol-
amine.
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with
the Diabetes Center, Mount Sinai School of Medicine, New York, New York.
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ADA, American diabetes Association;
ADMA, asymmetric dimethyl arginine; ARB, angiotensin receptor blocker; ASH, American Society of Hy-
pertension; ATP, Adult Treatment Panel; BAT, brown adipose tissue; BP, blood pressure; CHD, coronary
heart disease; CHF, congestive heart failure; CVD, cardiovascular disease; ESRD, end-stage renal disease; FA,
free fatty acid; HOT, Hypertension Optimal Treatment; IDL, intermediate density lipoprotein; IFG, impaired
fasting glucose; IGT, impaired glucose tolerance; IRS, insulin resistance syndrome; LCAT, lecithin-
cholesterol acyl transferase; LPL, lipoprotein lipase; NASH, nonalcoholic steatohepatitis; NHANES, National
Health and Nutrition Examination Survey; PCOS, polycystic ovary syndrome; RGZ, rosiglitazone; SC,
subcutaneous; SNS, sympathetic nervous system; SSPG, steady-state plasma glucose; TNF, tumor necrosis
factor; UKPDS, U.K. Prospective Diabetes Study; WHO, World Health Organization.
Reviews/Commentaries/Position Statements
PERSPECTIVES ON THE NEWS
2088 DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002
Three research presentations at this
symposium addressed further aspects of
the interrelationship between obesity and
hypertension. Weiguo Zhang et al. (Dal-
las, TX), noting that leptin might in prin-
ciple either increase blood pressure (BP)
by causing sympathetic activation or
lower BP by renal vascular and metabolic
effects, studied rodents with high-fat di-
et–induced obesity characterized by in-
creased plasma leptin and increased BP
and a second group with high-sodium di-
et–induced hypertension. They reported
that with adenoviral leptin gene therapy
to increase leptin levels, the BP decreased
in both animal models, with reduced food
intake and body weight in the high so-
dium diet animals. Raji et al. (Boston, MA)
(also reported in 1453-P) studied the ef-
fect of rosiglitazone (RGZ) on BP, noting
that potential mechanisms of the associa-
tion between hypertension and insulin re-
sistance include sympathetic activation,
sodium retention, and impaired vasodila-
tion (abstract numbers refer to the ab-
stracts of the 62nd ADA Scientific
Sessions, Diabetes 51 [Suppl. 2], 2002).
Twenty-four normal-to-high renin hyper-
tensive persons who were not receiving
angiotensin-converting enzyme inhibi-
tors (ACEIs) received RGZ 4 mg twice
daily for 16 weeks. Mean 24-h BP de-
creased from 138/85 to 134/80 mmHg,
the decrease correlating with the im-
provement in insulin sensitivity. “Non-
dippers” whose BP falls ⬍10 mmHg in
night versus day had similar BP fall to dip-
per, and showed restoration of circadian
variation. Rahmouni et al. (Iowa City,
Iowa) studied the molecular mechanisms
of insulin-induced sympathetic excita-
tion, showing that insulin increased sym-
pathetic activity in lumbar sympathetic
nerves and brown adipose tissue (BAT).
This effect was not altered by the PKC-␣
inhibitor LY333531, although mitogen-
activated protein kinase inhibitors
blunted the BAT sympathetic response.
Hypertension and diabetes
At a symposium at the ASH meeting on
the pathophysiology of hypertension in
diabetes, Luis Ruilope (Madrid, Spain)
further discussed the interrelationships
among diabetes, obesity, insulin resis-
tance, and hypertension. Ruilope sug-
gested that obesity is the initiating factor
and focused on the increasingly accepted
importance of the metabolic syndrome.
Obesity may affect BP via leptin, which
increases sympathetic activity and may
mediate increases in catecholamines, or
via activation of the renin-angiotensin
system. Angiotensin II levels are high in
obesity, and the presence of increased
glomerular pressures suggests activation
of the renin-angiotensin system.
It is crucial, Ruilope stated, that gen-
eral physicians diagnose the “quintet” of
central obesity, hypertension, dyslipide-
mia (high triglyceride and low HDL), and
glucose intolerance characterizing the
metabolic syndrome. Based on data from
the Third National Health and Nutrition
Examination Survey (NHANES) and us-
ing the criteria for metabolic syndrome of
the Adult Treatment Panel (ATP) III that
one have at least three of BP measure-
ments ⬎130/85, fasting glucose ⱖ110
mg/dl, fasting triglycerides ⱖ150 mg/dl,
HDL ⬍40 mg/dl if male and ⬍50 mg/dl if
female, and waist circumference ⬎102
cm if male and ⬎88 cm if female (1),
47,000,000 subjects in the U.S. are af-
fected (2). In Spain, despite “the so-called
Mediterranean diet,” Ruilope noted that
the metabolic syndrome is seen in ⬃40%
of the population over age 60 years. In a
survey of 4,057 patients in hypertension
and renal clinics in Spain, mean BMI was
29 kg/m
2
, ⬍20% had BP ⬍130/80
mmHg, 20% of the patients had diabetes,
and 15% had impaired fasting glucose
(IFG). In addition, 30% of the subjects
had microalbuminuria and an additional
10% had macroalbuminuria; decreased
renal function was present in one-third,
with the frequencies of diabetes and IFG
doubled in this group. Cardiovascular
disease (CVD) similarly appears to be as-
sociated with insulin resistance, with
studies from Sweden showing that one-
quarter of patients with myocardial in-
farction have previously undiagnosed
diabetes, and an additional 41% have IGT
(3).
Ruilope noted that most guidelines
merely suggest that obese individuals
with hypertension lose weight, without
specifically addressing treatment issues in
this group. Given the strong relationships
among obesity, hypertension, and diabe-
tes, to improve cardiovascular prognosis
it may be important to more fully under-
stand various approaches to BP for these
patients. Diuretics may be less efficacious
than ACEIs in lowering diastolic BP in
obese individuals and may increase glu-
cose levels (4). -blockers appear to in-
crease body weight, particularly in
persons with diabetes, as shown in the
U.K. Prospective Diabetes Study (5).
