D I AB E T E S C AR E , VO L U M E 22, N U M B E R 2, F E B R U ARY 1 999 345

RECOGNITION OF AN
E P I D E M I C Pediatric diabetologists
and other health workers involved with
minority communities have recognized an
e m e rging epidemic of type 2 diabetes
among youth over the past 20 years, pri-
marily affecting minorities. This phenome-
non parallels increased prevalence of
obesity in children and youth (1). Epidemi-
ologic data from several ethnic populations
a re summarized in Table 1. The initial
re p o rt of a high frequency of type 2 diabetes
in young patients came from the care f u l l y
studied Pima Indian population, in which
1% of those 1524 years of age (but none
under this age) had diabetes that was asso-
ciated with obesity and long-term diabetes
complications. Five of the individuals had
been treated with insulin, and four had
experienced ketoacidosis (2).
Some 13 years after this initial re p o rt ,
n u m e rous instances of type 2 diabetes were
re p o rted among native populations in Man-
itoba in the 514 years age-group, with a
p revalence of 0.8:1000; 1020% of new
cases of diabetes in youth in Manitoba were
in the type2 category. This type2 diabetes in
youth occurred exclusively in the First
Nation population (3,4). Similar observ a-
tions weremadein northwest Ontario in the
16 years age-group, but with a higher age-
s p e c i c prevalence of 2.5:1000 (5). In all of
these re p o rts, the sex ratio was re m a r k a b l y
skewed, with 46 female patients for every
male patient affected. In Cincinnati, Ohio,
o n e - t h i rd of all new cases of diabetes in the
1019 years age-group were classied as
type 2 diabetes, giving an age-specic inci-
dence of 7.2:100,000 per year. Type 2 dia-
betes comprised 24% of all childhood
diabetes before 1992, but by 1994, type 2
diabetes accounted for 16% of all new cases
in children (6). In theCincinnati re p o rt, as
well as in re p o rts from Arkansas (7,8),
African-Americans accounted for 7075% of
type 2 diabetes patients. Among Mexican-
American children from Ventura, Califor-
nia, 17 years of age, 31% of those with
diabetes have type 2 (9). The sex ratio in
these African-American and Mexican-Amer-
ican youngsters is less skewed than that
among the Native American population.
The phenomenon of a rapidly acceler-
ating incidence of type 2 diabetes in young
F rom the Childre n s Medical Services Center (A.L.R.) and theDepartments of Pathology and Pediatrics
( W. E . W.), University of Florida College of Medicine, Gainesville, Florida; and the Native American Researc h
and Training Center (J.R.J., R.S.Y.), Department of Family and Community Medicine, University of Arizona,
Tucson, Arizona.
A d d ress correspondence and reprint requests to Arlan L. Rosenbloom, MD, University of Florida College
of Medicine, Childre n s Medical Services Center, 1701 SW 16th Ave., Gainesville, FL 32608. E-mail:
ro s e n a l @p e d s . u . e d u .
Received for publication 20 May 1998 and accepted in revised form 9 October 1998.
A b b re v i a t i o n s :ADA, American Diabetes Association; ADM, atypical diabetes mellitus; HGNK, nonketotic
s e v e re hypoglycemia; HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of the young; ND,
NADH dehydrogenase subunit; OHA, oral hypoglycemic agents; VNTR, variable number of tandem re p e a t s .
A tableelsewhere in this issue shows conventional and SystmeInternational (SI) units and conversion
factors for many substances.
E m e rging Epidemic of Type 2 Diabetes in
Yo u t h
C O M M E N T A R Y
T
his review con sid ers th e epidemiologic eviden ce for an in creasin g inciden ce of type 2 diabetes
in you th , th e classi cation an d diagn ostic issu es related to di abetes in you n g p op u lation s,
path op h ysiologic m ech an ism s relevan t to th e in creasin g in ciden ce, th e role of gen etics an d
e n v i ronm en t, an d th e com mu nity ch allen ge for prevention and treatm en t. Type 2 diabetes in you th
h as been recogn ized to be frequen t in popu lations of n ative N orth Americans an d to com prise som e
30 percent of n ew cases of diabetes in th e 2n d decade of life, largely accou n ted for by m in ority pop-
u lations an d associated with obesity. Am on g Japan ese sch oolchildren , type 2 diabetes is seven times
m o re com mon th an type 1 , an d its in ciden ce h as in creased m ore th an 30-fold over th e p ast 20
years, con com itan t with ch an gin g food pattern s and increasin g obesity rates. T h e form s of diabetes
seen in ch ildren an d you th inclu de typical type 1 , occurrin g in all races; typ e 2, seen pre d o m i n a n t l y
in min ority you th ; atypical diabetes, seen as an au tosom al d om in an tly tran sm i tted d isord er in
African-American popu lation s; and m atu rity-on set diabetes of th e you n g M O D Y) , seen rarely an d
