From Pre-Diabetes to Type 2 Diabetes In

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From Pre-Diabetes to Type 2 Diabetes inObese YouthPathophysiological characteristics along the spectrum of

glucose dysregulationFIDA BACHA, MD1,2

SOJUNG LEE, PHD1NESLIHAN GUNGOR, MD3

SILVA A. ARSLANIAN, MD1,2

OBJECTIVE Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) areconsidered pre-diabetes states. There are limited data in pediatrics in regard to their pathophys-iology. We investigated differences in insulin sensitivity and secretion among youth with IFG,IGT, and coexistent IFG/IGT compared with those with normal glucose tolerance (NGT) andtype 2 diabetes.

RESEARCH DESIGN AND METHODS A total of 24obese adolescents with NGT,13with IFG, 29 with IGT, 11 with combined IFG/IGT, and 30 with type 2 diabetes underwent

evaluation of hepatic glucose production ([6,6-2

H2]glucose), insulin-stimulated glucose dis-posal (Rd, euglycemic clamp), first- and second-phase insulin secretion (hyperglycemic clamp),body composition (dual-energy X-ray absorptiometry), abdominal adiposity (computed tomog-raphy), and substrate oxidation (indirect calorimetry).

RESULTS Adolescents with NGT, pre-diabetes, and type 2 diabetes had similar bodycomposition and abdominal fat distribution. R

dwas lower (P 0.009) in adolescents with type

2 diabetes than in those with NGT. Compared with adolescents with NGT, first-phase insulinwas lower in those with IFG, IGT, and IFG/IGT with further deterioration in those with type 2diabetes (P 0.001), and -cell function relative to insulin sensitivity (glucose disposition index[GDI]) wasalso lower in those with IFG, IGT, and IFG/IGT (40, 47, and 47%, respectively), witha further decrease (80%) in those with type 2 diabetes (P 0.001). GDI was the major deter-minant of fasting and 2-h glucose levels.

CONCLUSIONS Obese adolescents who show signs of glucose dysregulation, including

abnormal fasting glucose, glucose intolerance or both, are more likely to have impaired insulinsecretion rather than reduced insulin sensitivity. Given the impairment in insulin secretion, theyare at high risk for progression to type 2 diabetes. Further deterioration in insulin sensitivity orsecretion may enhance the risk for this progression.

Diabetes Care 33:22252231, 2010

Pre-diabetes, defined as the presenceof elevated fasting glucose, abnor-mal glucose tolerance, or both, is as-

sociated with an enhanced risk fordevelopment of type 2 diabetes in adults(1), butthere arelimited data to define thesignificance in children. A recent change

in the definition of the abnormal fastingglucose to a lower level (100125 mg/dl)

has increased the prevalence of pre-diabetes in both adults and youth (2 4).It is unclear from the literature what role adefect in insulin secretion or an abnor-mality of insulin sensitivity might play inthe impairment of glucose regulation,leading to glucose intolerance or elevated

fasting plasma glucose.Epidemiological studies suggest that

subjects with impaired fasting glucose(IFG) have lower insulin sensitivity andhigher insulin secretion (5,6) basedlargely on fasting indexes of insulin sen-sitivity and an oral glucose tolerance(OGTT)derived single index of insulinsecretion (5). Adult studies reveal similaror lower insulin sensitivity in subjectswith impaired glucose tolerance (IGT)compared with those with IFG who havelower insulin secretion (7,8). These stud-ies are contrasted with clamp studies inPima Indians showing similar insulin sen-sitivity in subjects with IFG and IGT butlower insulin secretion in those with fast-ing dysglycemia (9).

Pediatric data are limited. In over-weight Latino children with a family his-tory of type 2 diabetes (10), children withimpaired versus normal fasting glucosehad no significant differences in insulinsensitivity or acute insulin response.However, the glucose disposition index(GDI), or insulin secretion relative to in-sulin sensitivity, was significantly re-

duced (15% lower) in children with IFG.A more recent study in obese adolescentsrevealed that subjects with IFG had de-creased glucose sensitivity of first-phaseinsulin secretion and liver insulin sensi-tivity, whereas those with IGT had moresevere degrees of peripheral insulin resis-tance compared with subjects with nor-mal glucose tolerance (NGT) (11). Werecently demonstrated that insulin secre-tion relative to insulin sensitivity shows asignificantly declining pattern: highest inyouth with NGT, intermediate in youth

with IGT, and lowest in youth with type 2diabetes (12).In an attempt to clarify the contro-

versy concerning the metabolic derange-ments in the different categories of thepre-diabetes state, the aims of the presentstudy were to 1) to investigate the meta-bolic characteristics of insulin sensitivityand secretion in obese youth, with IFGversus IGT, of similar body compositionand abdominal adiposity and 2) to com-pare them not only with those with NGTbut also with children with type 2diabetes.