␣-Blockers may then be particularly suit-
able for subjects with insulin resistance,
although this has not been demonstrated
in trials addressing clinical events. (In-
deed, there is some evidence of increase in
CVD risk with use of this agent [ALLHAT
Collaborative Research Group: JAMA
283:1967–1975, 2000].)
In a study presented at the ADA meet-
ing, Aguilar-Salinas et al. (882-P) re-
ported a nationwide survey of 1,962
individuals in Mexico tested after a 9- to
12-h fast, with 13.1% of the population
having the metabolic syndrome as de-
fined above, comprising 5.5, 10.6, 18.3,
24.8, and 31.4% of those with age in the
20s, 30s, 40s, 50s, and 60s, respectively.
Kim et al. (937-P) assessed 1,230 persons
in Korea, with the metabolic syndrome
present in 18%. Ogihara et al. (951-P),
addressing the interaction of genetics
with environment, compared 211 dia-
betic and 203 nondiabetic native Japanese
men with 68 diabetic and 150 nondia-
betic second-generation Japanese-
American men. Native Japanese had
lower proportion of total caloric intake
due to fat, particularly animal fat, and
lower BMI, with lower subcutaneous fat
levels than in Japanese-American men
based on computerized tomography, but
with similar visceral fat. Their fasting in-
sulin levels were lower with similar glu-
cose-stimulated insulin, suggesting less
insulin resistance, and the prevalence of
hypertension (35.3 vs. 67.9%), athero-
sclerosis of the lower extremities (5.5 vs.
24.4%), and ischemic heart disease (5.1%
vs. 24.4%) were all much lower among
native Japanese than among Japanese-
Americans, respectively, confirming the
impact of the metabolic syndrome. Fur-
ther illustrating the complexity of these
interrelationships, during a 5-year follow-
up, Tsai et al. (122-OR) examined the in-
fluence of age-related changes in fasting
plasma glucose on fat distribution in 216
Japanese-American men without diabetes
at enrollment. Fasting glucose showed
positive association with intra-abdominal
fat, independent of age, while having a
negative association with SC fat, particu-
larly in older subjects.
Hirose et al. (926-P) noted newly di-
agnosed hypertension in 9.5, 15.7, and
20.6% of initially normotensive Japanese
men in the lowest, intermediate, and
highest tertiles, respectively, of insulin re-
Bloomgarden
DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 2089
sistance at 7 years of follow-up, with age
and BMI being other significant factors in
a multivariate analysis. Lorenzo et al.
(944-P), however, reported that in a sur-
vey of individuals in San Antonio and
Mexico City, the evidence for association
of hypertension with IGT was equivocal,
although there was a doubling of risk of
hypertension among those with diabetes
compared with those with normal glucose
tolerance. Whyte et al. (979-P) presented
further analysis of the NHANES data.
Compared with subjects meeting none of
the ATP III criteria, men with three, four,
and five risk factors had 3.7-, 4.2-, and
5.2-fold increases, respectively, in 10-
year coronary heart disease (CHD) risk.
For women, CHD risks were increased
5.8-, 8.9-, and 11.3-fold, respectively. In
a provocative analysis, Wilson et al.
(980-P) analyzed 3,374 Framingham off-
spring with a mean age of 62 years, with
33, 31, 22, 10, 3, and 0.2% of men and
48, 31, 13, 7, 2, and 0.1% of women hav-
ing zero, one, two, three, four, and five of
the ATP III factors, respectively. Those
with at least three risk factors (and hence
classified as having the metabolic syn-
drome) had a 2.4-fold increase in risk
over persons with no risk factors of coro-
nary or overall CVD and an 11.2-fold in-
crease in risk of diabetes, over subsequent
follow-up. They noted, however, that
there was a similar increase in risk for
those with two or more risk factors, “sug-
gesting the definition of the syndrome
might be relaxed to include individuals
with only two metabolic abnormalities.”
Jon Levine (Nashville, TN) described
risk factor evaluation approaches for CVD
and diabetes at the ASH symposium,
pointing out that there are currently no
specific guidelines for therapy of the met-
abolic syndrome, which affects almost
half of the population over the age of 60.
The likelihood of developing a CVD event
increases with age, with cigarette use, and
with diabetes, which increases risk six-
fold. Middle-aged persons with diabetes
have a CVD rate similar to that in subjects
without diabetes, but with have a greater
history of myocardial infarction. There-
fore, it is recommended that subjects with
diabetes be treated as though they had
already had a CVD event. Improvement in
macrovascular disease prognosis with
glycemic control in individuals with dia-
betes is suggested by the findings of the
UKPDS. Levine noted that lipids and glu-
cose appeared to be stronger risk markers
for CVD than BP in subjects with diabetes
in this study, and recommended intensive
lipid treatment for diabetes to first reduce
LDL cholesterol, to second increase HDL
cholesterol, and to third decrease triglyc-
eride levels. In most of the statin trials, he
pointed out that there is greater benefit for
persons with than for those without dia-
betes because, although the relative risk
decrease is similar, the absolute risk de-
creases more because of underlying
higher CVD rates. Furthermore, these
agents may reduce new-onset diabetes
and may therefore be beneficial for per-
sons with the metabolic syndrome.
Systolic BP is a strong predictor of
CVD risk, particularly in subjects with di-
abetes. In the UKPDS, BP treatment de-
creased both microvascular and macro-
vascular disease. The higher the BP, the
greater the rate of loss of renal function,
further suggesting benefit of treatment,
with the most aggressive BP targets being
applied to individuals with diabetes. In
the Hypertension Optimal Treatment
(HOT) Trial, as diastolic BP was reduced
from 85 to 81 mmHg, events were re-
duced by 50% (6). Urine albumin is not
only a predictor of renal disease but also
of CVD, and in the HOPE trial the use of
ramipril decreased CVD in parallel with
the decrease in albuminuria (7). The tar-
get for treatment should be ⬍130/80
mmHg, which will require use of three
antihypertensive agents in the majority of
persons with diabetes.