on ly in C au casi an s. O f th e n on au toim m u n e form s of diabetes seen in you th , on ly type 2 di abetes
is increasin g in in cid en ce. P roper classi cation re q u i res con sid eration of on set acu te/severe ver-
su s in sid iou s , eth n icity, family h istory, presen ce of obesity, an d if n ecessary, stu d ies of diabetes-
related au toim m u n ity. I n su lin resistan ce pred icts th e developm en t of diabetes in P ima I n d ian s, in
o ffsprin g of p aren ts with type 2 diabetes, an d in oth er h igh -risk p opu lation s. African -Am erican
c h i l d ren an d you th h ave greater in su lin respon ses du rin g glu cose toleran ce testin g an d du ri n g
h y p e rglycem ic clam p stu d y th an do wh ites. T h ere is also evid en ce of altered -cell fu n ction pre-
cedin g th e developm en t of h yp erglycem ia. O f particu lar in terest is th e eviden ce th at abn orm al fetal
an d in fan ti le n u trition is associated with th e develop m en t of type 2 d iabetes in adu lth ood. T h e
th rifty p h en otype h yp oth esis states th at poor n u trition in fetal an d in fant life is detrimen tal to th e
developm en t an d fu n ction of th e -cells an d in su lin sen sitive tissu es, leadin g to in su lin re s i s t a n c e
u n d er th e stress of obesity. T h e th rifty gen otyp e h yp oth esis prop oses th at defecti ve in su li n action
in utero resu lts in decreased fetal growth as a con servati on m ech an ism , bu t at th e cost of obesity-
in d u ced diabetes i n later ch ild h ood or adu lth ood. T h e vast m ajority of type 2 diabetes i n ad u lts is
polygen ic an d associated with obesity. M on ogen ic form s M O D Y, m atern ally tran smitted m ito-
ch on d rial m u tation s are rare, bu t are m ore li kely to appear in ch i ldh ood. L in kage stu dies of th e
comm on polygen ic type 2 diabetes h ave em ph asi zed th e h eterogen eity of th e disord e r. T h e pre-
ven tion an d treatm en t of type 2 d iabetes in ch ildren an d you th i s a dau n tin g ch allen ge becau se of
th e en ormou s beh avioral in u ence, d ifficu lty in reversing obesity, an d typ ical n onadheren ce in th is
a g e - g rou p. T he em ergin g epidemic of type 2 diabetes in th e pediatric pop u lation , especially am on g
mi n orities wh ose pro p o rtion in th e U .S. popu lation is in creasin g, p resen ts a seriou s pu blic h ealth
p roblem . T h e fu ll effect of th is epid em ic will be felt as th ese ch ildren becom e ad u lts an d develop
th e lon g-term com plication s of diabetes.
Diabetes Care22:345354, 1999
ARLAN L. ROSENBLOOM, MD
JENNIE R. JOE, PHD
ROBERT S. YOUNG, PHD
WILLIAME. WINTER, MD
R e v i e w s / C o mme n t a r i e s / P o s i t i o n S t a t e m e n t s
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346 D I AB E T E S C AR E , VO L U M E 22, N U M B E R 2, F E B R U AR Y 1 999
Emerging epidemic of type 2 diabetes in youth
patients is not peculiar to North America.
Among Libyan Arabs 34 years of age, the
annual incidence of type 2 diabetes is
19.6:100,000 for male patients and
35.3:100,000 for female patients, com-
p a red with incidences for type 1 diabetes of
9.4 and 8.5, re s p e c t i v e l y. There is an even
sex ratio in the 14 years age-group, but a
twofold greater female incidence in the
1534 years group (10). Among Japanese
school children, the incidence of type 2
diabetes increased from 0.2 to 7.3:100,000
f rom 1976 to 1995. This increase was pri-
marily among junior high schoolaged
youngsters, who have a type 2 diabetes
incidence of 13.9:100,000, compared with
grammar school children, who have an
incidence of 2.0:100,000. The grammar
school incidence of type 2 diabetes is com-
parable to that for type 1 diabetes,
1.65:100,000, whereas the junior high
school incidence of type 2 diabetes is nearly
seven times that for type 1 diabetes in that
a g e - g roup (2.07:100,000). Japanese inves-
tigators have associated the increasing inci-
dence of type 2 diabetes with changing
food patterns and rising obesity rates
among Japanese school children (11,12).
They have also documented a high risk for
early nephropathy among thosedeveloping
type 2 diabetes before 30 years of age (13).
C h i l d ren have hyperinsulinism as a
result of obesity, as do adults, and child-
hood obesity is commonly associated with
i m p a i red glucose tolerance (14). The stre s s
of obesity and the increased demand for
insulin at the time of adolescence (15)
explain the largely pubertal and postpu-
b e rtal onset of type 2 diabetes in childre n .
Although type 2 diabetes in childre n
and youth is increasingly recognized as a
p roblem, the current American Diabetes
Association (ADA) position statement on
s c reening for type 2 diabetes makes no
s p e c i c mention of children and adoles-
cents at risk (16).
