Type 2 Diabetes in the Young.pdf

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Type 2 Diabetes in the YoungThe evolving epidemic

ZACHARY T. BLOOMGARDEN, MD

The topic of the International Diabe-tes Federation Consensus confer-ence, held 79 February 2003 in

Santa Monica, California, was Type 2 Di-abetes in the Young: The Evolving Epi-demic (1). The topic has become aclinical and health economic priority,with important implications for an in-creasing health care burden throughoutthe world. Aspects of these conditions

have recently been reviewed (1,2).

EpidemiologyWe are in the midst of an epidemic of lackof exercise, of obesity, of the insulin resis-tance syndrome (IRS), and of diabetes inyoung persons. The diabetogenic processbegins in fetal life, with low birth weightand poor nutrition combining with sed-entary lifestyle and dietary factors to pro-duce an insulin-resistant phenotype thatmay accelerate the development of renalpathology and cardiovascular disease

(CVD). Worldwide, the number of per-sons with diabetes has tripled since 1985.In Australia, 1.7and 1.4% of persons aged3544 and 4554 years, respectively, haddiabetes in 1981, and these rates in-creased to 2.5 and 6.2% in 2000 (3), sug-gesting a trend to earlier age of onset ofdiabetes.Obesity. The prevalence rates of obesity(BMI exceeding the 95th percentile)among U.S. children and adolescentsaged 6 11 and 1219 years, respectively,were 4.2 and 4.6% in 19631970, 4.0and 6.1% in 19711974, 6.5 and 5.0% in

19761980, 11.3 and 10.5% in 19881994, and 15.3 and 15.5% in 19992000, an alarming rate of increase.Obesity (weight corrected for height95th percentile) among U.S. children

increased between 1988 and 1999 from 7to 10% among those aged 25 years (Fig.1) (4,5). In a cross-sectional survey ofchildren 912 years old in Hong Kong,38% of girls, but 57% of boys, were over-weight, with overweight children of bothsexes showing higher systolic blood pres-sure, triglyceride, and insulin and lowerHDL cholesterol than the normal-weightgroup (6). In Australia, 5% of children

arecurrently obese andan additional 16%overweight (BMI 85th to 95th percentile)(7). These prevalences doubled over thepast decade after being nearly stablearound 10% from 1969 to 1985 (8).There appear to be ethnic differenceswithin countries, with African-Americanand Hispanic children aged 412 years inthe U.S. showing an increase to 22% prev-alence of overweight between 1986 and1998, while non-Hispanic whites showedno significant change with a 12% over-weight prevalence (9). It is noteworthy

that BMI may underestimate the preva-lence of obesity in young people. Recentanalysis of trends in British youth suggestthat waist circumference has increasedmore rapidly than BMI over the past twodecades, with 14 and 17% of boys andgirls, respectively, exceeding the 98thpercentile in this measure in 1997, while10 and 8% exceed the 98th percentile forBMI; both measures exceeded the 98thpercentile only in 23% of adolescentsbetween 1977 and 1987 (10).

These considerations suggest that thephenomenon of increasing type 2 diabe-

tes among children and adolescents maybe a result of increasing obesity and, par-ticularly, of increasing central obesity (2).There is a strong relationship betweenchildhood obesity and the development

of insulin resistance in early adulthood(11). Fasting insulin levels show correla-tion with blood pressure (12) and triglyc-eride and inverse correlation with HDLcholesterol levels (13), important compo-nents of the IRS.Diabetes. In populations with low prev-alence of diabetes, children with obesitymay be relatively protected against the de-velopment of diabetes, with an Italianstudy of 710 obese children showing just0.2% with type 2 diabetes and 4.5% withimpaired glucose tolerance (IGT) (14). Incontrast, a U.S. study of 167 obese ado-

lescents and children showed a 4% prev-alence of type 2 diabetes, all occurringamong Hispanic and black adolescents,while IGT was seen in 16, 27, and 26% ofthe obese white, black, and Hispanic ad-olescents, respectively, suggesting envi-ronmental and/or genetic differencescontributing to the more common occur-rence of glycemic abnormality in the U.S.than in Italy (15). In the U.K., the risk oftype 2 diabetes is 13.5 times greateramong Asian than white children (16,17).Gender is also important, with girls being

1.7 times more likely than boys to de-velop type 2 diabetes in analysis of a largeset of studies (18). Family history plays acrucial role, with more than two-thirds ofchildren with type 2 diabetes having atleast one parent with type 2 diabetes (19).

Among children with type 2 diabetes inJapan, onset in 77% is between 12 and 15years of age, 57% are female, and 26% areof normal weight, with 29% mildly, 26%moderately, and 19% severely obese. Jap-anese children with type 2 diabetes showfamilial clustering, with siblings having a

175- to 250-fold increase in diabetes overthe frequency in the general populationand parents a 4860% likelihood of hav-ing type 2 diabetes (20).

Certain ethnic groups show a partic-ularly high prevalence of glycemic abnor-mality among young persons, anddiabetes prevalence appears to be increas-ing. Type 2 diabetes was seen in 1% ofPima Indian children aged 1014 yearsand 23% of those aged 1519 in 19671976 but increased to 23 and 45%, re-spectively, in the two age-groups in

Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated withthe Diabetes Center, Mount Sinai School of Medicine, New York, New York.

Abbreviations:CVD, cardiovascular disease; HNF, hepatic nuclear factor; IGT, impaired glucose toler-ance; IRS, insulin resistance syndrome; MODY, maturity-onset diabetes of the young; NHANES III, ThirdNational Health and Nutrition Examination Survey; OGTT, oral glucose tolerance test; PCOS, polycysticovarian syndrome.