Thomas Giles (New Orleans, LA) re-
viewed clinical trial data focusing on the
patient with CVD, diabetes, and hyper-
tension. Potential strategies include ag-
gressive control of glycemia, which he
stated reduces complications “pretty
much across the board.” Blood pressure
plays an important role in adverse out-
comes. In the diabetes subgroup of the
HOT study, in which enrollees were ran-
domized to three groups, achieving dia-
stolic BP of 85.2, 83.1, and 81.1 mmHg
was associated with linear decreases in
adverse outcomes. In the UKPDS there
was a 10/5-mmHg difference in BP be-
tween the intensive and usual control
group of the BP substudy, with a 50%
decrease in congestive heart failure (CHF)
(8). Tight BP control decreased stroke
45% while glycemic control decreased
this end point only 5%. Similarly, BP
treatment decreased retinopathy to a
greater extent than that seen with glyce-
mic treatment. In the HOPE study, high-
risk subjects had a 22% decrease in the
combined CVD and mortality risk with
ramipril treatment. Individuals without
diabetes showed a decrease in new diabe-
tes onset with this treatment. The HOPE
study showed decrease in end points with
ramipril treatment to a similar extent in
those with and without diabetes. Partici-
pants in the HOPE study with diabetes
had a decrease in CHF by ⬎20%. Also,
the RENAAL study showed a decrease in
hospitalization for CHF in persons with
diabetes treated with losartan (9), and ad-
ditional observations with this agent were
reported in the LIFE trial, which further
showed a 25% lower rate of appearance of
new diabetes in nondiabetic subjects re-
ceiving losartan than among those treated
with the comparator agent atenolol (10).
Compared with the -blocker, in patients
with diabetes there was reduction in CVD
mortality with losartan (11).
Giles emphasized that -blockers are
of benefit in individuals with diabetes, as
shown in the MERIT trial of use of meto-
prolol in persons with CHF (12). Ad-
dressing use of calcium-channel blockers,
he remarked that in the FACET trial there
was worse outcome with amlodipine than
with fosinopril alone, but that the combi-
nation of the two led to better outcomes
than either alone; thus, that these are rea-
sonable agents when used in combination
with directly cardioprotective antihyper-
tensive agents (13). Giles recommended
as an overall strategy for the hypertensive
subject with diabetes, then, the use of ag-
gressive glycemic control as well as ag-
gressive BP control, with ACEIs “the
backbone of therapy” and angiotensin re-
ceptor blockers (ARBs) as additional im-
portant agents. -blockers are, he
suggested, underutilized and are as useful
in individuals with as in those without
diabetes. Calcium-channel blockers also
play important roles for individuals who
require multiple drugs to control BP.
Domenic A. Sica (Richmond, VA)
pointed out that end-stage renal disease
(ESRD) currently is caused by diabetes in
half of cases, a frequency predicted to fur-
ther increase over coming years. The re-
nin-angiotensin axis can be modified with
-blockers, with ACEIs, or with ARBs.
The combination of -blockers with ei-
ther of the latter two classes is effective,
while it is not certain whether combined
treatment with ACEIs and ARBs is effec-
tive. (There is however evidence that the
latter combination does at least reduce al-
Perspectives on the News
2090 DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002
buminuria [Rossing et al.: Diabetes Care
25:95–100, 2002].) In persons with dia-
betic nephropathy, BP lowering substan-
tially reduces the rate of decline in renal
function. With urine albumin excretion
rates of 30 –300 mg/day, there is pro-
found endothelial dysfunction at other
sites in the body as well. Left ventricular
hypertrophy showed strong concordance
with microalbuminuria in the LIFE study,
further evidence of this relationship. Mi-
croalbuminuria progresses to macroalbu-
minuria without treatment, suggesting
the benefit of aggressive treatment. ACEIs
are currently regarded as being the pri-
mary approach to treatment of subjects
with type 1 diabetes and nephropathy, al-
though the end points are less definite for
this protective effect existing for individ-
uals with type 2 diabetes and nephropa-
thy. More definite “hard end point”
studies have been done with the ARBs
irbesartan in the IDNT study (14) and
with losartan in the RENAAL study. One
must realize that the majority of persons
in these trials were treated with three an-
tihypertensive agents in addition to the
study drug, with diuretics being the first
choice and calcium-channel blockers
most often the second choice agents in
attempts to lower BP levels. Sica noted
that the degree of decrease in proteinuria
is greater with the ACEI trandolapril than
with calcium-channel blocker verapamil,
but that the combination of the two in
doses lowering BP to the same degree had
even greater effect on proteinuria, sug-
gesting benefit with this combination.
A number of studies at the ADA meet-
ing addressed specific pharmacologic
agents in the treatment of subjects with
diabetes and hypertension. Wang et al.
(1463-P) administered omapatrilat, an in-
hibitor of both enzymes degrading brady-
kinin, neutral endopeptidase, and
angiotensin-converting enzyme, to insu-
lin-resistant rats. Basal glucose produc-
tion decreased 35% and glucose pro-
duction showed a 2.7-fold greater sup-
pression by insulin, while no consistent
increase in insulin sensitivity was demon-
strated with ramipril or losartan. The ef-
fects were blocked by administration of
the bradykinin-2 receptor antagonist
HOE-140, suggesting increased bradyki-
nin action to mediate this effect. Black et
al. (12-LB) compared the antihyperten-
sive efficacy of omapatrilat with that of
enalapril in daily dosages up to 80 and 40
mg, respectively, in 3,377 patients with
diabetes. Of 775 previously untreated pa-
tients, systolic BP decreased 21 vs. 16
mmHg, with adjunctive treatment subse-
quently added in 15 vs. 25% to achieve
levels ⬍140/90 mmHg. For 1,823 previ-
ously treated patients, systolic BP de-
creased 10 vs. 5 mmHg, with adjunctive
treatment subsequently added in 31 vs.
37%. An important caution for the new
agent is that angioedema occurred in 1.3
vs. 0.4% of patients.