C L A S S I F I C ATION ISSUES T h e
new classication recommendations of the
ADA recognize major diff e rences in pre v a-
lence of the forms of diabetes among vari-
ous racial or ethnic groups (17). Table 2
summarizes distinguishing features of the
f o rms of diabetes as seen in youth. These
include the following: typical type 1 dia-
betes that occurs in all races but is re l a t i v e l y
r a re in Asians; type 2 diabetes seen pre-
dominantly in minority youth; atypical dia-
betes mellitus (ADM) that is seen as an
autosomal dominant condition in African-
American populations (18); and maturity-
onset diabetes of the young (MODY),
which is seen rarely and only in Cau-
Table 1Studies of type 2 diabetes in young populations
Frequency
Location Race/ethnicity Age-group Incidence Prevalence Sex ratio (M:F) Ref.
Arizona Pima Indian 524 0 ( 15 years) 1:5 2
9/1000 (1524 years)
Manitoba, Canada First Nation 514 0.8/1000 1:4 3,4
Ontario, Canada First Nation 16 2.5/1000 1:6 5
Cincinnati, Ohio African-American (70%) 1019 7.2/10
5
1:1.7 6
Ventura, California Mexican American 17 1:1.3 9
Libya Arab 034 19.6/10
5
(male) 1:1 (014 years) 10
35.3/10
5
(female) 1:2 (1534 years)
Japan Japanese 15 2.0/10
5
(primary grades) 1:2 11,12
13.9/10
5
(junior high) 1:1.2
Prevalence rates are given per 1,000, and incidence (annual), per 100,000 (10
5
).
Table 2Classication of diabetes seen in children and youth
Type 1 diabetes Type 2 diabetes ADM MODY
Age Throughout childhood Pubertal Pubertal Pubertal
Onset Acute, severe Mild to severe, often insidious Acute, severe Mild, insidious
Insulin secretion Very low Variable Moderately low Variable
Insulin sensitivity Normal Decreased Normal Normal
Insulin dependence Permanent No Variable No
Genetics Polygenic Polygenic Autosomal dominant Autosomal dominant
Race/ethnic distribution All (low frequency in Asians) African-American, Hispanic, African-American Caucasian
Asian, Native American
Frequency (of all diabetes 80% 1020% 510% Rare
in children and youth)
Association
Obesity No Strong Variable No
Acanthosis nigricans No Yes No No
Autoimmunity Yes No No No
Insulin sensitivity is given as a pathogenic factor. Insulin dependence is assumed to be in the absence of acute illness or other stress.
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D I AB E T E S C AR E , VO L U M E 22, N U M B E R 2, F E B R U AR Y 1 999 347
Rosenbloom and Associates
casians. The importance of atypical form s
of diabetes in African-American youth has
recently been emphasized by Arslanian and
Danadian (19), who proposed the term
youth-onset atypical diabetes (YOAD) for
d i s o rders that episodically display feature s
of type 1 and type 2 diabetes. Of the thre e
nonautoimmune forms of diabetes noted
above, there is only evidenceof incre a s i n g
incidence in the pediatric population for
type 2 diabetes.
In many re p o rts, it is difficult to deter-
mine how many of the patients being
re p o rted as having type 2 diabetes, part i c-
ularly among the African-American popu-
lation, might meet the criteria of ADM. For
example, ketoacidosis is common among
African-American adolescents with type 2
diabetes in Cincinnati, Ohio (20). In ADM,
t h e re is acute onset of hyperglycemia, with
ketosis or ketoacidosis as common feature s ,
followed by a clinical coursemore charac-
teristic of type 2 diabetes (18). It is also
unclear how many of the patients re p o rt e d
as type 1 might, in fact, have type 2 dia-
betes; a number of the youngsters re p o rt e d
f rom Chicago as having type 1 diabetes
w e re noted to be obese (21). As noted in
Table 2, obesity is not as common in ADM
as it is in type 2 diabetes in youth. The
b a c k g round prevalence of obesity in the
African-American population is high, how-
e v e r, and there f o re some children with
ADM will be signicantly overw e i g h t .
The initial classication of the etiology of
diabetes must occur at the time of diagnosis.
Thenew ADA classication and diagnostic
guidelines emphasize etiopathophysiologic
c l a s s i cation, and not classication by clini-
cal course (e.g., insulin-dependent versus
non-insulin-dependent). Nevertheless, ex-
cluding islet autoantibody testing, the clini-
cian remains dependent on clinical acumen
and reasoningin classifyingnew-onset dia-
betes patients. In Figs. 1 and 2, the pathways
in bold are the most likely outcomes for the
majority of children. In some cases, the diag-
nosis of type 2 diabetes is made on the basis
of the clinical courseduring follow-up.
The pragmatic rst step in classic a-
tion is to separate acute-onset diabetes
(usually with ketosis or frank ketoacidosis)
f rom insidious-onset diabetes and cases of
nonketotic severe hyperglycemia(HGNK).