2004 by the American Diabetes Association.

R e v i e w s / C o m m e 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

P E R S P E C T I V E S O N T H E N E W S

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19871996 (Fig. 2) (21). In a rural South-

Asian population in Bangladesh in 1995,IGT was reported in 5.7% of persons aged1529 (22). Among an indigenous popu-lation in Australia, IGT was found in 8.1%of persons aged 718 years (23). In theU.S., among Navajo Indians, diabetes orIGT was found in 3 and 13%, respec-tively, of girls and boys aged 1219 (24).In Canada, among the Cree-Ojibway ab-originals, diabetes and impaired fastingglucose (IFG) were found in 1 and 3% ofchildren aged 4 19 (25), respectively,and IGT in 10% of those aged 10 19(26). A 4% prevalence of diabetes among

adolescent girls in native populations inCanada has been reported from severalsurveys (27). The prevalence of diag-nosed diabetes among American Indiansaged 1519 in the southwestern U.S. in-creased from 3.2 to 4.5 per 1,000 from1990 to1997 (28).

Clinic-based studies have also been

used to assess changes in frequency of

type 2 diabetes in young persons. Inci-dence rates of type 2 diabetes amongyoung persons increased 10-fold from1982 to 1994 in Cincinnati, Ohio (29).From 1994 to 1998, the proportion of di-abetic children diagnosed with type 2 di-abetes in Florida increased from 9.4 to20% (30). Among newly diagnosed chil-dren and adolescents in Bangkok, type 2diabetes increased from 5% during19861995 to 17.9% during 19961999(31). In the United Arab Emirates, amongthose 18 years, 12.5% of persons with

diabetes have type 2 (32). A 10-countrystudy in Asia has shown 10% of youngpeople with diabetes attending major pe-diatric centers having type 2 diabetes,with considerable regional variation (33).Currently, approximately one-third ofchildren and adolescent presenting withdiabetes in Ohio, in Arkansas, and,

among Hispanics, in California have type2 diabetes (18).

Estimates of diabetes and IFG in theU.S. population from 1988 to 1994 areavailable from the Third National Healthand Nutrition Examination Survey(NHANES III). Of almost 3,000 personsaged 1219 tested in this representativenational sample, the prevalence of IFGwas 17.6 per 1,000, the prevalence ofHbA

1c6% was 3.9 per 1,000, while di-

abetes of all types (9 of the 13 diagnosedwith diabetes were on insulin) was diag-nosed in 4.1 per 1,000, suggesting that600,000 adolescents in the U.S. havesome degree of glycemic abnormality, al-though the estimates are imprecise be-cause of the relatively low prevalence(34). Using the capture-recapturemethod to estimate the prevalence of type

2 diabetes among school children inOsaka suggests a prevalence of almost 30per 100,000 (35). The trend to increasingobesity closely parallels that of increasingdiabetes among children in Japan, where1, 2, 3, and 4% of children were obeseand incident type 2 diabetes occurredamong 2,3, 5,and 8 per 100,000 childrenin Tokyo in 1975, 1980, 1990, and 1995,respectively, in an annual urine screeningfor diabetes in school children aged 6 and15 years (36). A similar increase in diabe-tes over time was seen in the city of Yoko-hama, further suggesting this to be a validset of observations (35). A urine-basedscreening program of some 3 million stu-dents in Taiwan has shown similar annualtype 2 diabetes incidence rates of 4 and 7per 100,000 boys and girls (37). In thesestudies, not only obesity but also elevatedblood pressure and cholesterol, both highand low birth weight, and positive familyhistory of diabetes were associated withtype 2 diabetes found at screening.

There may be underestimation of themagnitude of type 2 diabetes in youth be-cause of underdiagnosis with no or few

symptoms, misclassification as type 1 di-abetes for those persons with more severehyperglycemia, and case reporting mainlyby pediatric endocrinologists leading tofew data for those in the 15- to 19-yearage-group. The likelihood of underdiag-nosis for lack of symptoms can be appre-ciated from the Japanese studies, wherethe mean HbA

1cof those found at screen-

ing was 7.9%, with 46% having levels6.5%, while those presenting withsymptoms had mean HbA

1cat diagnosis

of 10% (38). A screening methodology

Figure 1Trends in childhood obesity (95th percentile weight-for-length age 6 23 months,BMI age 219 years) from birth through 19 years by age-group (from data in 5).

Figure 2Sex-specific prevalence of diabetes in Pima children age 10 14 and 1519 years, inthree time periods from 1967 to 1996. P 0.0001 for temporal trend for both age-groups (fromdata in 21).

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not relying on glycosuria would presum-ably find cases at even lower levels ofglycemia.