Jacob et al. (635-P) showed increase
in fasting glucose from 183 to 198 mg/dl
and in triglyceride from 221 to 265 mg/dl
in 61 hypertensive individuals with dia-
betes treated with metoprolol. In contrast,
the centrally acting anti-adrenergic mox-
onidine was associated with decrease in
fasting glucose from 206 to 186 mg/dl
and in triglyceride 222 to 182 mg/dl in 66
patients, with similar degrees of BP con-
trol. Viberti et al. (752-P) treated 223 hy-
pertensive persons with diabetes and
microalbuminuria with a combination of
perindopril 2– 8 mg and indapamide
0.625–2.5 mg daily. Albuminuria de-
creased 42%, significantly more than the
27% decrease in albuminuria in 224 such
patients treated with enalapril 10–40 mg
daily, suggesting synergistic benefitofthe
addition of a diuretic to ACEI treatment.
Buckalew et al. (152-OR) treated 74 dia-
betic hypertensive patients with mi-
croalbuminuria with the selective
aldosterone blocker eplerenone 200 mg
daily, showing 62% decrease in albumin-
uria, in comparison to 45 and 74% de-
creases in albuminuria in 74 and 67
patients treated with enalapril 40 mg daily
and with enalapril 10 mg plus eplerenone
200 mg daily, respectively. Withdrawal
for hyperkalemia was necessary in 6, 2,
and 14 subjects, respectively, in the three
groups. Blood pressure levels were simi-
lar, and the decrease in albuminuria was
independent of the degree of BP reduc-
tion, suggesting direct renoprotective ef-
fect of aldosterone blockade.
Management of the metabolic
syndrome
Lewis Landsberg (Chicago, IL), introduc-
ing a symposium at the ASH on the mech-
anisms and management of the metabolic
syndrome, stated that obesity and hyper-
tension were first noticed to be associated
more than 100 years ago, with prospec-
tive demonstration in the 1960s in the
Framingham Study. Jean Vague in the
1940s observed the association between
upper-body obesity and hypertension,
with Scandinavian studies over the past
two decades showing the quantitative re-
lationship between the waist-to-hip ratio
and these abnormalities. Hyperinsulin-
emia was shown to be a marker of the
insulin-resistant state over the past two
decades as well, with studies in the 1980s
pioneered by studies of Reaven that
showed the relationship between hyper-
tension and insulin resistance. Studies be-
ginning at that time showed the
relationship among hypertension, insulin
resistance, and sympathetic activation
and subsequent recognition of a role of
leptin in sympathetic activation and of in-
sulin in the association of hypertension
with obesity. Over the coming three de-
cades, 40% of the U.S. population is pro-
jected to become obese, with the
epidemic of obesity affecting the develop-
ing world as well. The age-adjusted prev-
alence of the metabolic syndrome is now
⬃24% in the adult population and
reaches 50– 60% over age 50 years.
James Poole of Baylor University
(Houston, TX) discussed hypertension
and lipid metabolism, pointing out the
complexity of their inter-relationship,
based on the contributions of the sympa-
thetic nervous system (SNS) and renin-
angiotensin system to the development of
hypertension in the metabolic syndrome.
There are three components to lipid me-
tabolism, exogenous lipid entry, endoge-
nous lipid synthesis, and remnant
metabolism. The endogenous pathway
produces VLDLs from endogenous pre-
cursors while the exogenous pathway
uses breakdown products of dietary lipids
to produce chylomicrons. Lipoprotein
lipase (LPL) acts in the vascular lumen
and is activated in the presence of specific
particles, leading to production of inter-
mediate-density lipoproteins (IDLs) from
VLDLs, which are metabolized by hepatic
lipase, leading to HDL production, with
HDL levels enhanced by the action of cho-
lesterol ester transport protein. On the ex-
ogenous side, chylomicrons are acted
upon and reduced in size to more com-
pact lipoproteins, upon which hepatic
lipase then acts. The remnant pathway
converts IDLs and chylomicron products
into discoid particles, which are then
acted upon by lecithin-cholesterol acyl
transferase (LCAT) to produce HDL3,
with LCAT acting on HDL3 to produce
HDL2.
Nicotinic acid, fibrates, and statins
Bloomgarden
DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 2091
play roles in treatment, and, perhaps, al-
cohol and estrogens could be used to raise
HDL cholesterol. Poole suggested a role
for inhibition of the SNS at the postsyn-
aptic level of the ␣-1 adrenoreceptor by
prazosin, doxazosin, and related agents,
which consistently influence metabolic
pathways in a fashion separate from their
effect on peripheral vascular resistance.
The drugs decrease total and LDL choles-
terol and, to a greater extent, triglyceride
levels. Actions include upregulation of
peripheral LDL receptors, decrease in gut
cholesterol absorption, and upregulation
of LPL expression, while synthesis and se-
cretion of VLDL decrease. The degree of
endothelium-dependent relaxation is also
under SNS regulation and improved by
␣-1 receptor blockade. Such treatment,
then, has the potential to decrease sys-
tolic, diastolic, and pulse pressure, to in-
crease HDL cholesterol and apolipo-
protein A1, to improve hyperinsulinemia,
and to decrease LVH and the atheroscle-
rotic process.
Ronald M. Krauss (Berkley, CA) fur-
ther discussed the atherogenic lipopro-
tein changes associated with insulin
resistance. The primary lipoprotein dis-
turbances involve low HDL and high tri-
glyceride levels, without a consistent
effect on LDL cholesterol “the way we
measure it in the clinic.” The metabolic
syndrome can be assessed with factor
analysis, which illustrates the strength of
the association of dyslipidemia with the
metabolic syndrome and its strong asso-
ciation with adiposity and hyperinsulin-
emia. Glucose intolerance and hyper-
tension in turn have relationships with
dyslipidemia with this approach to statis-
tical analysis. The dyslipidemia caused by
abnormalities of the lipases described by
Poole reflects impaired VLDL clearance,
the effects of hepatic lipase on HDL catab-
olism, and the effects of hypertriglyceri-
demia on VLDL production. LDL itself is a
heterogeneous set of particles, most aris-
ing from VLDL catabolism. The interme-
diate stage of clearance of abnormal
VLDLs leads to production of a small LDL
particles, with abnormal and increased
transport of cholesterol from HDL into
these particles contributing to the low
HDL cholesterol level. Peak LDL size is
inversely correlated with triglyceride lev-
els, with two groups of individuals in the
population, those with larger LDL and
low triglyceride levels and those with
smaller LDL and high triglyceride levels.