In adults, HGNK is often re f e rred to as
h y p e rglycemic nonketotic coma (HGNK
coma). For example, a child with new-
onset diabetes who has a glucose level
7501000 mg/dl in the absence of
s i g n i cant ketosis or ketoacidosis is
unlikely to have type 1 diabetes.
In children with acute-onset diabetes,
because ADM of African-Americans usually
p resents acutely, not unlike type 1 diabetes,
the ethnic background of the patient must
be considered. Nonobese non-Hispanic,
Hispanic, Native, Pacic Islander, and
Asian Americans with acute-onset diabetes
a re very likely to have type 1 diabetes and
usually re q u i re no further testing. If the
non-Hispanic, Hispanic, Native, Pacic
I s l a n d e r, or Asian American with acute-
onset diabetes is obese, islet and thyro i d
autoantibody testing should be considere d .
F i g u re 1Decision tree for classication of diabetes in children presenting with acute/severe symptoms.
The bold arrows indicate the most likely pathway for this condition. *No or g a n - s p e c i c autoimmunity.
**Autosomal dominant (AD) family history (FHx) of diabetes (DM) with an onset at 40 years of age.
F i g u re 2Decision tree for classication of diabetes presenting with insidious or no symptoms or with
hyperglycemia without signicant ketosis. Bold ar rows indicate the most likely pathway. Genetic stud -
ies of MODY genes and mitochondrial genes are not indicated. **Autosomal dominant (AD) family his -
tory (FHx) of diabetes (DM) in more than three generations.
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If all are negative, the child may indeed
have type 2 diabetes. Follow-up at 1 year
may be helpful in such cases. If insulin is
then continuously re q u i red or the child
manifests ketosis, type 1 diabetes is likely.
In African-American children with
new-onset acute-onset diabetes, islet
autoantibody testing can identify most of
the children who have type 1 diabetes. If
islet and thyroid autoantibody studies are
negative, a family history of early-onset dia-
betes in three or more generations suggests
ADM. In the absence of such a family his-
t o ry, the absence of obesity suggests type1
diabetes. Otherwise, the presence of obesity
suggests type 2 diabetes.
For children with insidious-onset dia-
betes (Fig. 2), obese children without a
t h ree or more generation history of early-
onset diabetes most likely have type 2 dia-
betes, which is not unlike type 2 diabetes in
adults. If the child with insidious-onset
diabetes is lean, islet autoantibody and thy-
roid testing may be helpful. The presence of
such autoantibodies strongly argues in
favor of type 1 diabetes. The absence of
such autoantibodies and their family his-
t o ry would separate such children into
MODY or type 2 diabetes. Because MODY
is rare, there is no routine value in testing
for hepatocyte nuclear factor (HNF)-4 ,
glucokinase, or HNF-1 mutations. Mito-
chondrial mutations account for 2% of
clinical type 2 (non-insulin-dependent)
diabetes in adults; there f o re, studies of the
mitochondrial genome remain re s e a rc h
tools, as do HNF-4 , glucokinase, and
H N F - 1 s t u d i e s .
PAT H O P H Y S I O L O G Y The dete-
rioration of glucose tolerance and the
development of type 2 diabetes re e c t
insulin resistance combined with re l a t i v e
insulin dec i e n c y. Limited -cell capacity
would have little signicance in the absence
of obesity. The emergence of type 2 diabetes
in all societies as rates of obesity incre a s e
and the strong familial tendency to develop
type 2 diabetes indicate that there may
have been an advantage to the metabolic
phenotype that is now detrimental (22).
Insulin resistance, documented as either
fasting hyperinsulinism or as the insulin
response to oral glucoseor to the hyperg l y-
cemic clamp, has been noted in the adult
nondiabetic offspring of Pima Indians, Mex-
ican Americans, and non-Hispanic whites
with type 2 diabetes (2326). In one longi-
tudinal study of such individuals, a high
cumulative incidence of type 2 diabetes was
associated with earlier ndings of insulin
resistance on intravenous glucose tolerance
testingand with increased rst phase insulin
release. Thus, in the prediabetic stage of the
evolution of their diabetes, these norm o-
glycemic individuals were maintainingan
i n c reased insulin secretion in the face of
insulin resistance (27).
Several recent studies have explore d
the metabolic diff e rences between African-
American and white children. In the
Bogalusa Heart Study, 5- to 17-year- o l d
black children had higher insulin re s p o n s e s
during an oral glucose tolerance test and
higher insulin-to-glucose ratios than did
white children. Among nearly 1,200 11- to
1 8 - y e a r-olds, black adolescents had higher
insulin levels and lower glucose-to-insulin
ratios than did whites, after correction for
o b e s i t y, indicative of reduced insulin sensi-
tivity among the black youngsters (28).
P re p u b e rtal black children also had lower
restingenergy expenditure and higher fast-
ing and rst phase insulin concentrations
during glucose clamp studies than did
white youngsters (2931). Among pubert a l
subjects, lower insulin sensitivity was also
seen in African-Americans (32). The lower
resting energy expenditure in black pre p u-
b e rtal children in the Bogalusa Heart Study
suggested a greater susceptibility to obesity.