Estimates from the Japan and Taiwanscreening programs suggest a cost of$10,000 (U.S.) per case found, so thatunless it is possible to demonstrate bene-fit, it may not be appropriate to recom-m e n d t h a t t h i s b e a p p l i e d t o a l lpopulations and it may be necessary torely on targeted screening case-findingapproaches. Indeed, cost-effectivenessanalysis in adults suggests this to be anoptimal approach for ascertainment of di-abetes (39), although these analyses havenot been carried out for children. Thus,screening for hyperglycemia amongyoung persons with hypertension, dyslip-idemia, insulin resistance and obesitymay offer the most effective approach to

diagnosis of type 2 diabetes in this age-group.The greatest costs of screening will be

those from treatment of persons who arediscovered to have illness, so cost-effectiveness studies of diabetes screeningamong young persons must include anal-ysis of the overall diagnostic and thera-peutic process. Screening for type 2diabetes in children appears, however, tomeet a number of criteria, suggesting thisto be an appropriate target. The disease iscommon, is serious in terms of morbidityand mortality, exhibits prolonged latencywithout symptoms, and can be assessedby blood glucose measurement with ac-ceptable sensitivity and specificity. Fur-thermore, a number of interventions canprevent or delay disease onset, and it maybe more effective to treat diabetes early inorder to delay or prevent the complica-tions. The consensus position of the

American Diabetes Association and theAmerican Academy of Pediatrics recom-mends testing at age10 years or onset ofpuberty for children with BMI above the85th percentile, with a first- or second-

degree relative having diabetes, in an at-risk race/ethnic group, particularly withsigns of insulin resistance such as acan-thosis nigricans, hypertension, polycysticovarian syndrome (PCOS), or dyslipide-mia (19). The NHANES III data suggestthat the American Diabetes Associationrisk criteria would lead to testing of 10%of youths, for a total of2.5 million ad-olescents between 12 and 19 years of age,of whom 5% might be expected to haveIFG or undiagnosed diabetes, while 1.8%of those not tested under such recom-

mendations would be expected to haveIFG (40).

The measurement of fasting plasmaglucose is preferred, with other potentialtests being the 2-h oral glucose tolerancetest (OGTT), a 2-h postprandial or ran-dom postprandial blood glucose, orHbA1c. This is similar in concept to rec-ommendations for screening of adults45 years of age with major risk factorsfor type 2 diabetes (41). The fasting glu-cose measurement without an OGTTmay, however, fail to identify all personsat risk. Furthermore, as children havelower mean glucose levels, the criteriaused for diagnosis of diabetes, IGT, andIFG in adults may not be sufficiently lowfor full appreciation of hyperglycemia inyounger persons. The glucose loadneeded for the OGTT may also need to be

more fully assessed. The notion ofpre-diabetes has become more importantwith these considerations. The term maybe considered to mean IGT and/or IFG(42) or, alternatively, to represent a statebefore the existence of abnormality in gly-cemia in persons who subsequently de-velop diabetes. In either form, theconcept may serve the purpose of in-form[ing] both the general public andhealth professionals about a modifiablestate which, if reversed, could reduce thelikelihood of type 2 diabetes(43). It is,however, possible that identifying ayoung person as being pre-diabeticcould cause psychosocial harm, particu-larly if effective intervention is not avail-able, so that caution is needed beforegenerally employing such approaches.

Pathogenesis of type 2 diabetes inthe youngGenetics. A number of monogenicdisor-ders causing diabetes in children havebeen described. These include -cell de-fects such as maturity-onset diabetes ofthe young (MODY), types 1 6, transient

neonatal diabetes, permanent neonataldiabetes, the syndrome of maternally in-herited diabetes and deafness, the Wol-fram syndrome, and the renal cysts anddiabetes syndrome. There are also syn-dromes of insulin resistance, includingtype A insulin resistance, leprechaunism,familial partial lipodysptrophy, and totallipodystropy, and obesity syndromes,such as Prader Willi, Alstroms, and Bar-det-Beidel. Diagnosis is important, asMODY-3 patients with hepatic nuclearfactor (HNF)-1 mutations are sensitive

to sulfonylureas (44) and actually tend toexhibit increased insulin secretory re-sponse to sulfonylureas and increased in-sulin sensitivity compared with personswith type 2 diabetes (45). They maytherefore exhibit hypoglycemia on sulfo-nylurea initiation and a marked rise inHbA1c if this treatment is discontinued.MODY patients with glucokinase muta-tions generally require no pharmacologi-cal treatment because the glycemicabnormality is mild.

Type 2 diabetes is probably caused bythe same continuum of genetic abnormal-ities in children as in adults. A number ofmajor predisposing genes have beenfound on chromosomes 1q, 12q, 20q,and 17q, with the only major gene iden-tified being the calpain 10 gene in Mexi-can Americans (46). Minor genes that

have been defined by thecandidateap-proach include the Pro12Ala polymor-phisms in peroxisome proliferatoractivated receptor (47) and the Kir 6.2E23K variant (48). The HNF-1 G319Sprivate mutation predisposes to type 2 di-abetes in Cree-Ojibway aboriginals inCanada (49). Carriers of 2 and 1 copies ofthe gene present 12 and 6 years earlier,respectively, than those without the vari-ant (50). Among children in this groupwith type 2 diabetes, there is a high prev-alence of HNF-1 G319S (51). As diag-nostic molecular testing is now available(for example, from www.diabetesgenes.org), it may be reasonable to employ thistest in appropriate populations.Familial factors and intrauterinegrowth retardation. The thrifty geno-type and thrifty phenotype hypotheseshave been combined into the concept ofadverse effect of undernutrition. With thelatter hypothesis, effects of intrauterineundernutrition and subsequent overnu-trition lead to insulin resistance, while thethrifty genotype hypothesizes a survivaladvantage accrued from many genera-

tions of episodic malnutrition increasingthe expression of this state. A U-shapedrelationship has been shown, with diabe-tes prevalence being highest among per-sons with either low or high birth weight(52). Those persons with highest prepu-bertal body weight and those with lowestbirth weight are particularly at risk of in-sulin resistance and diabetes (Fig. 3)(53,54). Other factors include family his-tory, with there being a marked increasein diabetes frequency with one parent andan even greater frequency with two par-

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ents having diabetes among Pima Indiansage 519 (55). Exposure in utero to amother with gestational diabetes is partic-ularly associated with increased risk of di-abetes (21) and appears to decreaseinsulin secretory capacity rather than de-creasing insulin action (56).Physical activity and insulin sensitiv-ity. Children differ from adults in meta-bolic response to exercise, showing alesser increase in the intramuscular inor-ganic phosphate-to-phosphocreatine ra-tio and a lesser decrease in pH (57).