The latter group of patients has higher
postprandial glucose and insulin levels
and lower insulin sensitivity, suggesting
small LDL size not only to be associated
with the dyslipidemia but also with the
insulin resistance of the metabolic syn-
drome.
These are highly atherosclerotic par-
ticles, less rapidly cleared by the LDL re-
ceptor and more rapidly entering the
subendothelial space and undergoing ox-
idation, with subsequent plaque forma-
tion and inflammatory response. Genetic
susceptibility accounts for 40–50% of the
variation in LDL size, with several candi-
date genes identified. Other important
modifying effects include dietary fat and
carbohydrate, obesity, and pharmaco-
logic agents. Niacin appears to have the
greatest effect, and fibrates are also useful
in reducing levels of small LDL particles,
while statins lower levels of all LDL frac-
tions, and all agents that lower triglycer-
ide levels also change the LDL size
distribution to include more of the larger
particles. In the Quebec Cardiovascular
Study, the combination of low HDL and
small LDL particle size was particularly
associated with development of CVD
(15). In the Familial Atherosclerosis
Treatment Study (FATS), treatment of
CHD with resins, statins, and niacin re-
sulted in angiographic regression, the sin-
gle most important predictor of which
was the increase in LDL particle size,
rather than the change in levels of LDL
and of HDL (16). This appears to be par-
ticularly relevant to the treatment of indi-
viduals with the metabolic syndrome.
Interestingly, the thiazolidinediones also
appear to cause changes in LDL particle
distribution with shift from small to large
LDL, with effects documented for trogli-
tazone and RGZ. The relationship be-
tween treatment of hypertension and
lipoproteins in the metabolic syndrome
suggests that ␣-blockers improve and
-blockers worsen this dyslipidemia,
with particular effects on levels of rem-
nant particles and the expected associa-
tion with triglycerides. Krauss suggested
that calculation of HDL-to-triglyceride ra-
tios could be used to infer LDL particle
size.
Gerold Reaven (Stanford, CA) dis-
cussed insulin resistance, hypertension,
and CHD. The steady-state plasma glu-
cose (SSPG) concentration during infu-
sion of somatostatin, glucose, and insulin
is a measure of insulin resistance, show-
ing 10-fold variability in apparently nor-
mal populations. BMI correlates with
higher SSPG, but only accounts for ⬃25%
of the variability in insulin action from
person to subject, with physical fitness, as
measured by maximal aerobic capacity,
also contributing approximately one-
quarter of the degree of insulin sensitivity.
The remaining half of the determination
of insulin sensitivity is presumably ge-
netic. Ethnic groups of European ancestry
appear to have greater insulin sensitivity
than other ethnic groups. Insulin resis-
tance will lead either to type 2 diabetes
and subsequent CHD, or, if insulin secre-
tion is maintained, to the development of
the metabolic syndrome without diabe-
tes, and, again, to greatly increased risk of
CHD. The metabolic syndrome is associ-
ated with increased SNS activity and hy-
pertension, with procoagulant effects,
with endothelial dysfunction, and with
high uric acid, nonalcoholic steatohepati-
tis, and, perhaps, certain forms of cancer.
Daylong hyperinsulinemia and hy-
pertriglyceridemia are characteristic of in-
dividuals with hypertension and of those
with CHD. First-degree relatives of per-
sons with hypertension show similar ab-
normalities. Hypertension is, however,
heterogeneous. When comparing sub-
jects with normal and high BP, hyperin-
sulinemia is seen in approximately half of
the latter but in only one-tenth of the
former group. There are important differ-
ences between individuals with hyperten-
sion and insulin resistance versus those
who are insulin sensitive with hyperten-
sion, as the former group shows evidence
of the characteristic dyslipidemia with
low HDL and high triglyceride, evidence
of glucose intolerance, and a greater prev-
alence of electrocardiographic abnormal-
ities, which suggests underlying CHD.
Those hypertensive persons with normal
lipid patterns are less likely to have car-
diac disease. Mononuclear cells from sub-
jects with insulin resistance show
enhanced endothelial binding, presum-
ably contributing to CHD development.
Asymmetric dimethyl arginine (ADMA) is
an endogenous inhibitor of nitric oxide
synthase that has been closely linked to
CHD. Comparing individuals with and
without insulin resistance, ADMA levels
are higher in the insulin-resistant group,
both with normal and with high BP.
Reaven also discussed the triglyceride-to-
HDL ratio, suggesting this to be as predic-
tive of the degree of insulin sensitivity as is
Perspectives on the News
2092 DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002
the fasting insulin level, as well as sugges-
tive of the individual’s level of coronary
disease risk. Insulin resistance is also as-
sociated with greater degree of sodium re-
tention and greater increase in BP on a
high-sodium diet.
In a presentation at the ADA meeting,
Lawrence et al. (1670-P) presented data
using isotope dilution and arterio-venous
difference techniques to measure the rate
of norepinephrine entry into the general
circulation and into blood draining SC
abdominal adipose tissue and forearm
muscle as indices of systemic and local
sympathoneuronal activity in 22 lean and
obese volunteers. Systemic SNS activity
was greater with obesity, increased fur-
ther after feeding, and correlated with BP,
while adipose tissue SNS activity was al-
most 50% lower with obesity and, unlike
the finding in lean control subjects, did
not increase after feeding. They suggested
that obesity is associated with local SNS
dysfunction despite increased systemic
SNS activity, suggesting potential benefit
of selective 
3
adrenoceptor agonists for
treatment of obesity. Despre´ setal.
(1679-P) characterized 907 men and 937
women aged 18 –74 years based on BMI
tertile, with cutoffs at 23.2 and 26.6 kg/
m
2
, and based on the 50th percentile of
waist circumference (with cutoff at 88 cm
for men and 74 cm for women). BP was
similar in men in the lowest BMI tertile
with higher abdominal girth to that of
men in the top BMI tertile; for women, the
highest systolic BP was seen in those in
the top BMI tertile with higher abdominal
girth. There was no association between
fasting insulin and BP when controlling
for waist, suggesting that rather than as-
sessing body mass per se it is more impor-
tant to measure waist circumference in
gauging the degree of obesity.