Nonetheless, there was little diff e re n c e
between black and white children in the
i n c reasing rates of adiposity documented
over 2 decades (33).
T h e re is also evidencefor altered - c e l l
function as the initial lesion in type 2 dia-
betes. Lean patients with mild disease had
i m p a i red insulin release but normal insulin
sensitivity in a Canadian and Swedish
study (34). A British study found impaire d
pulsatilesecretion in nondiabetic re l a t i v e s
of type 2 patients, indicative of a very early
-cell lesion (35).
Thepossibility that limited -cell capac-
ity and insulin resistance might be pro-
grammed in utero was initially suggested by
studies associating impaired glucosetoler-
ance or type 2 diabetes in adults with lower
b i rth weight, smaller head circ u m f e re n c e ,
and thinness at birth (36). The investigators
p roposed that reduced growth of the
endocrine pancreas was a consequence of
m a t e rnal undernutrition. It was subse-
quently demonstrated that glycemic
responseto insulin was also reduced in indi-
viduals who had been thin at birth (37).
These observations led to the thrifty pheno-
type hypothesis, that poor nutrition in fetal
and early infant life would bedetrimental to
the development and function of the - c e l l s
and insulin-sensitivetissues, primarily mus-
cle, leading to insulin resistance. With a sur-
feit of nutrients resultingin obesity in later
life, type 2 diabetes would ensue.
These observations have been con-
rmed in a large study in Sweden, where
reduced birth weight for length was associ-
ated with a threefold increased risk for type
2 diabetes by age 60 years, although at age
50 years, there was no evidence for
d e c reased -cell function, suggesting that
the fetal undernutrition was primarily
responsible for insulin resistance (38). In a
c o h o rt of 23,000 healthy men in the U.S.,
t h e re was a nearly twofold increased risk
for the development of diabetes in those
with low birth weight (39). In Pima Indi-
ans, high birth weights ( 4.5 kg) and low
b i rth weights ( 2.5 kg) are both associated
with an increased risk for type 2 diabetes,
suggesting that maternal diabetes, re s u l t i n g
in the higher birth weights, may have
e ffects similar to fetal malnutrition (40).
GENETIC MARKERS, LINKAGE,
AND DEFECTS The inheritance of
nontype1 diabetes can beclassied as poly-
genic or monogenic (Table 3). The vast
majority of type 2 diabetes cases are poly-
genic and occur in adults aged 40 years
and in association with obesity (41). The
348 D I AB E T E S C AR E , VO L U M E 22, N U M B E R 2, F E B R U AR Y 1 999
Emerging epidemic of type 2 diabetes in youth
Table 3Genetic classication of nontype 1 diabetes
Polygenic*
Monogenic
Mutations in nuclear DNA (nDNA)
MODY1: HNF-4 (chromosome 20q12-q13.1)
MODY2: Glucokinase (chromosome 7p15-p13)
MODY 3: HNF-1 (chromosome 12q24.3)
Atypical diabetes mellitus: glucokinase in one ADM family
Mutations in mitochondrial DNA (mDNA)
Monogenic is classied as other specic type per 1997 ADA guidelines. For more information see *Table
5 and Table 4.
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D I AB E T E S C AR E , VO L U M E 22, N U M B E R 2, F E B R U AR Y 1 999 349
Rosenbloom and Associates
autosomal dominant (MODY) and mater-
nally inherited (mitochondrial) monogenic
f o rms of type2 diabetes arerare. Monogenic
type 2 diabetes often presents in childhood
or early adulthood, however. According to
the 1997 ADA guidelines (17), the mono-
genic forms of type2 diabetes have been clas-
s i ed as other specic types of diabetes.
Studies of MODY and the mitochon-
drial diabetes syndromes have resulted in
fascinating discoveries that provide insights
for the study of the polygenic forms. The
rst locus (MODY1) mapped to the MODY
phenotype was located on chromosome 20
near the adenosine deaminase gene in the
l a rge RW pedigree (42). In studies of
F rench MODY families, the inheritance of
glucokinase was linked to the inheritance
of MODY, establishing glucokinase as the
candidate gene for MODY2 (43,44). More
than 30 distinct mutations in the gluco-
kinase gene have subsequently been iden-
t i ed in various MODY pedigrees (45,46).
In studies of MODY families that showed
no linkage to either the MODY1 or
MODY2 loci, a region of chromosome 12
(MODY3) was linked to the MODY phe-
notype (47,48). The gene for HNF-1 w a s
located within the MODY3 region, and by
sequencing the HNF-1 gene in subjects
a ffected with MODY3 and control subjects,
mutations were discovered in HNF-1
(49). This conrmed that HNF-1 was the
MODY3 gene. Next, HNF-4 , which is
located near the adenosine deaminase
gene on chromosome 20, was sequenced.