From the 1Division of Weight Management and Wellness, Childrens Hospital of Pittsburgh, Pittsburgh,Pennsylvania; the 2Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, ChildrensHospital of Pittsburgh, Pittsburgh, Pennsylvania; and the 3Childrens Hospital at Scott & White, Texas

A & M Health Science Center College of Medicine, College Station, Texas.Corresponding author: Fida Bacha, [email protected] 2 January 2010 and accepted 27 June 2010. Published ahead of print at http://care.

diabetesjournals.org on 30 June 2010. DOI: 10.2337/dc10-0004. 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

P a t h o p h y s i o l o g y / C o m p l i c a t i o n sO R I G I N A L A R T I C L E

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RESEARCH DESIGN AND

METHODS T w e n t y - f o u r o b e s eadolescents with NGT, 13 with IFG, 29with IGT, 11 with combined IFG/IGT,and 30 with type 2 diabetes (African

American n 45 and American whiten 62) adolescents were studied. IFGwas defined according to the 2003

American Diabetes Association (ADA)guidelines as fasting plasma glucose(FPG) of100125 mg/dl (13), basedon the average of two fasting glucosemeasurements at the time of the OGTT(at 15 and 0 min) or the average ofseven fasting glucose measurements ob-tained during the two clamp procedures(three samples every 15 min at the base-line of the hyperglycemic clamp andfour samples every 10 min at the base-line of the euglycemic clamp) and NGTwith 2-h post-OGTT glucose of 140

mg/dl. IGT was defined as normal FPG100 mg/dl and 2-h post-OGTT glu-cose of140199 mg/dl according to

ADA criteria (13). Those with combinedIFG/IGT had FPG 100125 mg/dland 2-h glucose between140 and 199mg/dl (13). All subjects were pubertaland had exogenous obesity with noclinical evidence of endocrinopathy as-sociated with obesity. They were not in-volved in any regular physical activityor weight reduction programs. Type 2diabetes in the adolescents was clini-cally diagnosed according to ADA and

Wo rld He al th Orga ni za tion crit er ia(14). Type 2 diabetic adolescents werenegative for GAD and insulinoma-associated protein-2 autoantibody.They were being treated with lifestylealone (n 7), metformin (n 11), met-formin insulin (n 10), or insulinalone (n 2). All other participantswere not taking any medications thataffect glucose metabolism. In type 2 di-abetic subjects, metformin and long-acting insulin were discontinued 48 hbefore the clamp studies. Some of the

participants (12 with NGT, 19 withIGT, and 17 with type 2 diabetes) havebeen reported before (12). All studieswere approved by the institutional re-view board of the University of Pitts-burgh. Informed consent was obtained.Clinical characteristics of the study sub-

jects are summarized in Table 1.

Clamp studiesParticipants were admitted twice within a1- to 3-week period to the Pediatric Clin-ical and Translational Research Center onthe day before the clamp studies, once for

a hyperinsulinemic-euglycemic clampand the other time for a hyperglycemicclamp in random order. The 2-h OGTT(1.75 g/kg Glucola [maximum 75 g]) wasperformed on the day before the first Pe-diatric Clinical and Translational Re-search Center admission.

In vivo insulin-stimulated glucosedisposal

A fasting blood sample was obtained fordetermination of cholesterol, LDL, HDL,

VLDL, triglycerides, A1C, proinsulin, andC-peptide. Fasting endogenous glucoseproduction was measured with a primedconstant rate infusion of [6,6-2H

2] glu-

cose (0.306 0.009 mol/kg/min; Iso-tech, Miamisburg, OH) (12). Insulin-mediated glucose metabolism (R

d) and

insulin sensitivity were evaluated during a3-h hyperinsulinemic-euglycemic clamp

(12). Continuous indirect calorimetry bya ventilated hood (Deltatrac MetabolicMonitor, Sensormedics, Anaheim, CA)was used to measure CO

2production, O

2

consumption, and respiratory quotient.Measurements were made for 30 min atbaseline and at the end of the euglycemicclamp (12).