Insulin resistance
At a symposium at the ADA meeting on
the insulin resistance syndrome (IRS), an
alternative term for the “metabolic syn-
drome,” James B. Meigs (Boston, MA) re-
viewed its definition and studies of its
prevalence. The syndrome was first pro-
posed and has continued to be studied by
Gerald Reaven, who suggested that risk
factors for heart disease and diabetes co-
occur and termed the complex “syn-
drome X” (17). The San Antonio Heart
Study showed that risk factors such as low
HDL, hypertension, obesity, and hyperin-
sulinemia proceed the development of di-
abetes (18). In the Framingham Offspring
Study, dyslipidemia, obesity, hyperinsu-
linemia, hypertension, and perhaps mi-
croalbuminuria occurred together with
greater-than-chance frequency (19). Fac-
tor analysis has been used to suggest that
insulin, triglyceride, HDL cholesterol,
obesity, and increased waist circumfer-
ence comprise the “central” components
of the syndrome, with high glucose levels
linked but existing as a separate factor and
with hypertension again as a separate
linked factor. Obesity and hyperinsulin-
emia may be the most crucial aspects of
the IRS. The presence of IRS trait clusters
predicts both the development of diabetes
and CVD mortality. There are sex and eth-
nic differences in the causes of the IRS.
Using the ATP-III factors and the
NHANES data set, women more com-
monly have increased waist circumfer-
ence, and men more commonly have
increased triglyceride levels, with overall
prevalence 24 and 23% in men and
women, respectively, and levels increas-
ing with age. Caucasians are more likely
to have high triglyceride levels, while BP
is more often elevated in African-
Americans. The prevalence of the IRS is
lowest among African-American males
and highest among Mexican-American
women. Combined analysis of data from
the Framingham, NHANES, and San An-
tonio studies confirms these differences,
with 24–28% of Caucasians and 32–38%
of Mexican Americans having the IRS.
The World Health Organization (WHO)
suggests different criteria, proposing that
the definition include increased 2-h post-
load glucose rather than fasting glucose as
in ATP-III, increased BMI rather than
waist circumference as in ATP-III, in-
creased triglyceride or low HDL, hyper-
tension (with different thresholds than
ATP-III), and albuminuria (which is not
included in ATP-III) (20). The Botnia
study, which uses this definition, reports
variation in prevalence from 34 – 46% in
different European populations.
Meigs noted that the syndrome traits
do not have equal predictive weights for
specific outcomes, so that, for example,
fasting blood glucose is more important
than BMI, which in turn exceeds HDL
cholesterol, with BP of least importance,
in predicting diabetes. Meigs suggested a
number of uncertainties, asking whether
simply counting the number of traits is
“good enough” or whether the traits
should be weighed or grouped in clusters.
If “trait clusters” are required rather than
just counting the number of positive find-
ings, the frequency decreases to ⬃15 and
25% in Caucasians and Mexican-
Americans, respectively, an example of
the impact of varying the definition on
syndrome prevalence. Further questions
are whether BMI or waist circumference is
better for classifying individuals, whether
insulin or urine microalbumin levels
should be measured, and whether per-
sons with diagnosed diabetes or diabetes
based on glucose tolerance testing should
be included. Meigs pointed out that one
could “just identify the traits and treat
them,” rather than treating the syndrome,
unless there is some way in which identi-
fying the IRS confers added benefit. He
concluded that there is not even agree-
ment as to the name of the syndrome, and
“we still don’t actually agree” on many im-
portant aspects of the condition, but that
it is clearly of great importance, as preva-
lence is likely to increase in the coming
years as obesity increases.
Frederick Brancati (Baltimore, MD)
discussed “emerging risk factors” for the
IRS, noting that from the perspective of
primary prevention it “sometimes feels
like an inevitable sequence of events” that
leads to diabetes and CVD. The Diabetes
Prevention Project (DPP) and other stud-
ies suggest benefit of interventions, but
even with optimal lifestyle modification
there remained a 20% 5-year risk in the
DPP and Finnish Prevention Study. Bran-
cati recalled that Osler in 1892 discussed
a number of risk factors for type 2 diabe-
tes, including heredity, ethnicity, social
class, adiposity, sedentary lifestyle, and
overindulgence, as well as what one might
now term novel risk factors such as “ner-
vous strain” and worry, brain lesions,
environment, infections, and liver distur-
bances. We now consider well-established
risk factors to be age, obesity, inactivity,
pregnancy, drugs, and endocrine and mo-
nogenic syndromes, and emerging risk
factors to include genes, the fetal environ-
ment, inflammation, dietary macronutri-
ents, and intracellular lipids, as well as
newer risk factors including liver disease,
mineral intake, stress and depression with
hypothalamic-pituitary-adrenal (HPA)
axis activation, abnormal lung function
with sleep apnea, and endothelial dys-
function.
Based on NHANES data, subjects
with hepatitis C show a 3.8-fold increase
in diabetes risk (21), although Brancati
Bloomgarden
DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 2093
pointed out that either hepatitis C could
cause diabetes, diabetes could increase
risk of hepatitis C, or both could be
caused by some underlying factor. The
considerably more common illness, non-
alcoholic steatohepatitis (NASH), is also
associated with insulin resistance (22,23).
In NHANES, 29.1% of adults in the U.S.
had increased transaminase levels, with
2.3% related to alcohol use and 1.6% to
hepatitis C, suggesting that almost one-
quarter of adults have NASH, which is
strongly associated with diabetes, partic-
ularly among women (24). Evidence that
this is not due to alcohol intake has been
assembled in a number of investigations.
“If it’s real,” Brancati stated, “it could be
associated with a very high population-
attributable risk.” Possible implications
are for use of therapeutic agents targeted
to the liver and for avoidance of hepato-
toxic substances.
Serum magnesium ⬍1.4 mg/dl is as-
sociated with doubling of diabetes risk,
although it has some ambiguous features
given that the mean level is lower in Afri-
can-Americans than Caucasians, but
magnesium is a stronger risk factor in the
latter group (25). The mineral zinc may
also be a factor, with Marreiro et al.