Obesity and dietary factors may alter theexpected metabolic response to exercise.This can be seen with high-fat feeding,which reduces the growth hormone re-sponse to exercise (58). Growth hormoneand epinephrine responses to exercise areblunted in obese subjects (69). Both intra-and extramyocellular triglyceride storesare greater in obese than in lean children(60). In children, there appears to be a

body composition threshold around the75th percentile of weight for height,above which abnormalities are seen infit-ness, as measured by the maximal oxygenconsumption, with reductions in insulinsensitivity also seen (61). Physical activityincreases insulin sensitivity in children(62), and this is also seen among obesechildren undergoing regular exercise whoshow a fall in fasting insulin that is re-versed by a return to a sedentary lifestyle(63).

Australian aborigines were a popula-

tion exhibiting high levels of physicalfit-ness in their traditional hunter-gathererlifestyle, with low BMI, blood pressure,and cholesterol, although with elevatedfasting insulin and triglyceride levels sug-gesting insulin resistance. With western-ization, this population changed to onewith high levels of unemployment, wel-fare dependency, poor education, over-crowded living conditions, poor health

with heavy infectious disease burden,particularly among children (perhapscausing an inflammatory load), and in-creased lifestyle-related chronic diseaseamong adults (64). The change in healthand socioeconomic status is associatedwith central obesity, early-onset type 2 di-abetes, and premature CVD with IRS fea-tures of dyslipidemia, hypertension,hyperinsulinemia, and microalbuminuria.

Low birth weight and diabetes inpregnancy have emerged as importantrisk factors in this group. The age profileof this group is similar to that of an un-derdeveloped country, with the majorityin theyounger age-groups andlife expect-ancy 20 years less than that of the nondis-advantaged Australian population. Thediabetes prevalence is 7% at age 2534,20% atage35 44, and 28% atage4554,

as compared with respective levels of nil,3%, and 6% in the nondisadvantagedpopulation, although the prevalence ofobesity is similar in both groups (65).During the period from 1987 to 1995, theaboriginal population had a marked in-crease in BMI, with the incidence of dia-betes among persons with BMI 25kg/m2 10 per 1,000 person-years, andmore than a tripling of this rate amongpersons with BMI of25 kg/m2 (66). The

Aboriginal Birth Cohort has traced 686singleton births of Australian Aboriginalmothers between 1987 and 1990, 70%from remote rural locations, with fol-low-up beginning in 1998 of 482childrenage 8 14 years showing decreased lineargrowth rates in the rural group, but withhigher blood pressure, cholesterol, andinsulin levels in the urban group and al-most a fourfold increase in prevalence ofBMI 25 kg/m2, suggesting early devel-opment of features of the IRS (67). Similarevidence of high prevalence of overweightand obesity in urban Aboriginal childrenhas been reported in other studies (68).

Studies in Japan suggest that weight

gain is caused by a reduction in energyexpenditure among young people, withparticipation by young people in Japan inexercise and sports showing a consistentdecrease in all age-groups (69). Twenty-seven and 43% of high school boys andgirls, respectively, in the U.S. participatein an insufficient amount of physical ac-tivity (70). Habitual leisure-time physicalactivity in girls decreases by approxi-mately two-thirds among Caucasian girlsand to an even greater extent among Afri-can-American girls in the U.S. as age in-

Figure 3Cumulative incidence of diabetes based on quintile of birth weight (Pvalue for trend0.005) and weight at age 11 (Pvalue for trend 0.001) (from data in 54).

Figure 4Median habitual activity (in metabolic equivalent times [METs] per week). F, blackgirls;, white girls (from data in 72).

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creases from 9 to 18 years (Fig. 4) (71).This is particularly related to televisionviewing (72), which shows an interactionwith decreased physical activity in rela-tion to obesity (73). There is high corre-lation between television viewing andconsumption of high-energy foods, fur-ther exacerbating this effect (74). Part ofthe cause may be the frequency of foodadvertisement on television programs di-rected at children. On average, childrensprogramming includes 12 food advertise-ments hourly, more than twice that inadult viewing, with the average child inthe U.S. seeing 20,000 advertisementsper year (75). Parental influences are alsoimportant, with the NHANES III surveyshowing nearly one-third of mothers ofoverweight children to believe that thechildren are at about the right weight

(76).Insulin resistance in young persons.The development of type 2 diabetes in-volves a loss of the balance between insu-lin sensitivity and secretion, as has beenreported in adults, where the normal in-verse relationship between the two factorsleads to a constant glucose disposition in-dex in a given person, with decline in thisparameter being associated with the de-velopment of IGT and type 2 diabetes(77). Insulin resistance in the young hasbeen reported in a variety of ethnicgroupsand is strongly associated with obesity(78). Furthermore, obese children exhibitglucose intolerance, which is strongly as-sociated with evidence of both insulin re-sistance and impaired insulin secretion(14).