In vivo insulin secretionFirst- and second-phase insulin and C-peptide secretion were evaluated during a2-h hyperglycemic clamp (12.5 mmol/l)as before (12).

Body compositionBody composition was determined by du-al-energy X-ray absorptiometry and sub-cutaneous abdominal adipose tissue andvisceral adipose tissue by a single-slicecomputed tomography scan at L

4L

5

(12).

Biochemical measurementsPlasma glucose was measured with a glu-cose analyzer (YSI, Yellow Springs, OH);insulin and C-peptide were measured by

radioimmunoassay as before (12). A1Cwas measured by high-performance liq-uid chromatography (Tosoh Medics), andlipids were measured using the standardsof the Centers for Disease Control andPrevention (12). Deuterium enrichmentof glucose in the plasma was determinedon a Hewlett-Packard (Palo Alto, CA)5973 mass spectrometer coupled to a6890 gas chromatograph (12). Pancreaticautoantibodies were determined in theNorthwest Lipid Metabolism and Diabe-tes Research Laboratories, University of

Washington (Seattle, WA) using the Na-

tional Institute of Diabetes and Digestiveand Kidney Diseasessponsored stan-dardization assay.

CalculationsFasting hepatic glucose production(HGP) was calculated during the last 30min of the 2-h isotope infusion accord-

ing to steady-state tracer dilution equa-tions (12). In the fasting state, an indexof hepatic insulin resistance was calcu-lated as the product of HGP and fastinginsulin levels (14). Insulin-stimulatedglucose disposal rate (R

d) was calcu-

lated during the last 30 min of the eu-glycemic clamp to be equal to the rate ofexogenous glucose infusion and ex-pressed per fat free mass (FFM) (milli-grams per minute per kilogram FFM).Peripheral insulin sensitivity was calcu-lated by dividing the R

dby the steady-

state clamp insulin level and expressedper FFM (milligrams per minute perFFM per microunits per milliliter) (12).Insulin-stimulated carbohydrate oxida-tion rates were calculated according tothe formulas of Frayn (12).

During the hyperglycemic clamp, thefirst- and second-phase insulin and C-peptide concentrations were calculated asdescribed previously (12). The GDI wascalculated as the product of insulin sensi-tivity first-phase insulin and expressedas milligrams per minute per kilogramFFM.

StatisticsStatistical analyses were performed using

ANOVA followed by a post hoc Bonfer-roni correction for five group compari-sons. A Kruskal-Wallis test was used formultiple group comparison of nonpara-metric variables and a 2 test to evaluatecategorical variables. Spearmans correla-tion and multiple regression analyseswere used to evaluate bivariate and mul-tivariate relationships, respectively.Nonparametric variables were log-

transformed for the regression analyses.Data are presented as means SD. Two-tailed P 0.05 was considered statisti-cally significant.

RESULTS

Study subjects and fasting metabolicprofileTable 1 depicts characteristics of the fivegroups of obese adolescents with NGT,IFG, IGT, combined IFG/IGT, and type 2diabetes. There were no significant differ-ences in age, sex, Tanner stage, or ethnic

Impaired glucose regulation in obese youth

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Table1PhenotypicandmetaboliccharacteristicsofobeseadolescentswithNGT,IFG,IGT,IFG/IGT,

andtype2diabetes

NGT

IFG

IGT

IFG/IGT

Type2diabetes

P

value*

24

13

29

11

30

Age(years)

13.9

1.9

14.9

1.9

14.5

2.0

14.3

2.1

15.3

1.7

NS

Sex(male/female)

9/15

7/6

6/23

5/6

13/17

NS

Ethnicity

AfricanAmerican

10

7

6

6

16

NS

Americanwhite

14

6

23

5

14

Tannerstage

IIIII

6

1

5

3

2

NS

IVV

18

12

24

8

28

BMI(kg/m

2)

36.2

4.1

33.5

6.9

37.3

7.3

36.0

6.5

36.8

5.3

NS

Waistcircumference(cm)

108.2

14.6

100.0

14.9

106.0

14.9

109.3

13.1

108.6

13.6

NS

Bodyfat(%)

46.5

5.5

41.3

7.4

45.5

5.1

44.7

5.3

41.7

6.3

NS

Subcutaneousabdomin

alfat(cm

2)

551.4

138.6

452.1

192.0

5

63.4

167.4

511.3

147.2

542.1

136.1

NS

Visceralfat(cm

2)

72.4(46.893.4)

67.8(46.891.0)