Indeed, affected individuals in the RW
MODY1 pedigree displayed a consistent
H N F - 4 mutation (50). ADM is inherited
as an autosomal dominant trait, similar to
M O D Y, but as noted above, displays a dif-
f e rent clinical phenotype than MODY (18).
In 1 of 10 ADM families, a unique gluco-
kinase mutation was identied (51).
Families with type 2 diabetes may
r a rely display maternal inheritance (Ta b l e
4) (52). In this situation, disease is passed
to offspring exclusively from the mother,
and never from the father. Mitochondria
a re inherited strictly from the mother via
the cytoplasm of the ovum, and matern a l l y
inherited disease results when mutations
occur in mitochondrial DNA. Individuals
a ffected with the mitochondrial diabetes
s y n d romes may display, in addition to dia-
betes, sensorineural hearing loss, car-
d i o m y o p a t h y, optic neuro p a t h y, myopathy,
e n c e p h a l o p a t h y, lactic acidosis, stro k e - l i k e
s y n d rome, or epilepsy (53). All of the mito-
chondrial mutations involve tRNA muta-
tions except for the NADH dehydro g e n a s e
subunit (ND) 1 mutation. Some patients
with mitochondrial diabetes syndro m e s
have displayed an acute-onset insulin-
dependent form of diabetes, although in
most individual patients, the monogenic
f o rms are clinically indistinguishable fro m
other type 2 diabetes.
Genetic studies of the common, poly-
genic formof type 2 diabetes have been car-
ried out almost exclusively in adults.
Multiple loci have demonstrated associations
or linkages to type 2 diabetes (Table 5). It is
a p p a rent that these associations and linkages
a re not observed in all populations studied.
The most important locus found thus far is
on chromosome 2 (N I D D M 1) (76). In the
study group of Mexican-American sib pairs
with type 2 diabetes from Starr County,
Texas, N I D D M 1accounted for 30% of
genetic susceptibility to type 2 diabetes.
R e s e a rchers are working to identify the spe-
c i c NIDDM1 gene. Other loci that have
been associated with type 2 diabetes are
e x p ressed in the -cells (glucokinase, islet-
associated polypeptide, insulin, sulfonylure a
re c e p t o r, pro h o rmone convertase 2), targ e t
cells (apolipoprotein A1/C3/A4 cluster,
a p o l i p o p rotein B,
3
- a d re n e rgic re c e p t o r,
glucokinase, insulin re c e p t o r, insulin re c e p-
tor substrate-1, muscle glycogen synthase 1,
p h o s p h o e n o l p y ruvate carboxykinase 1, R a s
associated with diabetes), and other sets of
cells (cholycystokinin type B re c e p t o r,
g rowth hormone). This eld deserves furt h e r
s t u d y, with emphasis on inheritance of early-
onset polygenic type 2 diabetes.
T h e re are exciting new data that have
demonstrated an association between the
VNTR (variable number of tandem re p e a t s )
region of the human insulin gene and size
at birth (79). This may provide a biologic
and genetic link between the insulin gene,
small size at birth, and type 2 diabetes. This
could explain the epidemiologic n d i n g
that small size at birth is associated with an
i n c reased risk for type 2 diabetes later in life
(3638). The association between the
VNTR region and type 1 diabetes was pro-
vided by Bell et al. (61) more than 10 years
ago. The association of small size at birt h
and the later development of type 2 dia-
betes is very strong. Unresolved, however,
is whether this is the result of nature or
n u rt u re, i.e., whether the insulin re s i s t a n c e
is primarily genetic or a consequence of
poor intrauterine nutrition.
T h e re is no evidence that viruses cause
type 2 diabetes or insulin resistance. Of the
m o re than 14 loci that have been linked or
associated with type 1 diabetes, only
IDDM2, the insulin gene, inuences sus-
ceptibility to both type 1 and type 2 dia-
betes (61,79).
T R E ATMENT AND
PREVENTION: THE
COMMUNITY CHALLENGE
Treatment issues
Treatment of type 2 diabetes in the pedi-
atric population is similar to treatment of
Table 4Mutations in mitochondrial DNA associated with diabetes
Additional potential Accompanied by
Class of mutation Gene Mutation clinical features the A3243G mutation
rRNA 12SrRNA C946A HC Yes
A 1 0 4 1 G H C Ye s
tRNA tRNA
Leu(UUR)
A3243G MELAS, DF
A3252G MM No
C3256T MM, LHON No
A3260G MM, CM No
T3271C MELAS No
tRNA
Lys
A8344G MERRF No
tRNA
Glu
T14709C MM No
NADH dehydrogenase
ND1 G3316A No
T3394C HC, LHON Yes
ND2 G4491A HC Yes
ND4 G11963A HC Yes
CM, cardiomyopathy; DF, sensorineural hearing loss; HC, hypertrophic cardiomyopathy; LHON, Lebers
hereditary optic neuropathy; MELAS, mitochondrial myopathy/encephalopathy/lactic acidosis/stroke-like
syndrome; MERRF, myoclonic epilepsy, ragged-red bers; MM, mitochondrial myopathy.