There are important ethnic differ-ences in the degree of insulin resistance(79). In a study comparing 22 black and22 white nonobese prepubertal children,the former group was found to have a sig-nificant decrease in insulin sensitivitywith hyperinsulinemia, showing, how-ever, lower glucose disposition indexes,

suggesting an increase in ultimate diabe-tes risk. Circulating levels of the insulin-sensitizing adipocyte secretory productadiponectin were 60% higher in whitechildren. Important dietary differenceswere found, with the black children con-suming 10% fewer calories from carbohy-drates and showing a 36% increase in thedietary fatto carbohydrate ratio, whichhad strong negative correlation with insu-lin sensitivity. Whether this is causally re-lated to metabolic abnormalities remainsto be determined (80). One important de-

terminant of obesity may be the relativepropensity to retain fat in adipose tissue,with evidence that rates of lipolysis arelower in black than in white boys and girls(81).

Comparing obese and normal-weightblack and white adolescents, insulin sen-sitivity is decreased with obesity regard-le ss of e t hnic i t y, showing inve rsecorrelation with body fat (82). A numberof studies have shown that black childrenhave higher total fat and cholesterol in-take, prefer greater sweetness in liquids,are physically less active, and spend moretime watching television. Black girls havehigher total energy intake than whites, donot perceive themselves as heavy, and ac-tually express a desire to be on the fat side(83 89). Clearly, then, there must be acomplex interplay of cultural/environ-

mental and genetic factors explaining themetabolic differences observed betweenthe two ethnic groups.

Of particular importance as a deter-minant of insulin resistance is central obe-sity (90). In a cross-sectional study of 14adolescents with IGT matched with 14control subjects of similar age, BMI, bodyfat, and leptin, the children with IGT wereinsulin resistant, with increased in-tramyocellular fat measured by 1H nu-clear magnetic resonance spectroscopyshowing strong correlation with insulinsensitivity and with 2-h postload plasmaglucose. Those with IGT had higher vis-ceral and lower subcutaneous abdominalfat and decreased first-phase insulin se-cretion and glucose disposition index(91). Comparing black and white chil-dren with obesity and similar insulin sen-sitivity levels, blacks have lower hepaticglucose output, lower total and LDL cho-lesterol, and lower triglyceride levels,with considerably lower visceral fat levels.Blacks who do have visceral obesity, how-ever, have a fall in the glucose dispositionindex (92), suggesting greater diabeto-

genic risk of obesity among blacks, butgreater atherogenic risk among whites.Important additional risk of diabetes isseen among black children with a positivefamily history of diabetes, who show an20% lowering of insulin sensitivity inthefirst decade of life (93).

A major cause of insulin resistance ispuberty (94). Insulin sensitivity decreasesby 30% during puberty with compen-satory increase in insulin secretion(95,96). Insulin action decreases similarlyduring puberty in black and white chil-

dren (97). The further metabolic derange-m e n t o f P C O S i s a s s o c i a t e d w i t hdecreased glucose disposition (98), with30% of adolescent girls with PCOS hav-ing IGT and 4% type 2 diabetes (99). Ad-olescents with PCOS who develop IGThave similar degrees of obesity and eleva-tions in circulating testosterone to thosewith normal glucose tolerance but showblunting offirst-phase insulin secretion inresponse to intravenous glucose with aconsequent decrease in the glucose dispo-sition index (100).

ComplicationsMicrovascular disease. Among Pima In-dians with type 2 diabetes diagnosed dur-ing childhood, microalbuminuria wasseen in 22% at diagnosis and in 58% atfollow-up, macroalbuminuria in 0 and

16%, and hypercholesterolemia in 18 and30%, suggesting the tendency to progres-sion of both micro- and macrovasculardisease (101). In another study of 178Pima Indians with onset of type 2 diabetesbefore age 20, a urinary protein-to-creatinine ratio0.5 g/g was seen in 20%after 25 years, implying a similar relation-ship between duration of diabetes and ne-phropathy to that seen in persons withadult onset of diabetes, while there wasrelative protection against retinopathy,which had developed in 15% (Fig. 5)(102). Retinopathy progression rates aresimilar in Japanese young persons withtype 1 and type 2 diabetes, but nephrop-athy occurs approximately two timesmore commonly among young personswith type 2 than among those with type 1diabetes (104). After a 20-year diabetesduration, 50 of 1,065 Japanese personswith onset of type 2 diabetes before age30, whose mean age at diagnosis was 20,required dialysis and 128 had developedproliferative retinopathy before age 35, ofwhom 23% were on dialysis. An addi-tional importantfinding is that both pri-

mary and acquired renal disease notcaused by diabetes appear to be commonin populations with a high prevalence oft ype 2 dia be t e s in young pe rsons(105,106). Children developing end-stage renal disease have a 1,000-fold in-c re a se in C VD mort a l i t y in youngadulthood that is associated with hyper-tension and dyslipidemia, suggesting aparticular challenge (107). In a study ofManitoba Cree young adults, mortalitywas 9%, 6% required dialysis, 38% of thewomen who had become pregnant had