(569-P) in a study presented at the ADA
meeting randomizing 56 obese women
with normal zinc levels and normal glu-
cose tolerance to placebo or zinc 30 mg
daily for 4 weeks, the latter showing a fall
in insulin from 29 to 21 U/ml, which is
indicative of improvement in insulin sen-
sitivity. Mineral supplementation may,
then, play a role in preventive treatment
of diabetes. As suggested by Osler, de-
pression and stress may be factors in dia-
betes (26), although again the direction of
causality is uncertain, with Brancati not-
ing that subclinical hypercortisolemia
from depression could cause insulin resis-
tance (27). In the Atherosclerosis Risk in
Communities Study, depressive symp-
toms were associated with increased fast-
ing insulin, BMI, and triglyceride levels,
with a 1.52-fold increase in risk of diabe-
tes in the highest quartile of symptoms
(28). A therapeutic implication is that de-
pression/stress reduction might be rele-
vant to diabetes prevention, or, perhaps,
that anti-depressant treatment could
ameliorate subtle abnormalities in the
HPA axis.
Abnormal lung function and sleep ap-
nea may be related to diabetes, as 2-h in-
sulin levels show a progressive rise with
increased frequency of sleep apnea. There
is also an association of decreased forced
vital capacity with diabetes, which might
be related to cigarette use or to obesity. At
the ADA meeting, Resnick et al. (955-P)
reported overnight polysomnogram re-
sults in 4,882 persons ⱖ40 years old
without history of CVD; of these subjects,
426 had diabetes. Subjects with diabetes
had similar REM sleep times (18.9 vs.
20.1%), adjusted for age and BMI, but a
twofold higher prevalence of periodic
breathing, indicative of a central nervous
system disorder and diagnosed if ⱖ10
consecutive minutes of a crescendo-
decrescendo breathing pattern was ob-
served. This suggested alterations in
autonomic or metabolic control of venti-
latory systems during sleep. It would be of
interest to learn whether nondiabetic in-
dividuals with the metabolic syndrome in
that study also had evidence of sleep ab-
normality.
Leif Groop (Malmo, Sweden) dis-
cussed genetic associations with what he
termed the “dysmetabolic” syndrome.
The Botnia study, named for the gulf of
Botnia, which lies between Sweden and
Finland, involves 9,315 persons from
1,389 families from the two countries.
Groop noted that insulin sensitivity itself
is only mildly hereditable, with monozy-
gotic twins showing correlation with r ⫽
0.49, but dizygotic twins only showing
r ⫽ 0.1. Waist circumference, however, is
much more strongly inherited. Genetic
contributions to insulin resistance have
been investigated by analyzing potential
candidate genes and by random gene
searches of the entire genome to find ex-
cess allele sharing in certain regions. A
number of genes have been identified.
The -3 adrenergic receptor variant hav-
ing substitution of tryptophan for argi-
nine in position 64 is associated with the
IRS (29,30), as well as with decreased
metabolic rate, which might predispose to
obesity. There is also a mutation at posi-
tion 27 of the -2 adrenergic receptor as-
sociated with high FFA levels. An intronic
variant of the skeletal muscle glycogen
synthase gene is associated with both in-
sulin resistance and increased CVD mor-
tality. (31,32). The mechanism of the
association may be of affected subjects
having a lesser effect of exercise on muscle
metabolism. The proline 12 to alanine
variant of the peroxisome proliferator–
activated receptor (PPAR)-␥ is a protec-
tive mutation that may account for 20% of
the population risk of diabetes among
Caucasians. (33). The variant is associ-
ated with a decrease in fat cell production
and becomes manifest in individuals con-
suming a diet high in saturated fats. A
mutation of calpain 10 is associated with
insulin resistance and elevated FFA levels.
Groop noted that calpain 10 mRNA ex-
pression is upregulated in individuals
without family history of type 2 diabetes,
but not in those at risk, and the level of
expression in muscle is associated with
insulin insensitivity. The winged helix/
forkhead transcription factor gene
(FOXC2) is another potential protective
allele, which is expressed to a greater ex-
tent in visceral than in subcutaneous fat
(34). Finally, a gene on chromosome
18P11 is linked to type 2 diabetes only in
the highest BMI quintile of the popula-
tion. The melanocortin receptor (which is
also the ACTH receptor) is present in that
region and may account for the linkage.
Other linkages have been found without
identification of potential causative genes,
including one on chromosome 17 and
one on chromosome 9. Thus, Groop con-
cluded, a number of common variants,
many of which influence FFA metabolism
or impair scavenger factors, increase dia-
betes susceptibility.
In a study reported at the meeting,
Hara et al. (157-OR) reported that allelic
variations in the gene for PPAR-␥ coacti-
vator-1 were associated with differences
in fasting insulin in 537 type 2 diabetic
subjects and 417 nondiabetic subjects.
Emphasizing the complexity of gene dis-
covery, Yang et al. (1049-P) used DNA
microarrays to analyze gene expression of
SC adipose tissue and skeletal muscle bi-
opsies specimens from eight insulin-
sensitive and eight insulin-resistant
persons. Of the thousands of sequences
tested, 618 genes/expressed sequence
tags were differentially expressed in adi-
pocytes from the two groups, of which
199 upregulated genes could be assigned
to known functional pathways, 101 in-
volved in cell proliferation and 30 in cell
growth.
Robert S. Schwartz (Denver, CO) dis-
cussed the IRS in the elderly, pointing out
that aging is “the most important environ-
mental factor” in causing insulin resis-
tance. Body weight tends to increase
through age 55 years in cross-sectional
studies, but in longitudinal studies,
weight actually tends to increase through
age 65–70 years. Furthermore, there is a
Perspectives on the News
2094 DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002
decrease in lean body mass with age, so
“for any given weight old people are fatter
than young people.” The deposition of fat
shifts more to the visceral location in
males after puberty and in women at
menopause, and, while at all BMI levels
individuals with a low waist-to-hip ratio
(WHR) have diabetes risk approximately
half that of those with normal or high
WHR, even those individuals with normal
BMI but high WHR have a threefold in-
crease in diabetes rate. Thus, if obesity is
more frequent with aging and , particu-
larly, central obesity, one can expect the
concomitants of hyperinsulinemia, diabe-
tes, hypertension, dyslipidemia, coronary
disease, elevated thrombotic factors, and
homocysteine, as well as other features of
obesity such as osteoarthritis, sleep ap-
nea, and increased mortality rates. Analy-
sis of NHANES data shows that the
prevalence of diabetes increases with age
in the U.S. population (35), and even in-
dividuals with normal glucose tolerance
have higher postload glucose levels with
increasing age.