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350 D I AB E T E S C AR E , VO L U M E 22, N U M B E R 2, F E B R U AR Y 1 999
Emerging epidemic of type 2 diabetes in youth
the disease in adults: most patients can
manage the disease by diet and exerc i s e
(4,80,81). Oral hypoglycemic agents
(OHA), including sulfonylureas and
biguanides, have been prescribed for youth
unable to manage their diabetes by diet and
e x e rcise (4,80). Studies are needed that
evaluate the long-term safety and efficacy of
OHA in youth, particularly given re c e n t
re p o rts of serious hepatic dysfunction in
1.9% of adult patients taking tro g l i t a z o n e
(82,83). Side-effects of - g l u c o s i d a s e
inhibitors limit their use with youth (4,80).
Some youths may re q u i re insulin when
OHA are ineffective (81). The occasional
patient presenting with diabetic ketoaci-
dosis as a result of underlying infection
may also re q u i re insulin, which can be
stopped at a later time as blood sugar con-
centrations are stabilized (4,80,84).
Self-administration of insulin is a mat-
ter of survival for youth with type1 dia-
betes and there f o re becomes integrated into
the daily routine. The situation is diff e re n t
for most youth with type 2 diabetes, how-
e v e r, and several studies comment on the
n o n a d h e rence of the majority of patients in
this age-group to recommended lifestyle
m o d i cations and medical tre a t m e n t
(4,8,80,81). Especially problematic are the
youngsters with ADM who re q u i re insulin
but do not become acutely ill when they fail
to take their injections (18). Although ado-
lescents begin to exert more control over
their health behavior as they enter adult-
hood, studies indicate that most adoles-
cents do not relate unhealthy behaviors
with negative health outcomes (85,86).
Studies of Mexican-American youth in Cal-
i f o rnia (80), Native American youth in
Canada (4) and the U.S. (83), and Japanese
youth (82) attribute nonadherence to sev-
eral factors. These include lack of impro v e-
ment in health status while on OHA, denial
about their diabetes because they are
asymptomatic, and peer pre s s u re to con-
sume high-caloric foods and beverages
high in sugar content.
N u m e rous cultural and socioeconomic
b a rriers interf e re with the implementation of
d i e t a ry changes in minority youth with dia-
betes. Theremay be lack of familiarity with
recommended food items, which may be
c o s t l y, difficult for families to obtain, and
re q u i re special preparation (4,80). Finally,
many youth who are obese nd it difficult to
engage in strenuous physical activity (87).
P rescribed lifestyle and behavioral
changes for patients with type 2 diabetes
a re complex and of lifelong duration. Inves-
tigation is needed about how youth diag-
nosed with type 2 diabetes understand
their disease and the treatment rationale.
One recent study attributes poor compli-
ance in African-American youth with type
2 diabetes to lack of understandingabout
the disease and its management (8). Self-
c a re regimens need to be stru c t u red to
enable the youth to critically analyze
behavior choices in the context of their
health. A recent study suggests that patient
a d h e rence may be facilitated if the health
c a re provider actively involves the patient
in developing the self-care regimen (88).
Prevention
Studies of programs of type 2 diabetes pre-
vention that target African-American and
Table 5Loci linked to or associated with type 2 diabetes in adults
Locus/abbreviation Location Populations studied (Ref.)
Expressed in the -cell
Amylin (islet-associated polypeptide; IAPP) 12p12.3p12.1 Japanese (54)
-cell K
ATP
channel subunit
Sulfonylurea receptor (SUR) 11p15.1 U.K./U.S. Caucasians (55); French (56)
Glucokinase (GCK) 7p15p13 African-Americans (57); Mauritian Creoles (58);
Japanese (59); South Indians (60)
Insulin (INS) 11p15.5 U.S. Caucasian (61)
Prohormone convertase 2 (PCSK2) 20p11.2 Japanese (62)
Expressed in target cells
Apolipoprotein A1, C3, A4 loci (apoA1/C3/A4) 11q23 Chinese Americans (63)
Apolipoprotein B (apoB) 2p24 Chinese Americans (63)
3
-Adrenergic receptor (ADRB2) 5q32q34 Pimas (64); Japanese (65)
Insulin receptor (INSR) 19p13.2 U.S. Caucasians, Hispanics (66);
Mexican Americans (67); ChineseAmericans (63)
Insulin receptor substrate-1 (IRS-1) 2q36q37 Mexican Americans (68)
Muscle glycogen synthase (GSY1) 19q13.3 Finns (69); Japanese (70)
Phosphoenolpyruvate carboxykinase (PCK1) 20q13.31 French (71)
Rasassociated with diabetes (RAD) 16q U.S. Caucasians (72)
Expressed in other sets of cells
Cholycystokinin type B receptor (CCKBR) 11p15.5p15.4 French (73)
Growth hormone (GH1) 17q22q24 U.S. Caucasians (74)
Loci associated with type 2 diabetes where the specic
gene etiology has not been identied
Chromosome 1 1, D1S191 U.S. Caucasians (75)
Chromosome 2 (NIDDM1) 2, D2S125 Mexican Americans (76)
Chromosome 11 11, D11S935 Caucasians, North European ancestry (77)
Chromosome 20 20q, D20S197 U.S. Caucasians (78)
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Mexican-American youth are unavailable.