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pregnancy loss, 35% were lost to clinicalfollow-up, and 67% had poor glycemiccontrol (108).Macrovascular disease. Fibrous plaquelesions are present in the aorta and coro-nary arteries of children and young adultsand associated with obesity, dyslipide-mia, and cigarette use (109). Risk factorsfor CVD predate the onset of type 2 dia-betes in adults, but there are no prospec-tive studies on CVD risk factors and long-t e r m o u t c o m e s i n c h i l d h o o d a n dadolescent type 2 diabetes. The dyslipide-mia of type 2 diabetes is not fully cor-

re c t e d by st r ic t glyc e mic c ont rol ,suggesting the need for assimilation ofnew concepts for pediatric treatment.Certainly, correction of risk factors, in-cluding those involved in dyslipidemia,such as triglyceride, VLDL, LDL, smalldense LDL, apolipoprotein B, HDL, andapolipoprotein A-1 should be an impor-tant treatment emphasis (110). Treatmentof hypertension is important, (111,112),as is cigarette discontinuation (113) andtreatment of microalbuminuria and otherrenal disease manifestations (114). Obe-

sity is itself important to address (115).Attention to control of glycemia is reason-able (116), although little evidence showsthat intensive glycemic control delays orprevents macrovascular disease. An im-portant clinical factor is the presence offamily history of complications. Finally,treatment of hypercoagulability and de-creased fibrinolysis is important (117), al-though the relatively small risk of Reyessyndrome,which is rare after puberty, hasdissuaded pediatricians from using aspirin.

The National Cholesterol EducationProgram lipid guidelines for children in-clude LDL 110, HDL 45, and triglyc-eride125 mg/dl asdesirable,whereaslevels130, 35, and 125 mg/dl, re-spectively, are termed undesirable(118). The American Diabetes Associa-tion has recently proposed that desirable

levels of LDL for children without andwith diabetes be considered 130 and100 mg/dl, respectively (119). Pharma-cological treatment is generally institutedwith caution in young persons, startingwith dietary lipid management withstaged diet, and niacin and cholestyra-mine are the best-studied agents in chil-dren, although safety studies for statinsare now appearing (120,121). Microalbu-minuria measurement at diagnosis andyearly thereafter, as well as ACE inhibitortreatment for children with microalbu-minuria or hypertension, appear appro-priate, with recognition of the potentialteratogenicity of these agents. Blood pres-sure goals among children need to be ad-

justed for age, height, and sex, and thereis currently no evidence as to whether the95th or 90th percentile should be chosenas the appropriate target (122).Other complications associated withtype 2 diabetes in young persons. Non-alcoholic fatty liver disease is associatedwith obesity and insulin resistance.

Among young persons with diabetes inthe Manitoba Cree, there was a 16% prev-

alence of alanine aminotransferase eleva-tion to three times the upper level ofnormal (123). Of the Cree group, 38%smoked cigarettes, and some authorshave suggested urine cotinine screeningbecause of the high frequency ofcovertcigarette use (124).

TreatmentGoals of treatment include the achieve-ment of glycemic control (at HbA

1c

7%), striving for a level as near to nor-mal as possible in order to eliminate

symptoms of hyperglycemia and reducemicrovascular complications (125). Fur-thermore, maintenance of reasonablebody weight, improvement of CVD riskfactors, and improvement of physical andemotional well-being are additional rea-sonable goals. Strategies for glucose self-monitoring need to be delineated,particularly addressing evidence thatsuch approaches are cost-effective andnecessary for young persons with type 2diabetes. Such a treatment approach maybe aided by participation in a structureddiabetes education program. For youngpersons, the important role of the familyin diabetes management cannot be under-estimated, and it is crucial to include di-rect family supervision in optimizingglycemia (126). One needs to take intoaccount familial and/or psychosocial dys-

function, ethnic influences, and barriers tocompliance, recognizing that the long life-span of children requires the developmentof safeand effective therapeutic approaches.

A proposed therapeutic algorithm forasymptomatic children with type 2 diabe-tes therapy is to start with lifestyle inter-vention approaches to diet and exercise;then to add monotherapy, particularlyemphasizing the use of metformin; thento use combinations of two oral medica-tions, although recognizing that neithersulfonylureas nor thiazolidinediones havebeen fully studied in the pediatric age-group; and then to add insulin. For symp-tomatic children, with blood glucose300 mg/dl or when ketoacidosis ispresent, a reasonable approach is to startwith insulin with subsequent efforts totaper this and substitute metformin(127). If diabetes is diagnosed early in ayoung person, lifestyle intervention maysuffice, although this only appears to beapplicable to10% of patients at the timeof presentation. Such approaches requireintensive and expensive counseling ef-forts, and it remains to be seen whether

they can be employed in clinical practice.Pharmacological treatment. Pharmaco-logical treatment may include insulin,metformin, insulin secretagogues, thiazo-lidinediones, and -glucosidase inhibi-tors. Insulin is familiar to pediatriciansand pediatric diabetologists and is effec-tive in treating acute metabolic decom-pe nsa t ion, pa rt ic ula rly whe n i t i suncertain whether the patient has type 1of type 2 diabetes. It may in addition con-vey a message of more serious illness, per-haps improving compliance (128). In

Figure 5Prevalences of diabetic nephropa-thy (A) and retinopathy (B) among Pima Indi-ans versus diabetes duration among personsdeveloping diabetes before age 20 (E), 2039(f), and 40 () years.

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clinical practice in the U.S., approxi-mately one-half of young patients withtype 2 diabetes receive insulin and one-half oral agents, most commonly met-formin (127).

Metformin is approved in the U.S. forpediatric use. It is typically used as theinitial pharmacological treatment in theabsence of severe hyperglycemia, lower-ing HbA

1cby 1.1% and fasting blood glu-

cose 64 mg/dl in such patients (129). Itwill be important to obtain outcome stud-ies. Analysis of efficacy of metformin in agroup of Cree in Canada showed little ef-fect of metformin on HbA

1c or body

weight after 1 year among adolescentswith type 2 diabetes, although gastroin-testinal side effects were more commonwith treatment (130). Poor adherence tooral therapy among relatively asymptom-

atic young persons with type 2 diabetesmay be a major barrier to improvement inoutcome.