In treatment, lifestyle intervention
may be particularly appropriate for older
subjects with the IRS, as shown in the
DPP, where metformin had considerably
less impact in those over age 60 years,
while diet and exercise had similar benefit
to that seen in younger age-groups.
Schwartz also noted that although weight
loss may not be as great with a program
focused on exercise as with one focused
on diet, the decrease in intra-abdominal
fat will be similar with both approaches.
Another area that may be important for
future treatment is the potential for hor-
monal mediators of the features of the IRS
that appear with aging. Schwartz noted
that the IRS has many features in common
with hypercortisolemic states, leading
one to wonder whether this may be a fac-
tor. There is also intriguing evidence of
relative decrease in growth hormone ac-
tion with aging, shown by a decline in
insulin-like growth factor 1 levels. Cer-
tainly, growth hormone deficiency is as-
sociated with increased fat mass, decreased
muscle mass, and decreased insulin sen-
sitivity. Finally, many features of hypogo-
nadism appear with age, and there is some
evidence that low testosterone is present
with aging in men, perhaps similarly to
the estrogen deficiency following meno-
pause in women.
Michael Goran (Los Angeles, CA) dis-
cussed the IRS in children. He pointed out
that type 2 diabetes is now an important
problem among obese children and ado-
lescents, having increased 10-fold in fre-
quency over the past two decades in the
U.S., particularly in minority popula-
tions. In a recent clinic-based study, 25
and 21% of obese children and adoles-
cents, respectively, had IGT (36), and
Goran described studies of Hispanic chil-
dren with positive diabetes family history
with IGT present in 38%. An important
concept is that a healthy -cell compen-
sates for insulin resistance, but that in ad-
olescents at risk of diabetes—because of
underlying -cell abnormality—the pro-
cess is accelerated by the sudden decrease
in insulin sensitivity occurring with pu-
berty, which amounts to ⬃30% in normal
adolescents (37) and is particularly prom-
inent with obesity (38). Increased skeletal
muscle intracellular lipid may play a role
in this process (39). Approaches to treat-
ment include metformin, which has been
shown of benefit in adolescent girls with
the polycystic ovary syndrome (PCOS)
(40). There has been virtually no study of
whether exercise is of benefit, and it will
also be important to understand whether
there is recovery of insulin sensitivity fol-
lowing puberty and what role this may
play in the improvement of the IRS in af-
fected adolescents.
In a study presented at the ADA meet-
ing, Goran et al. (1439-P) reported Afri-
can-American and Hispanic adolescents
to have 35 and 29% decreases in insulin
sensitivity, respectively, compared with
Caucasians; these decreases were not ex-
plained by having higher visceral fat lev-
els. Goran also found that the Hispanic
adolescents had greater hepatic insulin
uptake than the African-American group,
which may explain the relatively low in-
sulin levels in the former and higher in-
sulin levels in the latter group. Klein et al.
(938-P) reported on the prospective
NHLBI Growth and Health Study of
2,379 girls aged 9 –10 years at onset,
showing that African American girls had
higher BMI and fasting insulin levels ini-
tially, with a relative increase in obesity,
compared with Caucasians during the 10
years of follow-up. Controlling for BMI
and pubertal status, African-American
ethnicity was associated with higher insu-
lin levels, with differences between the
groups increasing over time, potentially
increasing risk of diabetes and CVD.
In view of the association of low birth
weight with diabetes and CVD, Hermann
et al. (1218-P) compared 14 men with
birth weight below the 10th percentile
and 16 matched control subjects with
normal birth weight, all of whom were 21
years of age, and showed that glucose up-
take during insulin infusion increased
1.5-fold vs. 2.5-fold, which is suggestive
of insulin resistance, albeit forearm endo-
thelial function and vascular reactivity to
insulin were comparable. Jeffery et al.
(1441-P), Kirkby et al. (1446-P), and
Mallam et al. (1449-P) described results
of the EarlyBird study of 307 5-year-old
children and their parents. Only 1.4% of
term infants had birth weight ⬍2.5 kg,
and there was no significant relationship
between birth weight and insulin resis-
tance, while current weight did show
modest correlation with insulin sensitiv-
ity. Little correlation was noted between
paternal and child insulin sensitivity.
Resting energy expenditure measured by
indirect calorimetry did not correlate with
insulin sensitivity and showed positive
correlation with body weight. Interest-
ingly, girls had 27% more insulin resis-
tance, in part due to higher SC fat and
lower physical activity, and had higher
triglyceride levels and lower HDL and sex
hormone binding globulin levels.
Dunaif et al. (1054-P) reported stud-
ies of an allelic variation on chromosome
19p closely linked to the insulin receptor
gene associated with PCOS. Women with
PCOS positive for this allele had increased
glucose without compensatory hyperin-
sulinemia, while brothers of women with
PCOS who had the allele had high proin-
sulin levels, suggesting -cell dysfunc-
tion. Hirschler et al. (1763-P) studied 74
obese Hispanic adolescents with mean
age 12 years, 55% with acanthosis nigri-
cans, with the physical finding showing
strong correlation with the degree of obe-
sity but not with glucose intolerance or
insulin resistance per se. In a small study,
Sellers et al. (1765-P) raised important
caution about the use of metformin in
children with type 2 diabetes. The au-
thors randomized 18 children who had
been treated without drugs for at least 3
months and who had HbA
1c
⬎7% to ei
-
ther metformin, titrated slowly to a max-
imum of 2,250 mg daily, or placebo.
HbA
1c
and BMI were the same in both
groups at 3, 6, and 12 months; five and
four children in the metformin and pla-
cebo groups, respectively, required addi-
tion of insulin, and four in each group had
⬍50% compliance. Side effects were ob-
Bloomgarden
DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 2095
served in four of the subjects who re-
ceived metformin but in none of the
subjects in the placebo group.
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