82.0(55.6104.0)

50.7(40.692.6)

78.3(62.488.6)

NS

A1C(%)

5.3

0.4a

5.6

0.4b

5.4

0.4c

5.2

0.5d

6.6

0.8a,b,c,d

0.001

Fastingglucose(mg/dl)

92.0(88.396.1)

102.6(100.17104.75)

92.15(89.094.5)

104.5(101.8108.7

)

118.4(103.1138.5)

0.001

Fastinginsulin(U/ml)

37.4(29.844.2)

26.3(21.756.6)

39

.1(27.455.6)

36.8(28.456.1)

40.4(33.957.2)

NS

Fastingglucoseto-insu

linratio

2.5(2.03.3)

3.9(1.94.8)

2.2(1.73.5)

2.8(2.03.8)

3.1(2.44.1)

NS

Proinsulin-to-insulinra

tio

0.17(0.100.2

)

0.14(0.120.16)

0.13(0.090.15)

0.18(0.090.25)

0.20(0.090.35)

0.002

Postabsorptivehepatic

glucoseproduction

(mg/kg/min)

1.9(1.72.3)

2.1(2.02.7)

2.1(1.72.6)

2.5(1.92.9)

2.4(2.13.2)

0.007

Postabsorptivehepatic

insulinresistance

(mg/kg/min

U/ml)

75.1(53.3106.6)

83.7(48.3116.3)

83.9(58.6130.9)

98.2(60.2169.7)

102.4(71.4180.1)

0.05

Cholesterol(mg/dl)

170.1

36.6

157.2

36.9

171.3

35.9

175.1

39.8

158.1

29.4

NS

HDL(mg/dl)

39.1(34.449.6)

36.9(30.645.3)

38

.0(32.444.6)

38.1(33.545.6)

38.7(33.141.8)

NS

LDL(mg/dl)

104.0

34.4

94.1

30.7

103.3

32.5

110.1

32.0

94.0

27.3

NS

Triglycerides(mg/dl)

110.0(92.0161

.0)

84.0(75.5157.5)

108

.0(92.0189.0)

109.0(102.5142.8

)

108.0(87.0148.8)

NS

Triglycerides-to-HDLratio

2.8(1.83.8)

2.0(1.75.0)

2.9(2.15.3)

3.0(2.73.8)

3.1(2.24.4)

NS

Dataaremeans

SDormedians(25thpercentile75thpercentile).Body

compositiondatawasmissingfor2subjectswithNGT,2withIGT,and5withtype2diabeteswhoexceededtheweightlimitof250pounds

ofthedual-energyX-rayab

sorptiometrymachine.*P

valuefromANOVAforcontinuousvariableswithmeanspresentedandKruskal-Wallistestwithmedianspresented.Pvaluefrom

2

testforcategoricalvariables.

Superscriptlettersaresign

ificantposthocanalysis(Bonferronicorrection,P

0.05):atyp

e2diabetesvs.NGT;btyp

e2

diabetesvs.IFG;ctyp

e2diabetesvs.IGT;dtyp

e2diabetesvs.IFG/IGT.NS,notsignificant.

Bacha and Associates



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distribution among the five groups. Allsubjects were pubertal. There were no sig-nificant differences in BMI, percent bodyfat, or abdominal visceral or subcutane-ous fat among the five groups.

Fasting glucose was different amongthe groups as expected on the basis ofpredefined categorization. There was nodifference in fasting insulin levels

among the five groups. Fasting endoge-nous glucose production (HGP) wassignificantly higher in the type 2 dia-betic group compared with the NGTgroup (post hoc P 0.004) with nodifference among the pre-diabeticgroups. Postabsorptive hepatic insulinresistance tended to be higher in thetype 2 diabetic group versus the NGTgroup (post hoc P 0.07) with no dif-ference among the other pre-diabeticgroups. The proinsulin-to-insulin ratiowas higher in the type 2 diabetic groupbut not significantly higher in the pre-

diabetic groups compared with theNGT group. The fasting lipid profilewas not different among the groups(Table 1).