Sulfonylureas are well studied inadults and are effective, safe, and inex-pensive, although they may cause weightgain and hypoglycemia and have no effecton lipids. Newer sulfonylureas and non-sulfonylurea insulin secretagogues andcombination approaches with metforminmay allow greater flexibility and improve-ment in outcome. The thiazolidinedionesare being used in studies for pediatric use,and although associated with weight gain,their reduction in visceral fat suggestsoverall benefit if long-term safety con-cerns can be addressed. The safety profilewith regards to edema and congestiveheart failure may be more favorable in pe-diatrics, although this needs to be deter-mined. -Glucosidase inhibitors are usedinfrequently but are safe and have beenshown to have a role in prevention (131),although their gastrointestinal side effectsmay decrease acceptance among youngpersons.

PreventionIt may be possible to combat the trend toincreasing obesity with programs aimedat increasing activity levels in children. InSingapore from 1992 to 2000, the Trimand Fit program led to a fall in obesityprevalence from 16 to 14% of primaryand secondary school students (132). Anexercise intervention in Japan decreasedthe prevalence of overweight from 40 to37% among boys and to 32% among girlsbetween ages 10 and 13, with no changein a control group (133).

In an analysis of 173 Mexican-American children age 9 years from a low-income neighborhood, ingestion of totaland saturated fat was greater than recom-mended national dietary guidelines andreported daily fruit and vegetable intakewas half of what was recommended. Theirphysical fitness level, measured withmodified Harvard exercise protocol, waslow, they watched television on average of3.5 h daily, and they had high body fat.Sixty percent hada first- or second-degreerelative with diabetes (134). The Biene-star school-based diabetes preventionprogram, based on the concept that in-creasing knowledge is not sufficient tochange health behavior, aimed to create anetwork of social support in the class-room, home, school cafeteria, and amongfriends and classmates. School cafeteria

staff and parents may themselves need ed-ucation to decrease saturated fats and in-crease fruits and vegetables and toparticipate in the development of healthyfood and exercise habits among children.Of 93 sessions in the program, one-thirdwere for children and the rest for schoolpersonnel and parents. Using such an ap-proach, in a population of 1,420 students,fasting capillary glucose at baseline was110 125 mg/dl in 35 and 125 mg/dl in7, with a decrease in fasting blood glucosefrom 127 to 97 mg/dl among children inthe intervention program compared witha fall from 117 to 99 mg/dl children notparticipating in the program. Of the re-maining children whose initial blood glu-cose was 110 mg/dl, 10 of 651 in theintervention group, but 19 of 618 in thecontrol group, had glucose 110 mg/dlafter the 1-year program. Physical fitnessincreased in the intervention group butdecreased in the control group. The inter-vention group showed higher calorie in-take, which was compatible with theincreased physical activity. BMI increasedin both groups, but the intervention

group had a 1.3% and the control group a0.65% decrease in body fat (135).

Risk reduction and prevention strate-gies for obesity, as for all illnesses, are dif-ficult and time consuming because of themulticausal etiology of the condition, het-erogeneous time perspectives, low com-pliance, competition for prevention ofother illnesses, calls for additional evi-dence, economic priorities, and informa-tion overload of the persons who aretargeted for this and other interventions(136). One difficulty is the perception by

physicians and overweight persons thatlarge weight loss is required. Analysis of astrategy of weight gain prevention in Hol-land, assuming that the expected 3.5%mean increase would be prevented for 10years, suggested that a decrease in osteo-arthritis by 5 6% and consequent de-crease in work loss by 23% could beanticipated (137). Furthermore, personswho develop obesity must have greaterannual weight gain than persons who re-main nonobese, so simply sustaining astable weight represents an importantachievement, and the recommended510% maintained weight loss for per-sons with or at risk of diabetes would behighly effective, although neither physi-cians nor patients are satisfied with suchoutcomes. For overweight and obese chil-dren, appropriate goals may include

weight maintenance or even retardationof weight gain.There are a number of barriers to ef-

fective weight loss in obese persons withdiabetes (138). Physical activity is partic-ularly a problem in older persons withdiabetes, who often have contraindica-tions to exercise and may not be able toperform even mild exercise to aid in theirattempts at weight loss (139). The de-crease in fitness among young personswith obesity and pre-diabetes may simi-larly potentiate their weight gain. A par-ticular problem in adults, which may beimportant in children as well, is weightgain before and during holidays, amount-ing annually to an average of 0.6 kg andhardly offset by the average 0.1-kg weightloss following the holiday (140). There isa weak but significant negative correla-tion between obesity and decreased senseof smell, so that the obese person mayovereat because of failure to achieve olfac-tory satisfaction (141).

Another set of barriers to weight lossis in beliefs and behaviors of the healthcare provider. Physicians feel thatfat pa-

tients do not comply with advice, and theskills to assist with weight loss decreasedamong physicians between 1992 and1997 with diminishing notice of weightproblems (142). Physicians identify fewpersons potentially with sleep apnea, con-sistently failing to ask questions to iden-tify the syndrome (143). Whether similarcharacteristics apply to providers of treat-ment for young persons is again notknown.