Because the disease has been recognized in
Native American youth for 15 years, a
number of summer camps and school-
based education and prevention pro g r a m s
that focus on type 2 diabetes have been
implemented for this population in the
U.S. and Canada. School-based pro g r a m s
emphasize modication of the food supply
in school meals, provide some classro o m
education about diabetes, and create a
school environment that supports healthy
lifestyle behaviors, including incre a s e d
e x e rcise (84,89,90). Programs for childre n
in Headstart and K6 encourage family
involvement (84), whereas pro g r a m s
designed for high school children use social
networks and peer pre s s u re as a passive
s u p p o rt system to promote behavior
change and reduce health risk factors (88).
Evaluations of these programs indicate that
they are successful in promoting short - t e rm
behavior changes, but longitudinal studies
need to be conducted to determ i n e
whether these programs induce persistent
behavior changes that reduce health risks
for type 2 diabetes in this age-gro u p .
T h e re are 1-week summer camps for
Native American youth with type 2 diabetes
or at high risk for the disease that provide a
diabetes education programwithin a con-
t rolled environment that enables the part i c-
ipant to experience the benets of exerc i s e
and good nutrition. Studies of camps in
Canada and in the U.S. re p o rt norm a l
glycemic levels in youth with type 2 diabetes
after 5 days of controlled diet and incre a s e d
physical activity (4,84,91). Behaviors
l e a rned at the camps are not maintained,
h o w e v e r, and most youth experience poor
glycemic control after re t u rning home. One
study re p o rts that some youths part i c i p a t i n g
in these camps in consecutive years do
attempt to integrate thelifestyle changes into
their home environments (84).
A number of school-based nutrition and
e x e rciseprograms aimed at diabetes pre v e n-
tion exist on re s e rvations across the U.S.,
but studies evaluating the effect of these pro-
grams havenot been published. The Path-
ways program is in year 5 of a 9-year re s e a rc h
e ff o rt to develop a culturally appro p r i a t e
school- and family-based prevention pro-
gram promoting increased physical activity
and a healthy diet to prevent obesity and
reduce risk for diabetes in grade 35 Indian
c h i l d ren. A collaborative eff o rt amonguni-
versities, six Indian nations, re s e rv a t i o n
schools, and Indian families, the pro g r a m
draws on asocial learningtheory model sim-
ilar to that used in theChild and Adolescent
Trial for Cardiovascular Health (CAT C H ) .
The programstresses family participation as
one key to program success (91,92).
Most diabetes prevention eff o rts in
Indian communities have been secondary
or tert i a ry prevention programs targ e t i n g
adults with type 2 diabetes. The appro a c h e s
often combine a number of strategies,
including health education, health fairs, t-
ness programs, nutrition education, etc.,
and are delivered in a shotgun method with
the expectation that one or two of thestrate-
gies will be effective. Prevention pro g r a m s
a re often implemented with little or no pilot
testing, assuring poor outcomes. Although
many programs incorporate some culturally
a p p ropriate strategies, such as using cultural
motifs in education pamphlets or the lan-
guage of the target audience, they often
neglect thesociocultural health beliefs of the
t a rget population.
Developing culturally relevant pre v e n-
tion programs necessitates analysis of socio-
cultural health beliefs and behaviors as well
as the level of knowledge about the disease
held by the program recipients. For exam-
ple, one study of Indian youth who have
family members with diabetes re p o rts that,
although the youth had some knowledge
about the disease, they did not relate com-
plications such as retinopathy or amputa-
tion to diabetes. Furt h e rm o re, over half of
the study population expressed the belief
that diabetes was contagious or was caused
by bad blood, and over a third of the
g roup attributed the disease to weakness
(93). This study highlights the necessity for
health care providers to be informed about
the attitudes, beliefs, and knowledge levels
of the target population when designing
education and prevention programs if these
p rograms are to be meaningful, re l e v a n t ,
and eff e c t i v e .
C O N C L U S I O N S N o n a u t o i m m u n e
f o rms of youth-onset diabetes are becoming
i n c reasingly prevalent as rates of obesity in
c h i l d ren and adolescents accelerate. This
t rend is particularly pronounced in minor-
ity populations. Research directed to an
understanding of the basic biology of
insulin production in youth deserves high
p r i o r i t y. The development of therapy for
nontype 1 diabetes that is safe and accept-
able to youth is also important. Most impor-
t a n t l y, behavioral and dietary programs that
a re able to effect long-term change and pre-
vent obesity need to bedeveloped within
the communities aff e c t e d .
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