Predictors of long-term success inweight reduction are early weight loss,




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which encourages ongoing participation,male sex, lower age, greater education,more social support, weight history, andbehavioral and cognitive strategies; treat-ment characteristics associated with suc-cess include approaches that empowerself-confidence and feelings of control,wit h a good we ight -ma int e na nc e / follow-up approach. The National

Weight Control Registry reports showthat 90% of successful dieters show simi-lar approaches to weight maintenance:following a low-fat, high-carbohydratediet, frequently self-monitoring theirweight, eating breakfast, and being phys-ically active (144). Diet may itself be as-sociated with adverse consequences, witha study of 810 teenagers in the U.S. show-ing that for boys, advice from mothers todiet was associated with more worry

about weight gain,and much greater like-lihood of binge eating (145).Pediatric obesity is a novel concern,

for which prevention is optimal but notlikely with current approaches. Predictorsof weight gain aretherefore neededso thatintervention at early stages of this costlycondition can be initiated. For obese dia-betic adolescents, diet, exercise, behavior,and drug treatment are options, althoughvery few drug or surgery studies havebeen carried out in obese children, sug-gesting that we may be undertreatingobese children. Attitudes, prejudice, andstigmatization by the medical professionmay be important obstacles. Weight lossis effective among adolescents in increas-ing insulin sensitivity and reducing bloodpressure (146).

Another set of approaches to lifestylemeasures at risk reduction can be gainedfrom the perspective of studies of groupswith a particularly high risk of diabetes.Potential interventions include glycemiccontrol of diabetic pregnancy and reduc-tion of risk of low birth weight by preven-tion of smoking and genital infection.

Encouraging breast-feeding may mini-mize excessive energy intake and perhapsimprove insulin sensitivity in the childbecause of the higher polyunsaturated fatcontent of breast milk than cow milk.Pima Indian studies show a lower preva-lence of type 2 diabetes with breast-feeding during infancy (147). In studiesof Native Canadians, exclusive breast-feeding results in a fourfold decrease indiabetes during adolescence (148). Sup-portive environments for regular physicalactivity and healthy food supply may lead

to a decrease in diabetes development.School lunch (and breakfast) programscan be highly effective in providinghealthier diet in these settings.

In a trial of 192 children in two Cali-fornia schools, television and videotapeviewing and video game use was reducedfrom 12 to 8 h/week in the interventiongroup versus no change in the controlgroup. Those in the intervention grouphad a 0.45-kg/m2 lesser increase in BMIand a 2.3-cm lesser increase in waist cir-cumference that the control group duringthe 6-month study (149). The Kids NFitness program promotes health andwellness in classrooms across the U.S.(150), with similar programs having beenshown to decrease weight gain among at-risk young persons from 1.2 to 0.2 kg/month (151).

Metformin was shown to be of equalefficacy to intensive lifestyle interventionin decreasing conversion from IGT to di-abetes among younger obese adults in theDiabetes Prevention Program (152). In astudy of 29 obese hyperinsulinemic ado-lescents with a positive family history oftype 2 diabetes randomized to metforminversus placebo, however, although BMIand fasting insulin improved modestlywith treatment, no change could be dem-onstrated in insulin sensitivity, HbA

1c,

lipids, or glucose disposal; therefore, it isuncertain whether this medication willhave a role in the prevention of type 2diabetes among young persons (153).

SummaryType 2 diabetes is becoming an increas-ingly prevalent disorder among youngpersons who are driven, as is the case inadults, by lifestyle factors leading to in-creased body weight. Genetic and familialfactors, fetal environmental factors, par-ticularly maternal gestational diabetesand intrauterine growth retardation, andlack of physical activity during childhood

and adolescence lead to increasing levelsof insulin resistance that appear to be cru-cial in the pathogenesis of type 2 diabetesin the young. The disorder is associatedwith microvascular disease, with a sug-gestion of greater risk of nephropathythan of retinopathy, and may also lead toearly macrovascular disease. Treatmentincludes lifestyle modification and thepharmacotherapeutic approaches utilizedin adults with type 2 diabetes, with stud-ies to date supporting the roles of insulinand metformin, suggesting the impor-

tance of studying insulin secretagoguesand thiazolidinediones as approaches inthe treatment of type 2 diabetes in theyoung. The development of effective ap-proaches to disease prevention will be ofgreat importance.

AcknowledgmentsFinancial support forthe International Diabetes Federation Consen-sus conference was provided by Johnson &Johnson.

The conference organizing group membersare George Alberti (London), Francine Kauf-man (Los Angeles), Martin Silink (Westmead,Australia), and Paul Zimmet (Caulfield, Aus-tralia). Presentations were made by Silva A.Arslanian (Pittsburgh, PA; insulin resistance),PeterBennett (Phoenix,AZ; pathogenesis),So-nia Caprio (New Haven, CT; insulin resistanceand approaches to risk reduction), Lee-MingChuang (Taipei, Taiwan; screening), DanCooper (Irvine, CA; exercise), Heather Dean(Manitoba, Canada; microvascular disease),Andrew Hattersley (Exeter, U.K.; genetics),Francine Kaufman (screening and treatment),Kaichi Kida (Ehime, Japan; epidemiology)Kerin ODea (Casuarina, Australia; Australianaborigines), Michael Marmot (London; socio-economic considerations), Chittaragnan Ya-jnik (Rasta Peth, India; fetal and neonatalorigins of insulin resistance), Stephan Rossner(Stockholm, Sweden; obesity), Martin Silink(CVD risk management), Roberto Trevino(San Antonio, TX; prevention), Frank Vinicor(Atlanta, GA; epidemiology), and Paul Zimmet

(epidemiology).

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