In vivo insulin-stimulated glucosedisposal and insulin secretionTotal, oxidative, and nonoxidative glu-cose disposal were lower in the type 2

diabetic group compared with the NGTgroup. Oxidative glucose disposal waslower in the type 2 diabetic group com-pared with the NGT (P 0.016), IFG(P 0.003), and IGT (P 0.023) groupsin post hoc analysis but was not differentfrom that in the IFG/IGT group (Fig. 1A).First-phase insulin levels were signifi-cantly lower in the IFG (post hoc P 0.02), IGT (P 0.009), and IFG/IGT(P 0.011) groups and lowest in the type2 diabetic group (P 0.001) comparedwith the NGT group (Fig. 1B). Similarly,first-phase C-peptide levels were lowest

in the type 2 diabetic group and signifi-cantly different between the type 2 dia-betic and NGT groups (P 0.001).Second-phase insulin (Fig. 1B) levelswere significantly reduced in the type 2diabetic group compared with the NGT(P 0.001) and IGT (P 0.001) but notthe IFG (P 0.3) or IFG/IGT groups.GDI, which represents insulin secretion

relative to insulin sensitivity, was signifi-cantly impaired in all categories of pre-diabetes, was lowest in type 2 diabetes,and was significantly different from IFGand IGT but not IFG/IGT (Fig. 1C). Youthwith type 2 diabetes receiving differenttreatment modalities did not differ with re-spect to their peripheral glucose disposal,insulin secretion, or GDI (data not shown).

Determinants of fasting glucose andoral glucose toleranceFasting glucose correlated with hepaticinsulin resistance (r 0.30, P 0.004),

Figure 1A: Insulin-stimulated total, oxidative, and nonoxidative glucose disposal in subjects with NGT (open bars), IFG (dotted bars), IGT(striped bar), IFG/IGT (diamond bars), and type 2 diabetes (T2DM) (filled bars). P values are for trend (ANOVA P values). B: First- andsecond-phase insulin levels duringthe hyperglycemic clamp in NGT(E),IFG(),IGT(),IFG/IGT ( ), and type2 diabetes (f). C: GDI in subjectswith NGT(open bar), IFG(dotted bar), IGT(striped bar), IFG/IGT (diamond bar), and type 2 diabetes (filled bar). In A and C, letters aresignificantpost hoc analysis (Bonferroni correction): P 0.05 (a, type 2 diabetes versus NGT; b, type 2 diabetes versus IFG; c, type 2 diabetes versus IGT; e,NGT versus IFG/IGT; f, NGT versus IGT). Data are means SD.




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with first-phase (r 0.58, P 0.001)and second-phase (r 0.47, P 0.001) insulin, and with GDI (r 0.57,

P 0.001) but not with peripheral insu-lin sensitivity. Similarly, 2-h OGTT glu-cose correlated with first-phase (r 0.48, P 0.001) and second-phase(r 0.40, P 0.001) insulin and withGDI (r 0.63, P 0.001) but not withinsulin sensitivity. In a multiple regres-sion analysis with age, sex, ethnicity, BMI,hepatic insulin resistance, and GDI as in-dependent variables and 2-h OGTT glu-cose or fasting glucose as the dependentvariable, GDI was the significant determi-nant of the variance in the 2-h glucose( 0.47, P 0.001) and the fasting

glucose ( 0.32, P 0.009). Withvisceral adipose tissue or fat mass insteadof BMI in the regression model, GDI re-mains the significant determinant of thevariance in mean fasting glucose ( 0.4, P 0.001) and in 2-h glucose ( 0.5, P 0.001). The relationship be-tween GDI and 2-h OGTT glucose or fast-ing glucose is depicted in Fig. 2.

CONCLUSIONS In this study, wehypothesized that for similar degrees ofadiposity insulin sensitivity will not differ

among the different pre-diabetic groupscompared with youth with NGT but willbe lower in youth with type 2 diabetes,whereas insulin secretion will be im-paired in all categories of glucose dys-r e g u l a t i o n . C o n s i s t e n t w i t h o u rhypothesis, the current findings demon-strate that all pre-diabetes states in obeseyouth of similar BMI, percent body fat,and abdominal adiposity are character-ized by reductions in -cell function rel-ative to insulin sensitivity, with nodifference in insulin sensitivity. In youthwith IFG, insulin-stimulated glucose dis-

posal is preserved compared with that inthose with NGT, whereas first- and sec-ond-phase insulin secretion is 50 and

30% impaired. In youth with IGT, first-phase insulin is 40% lower comparedwith that in those with NGT with preser-vation of second-phase insulin. Whenboth defects, IFG and IGT, coexist, theimpairment in insulin secretion is a mix-ture of both with 55% lower first-phaseinsulin and 30% lower second-phase in-sulin. In the full-blown diabetic state, in-sulin-stimulated glucose disposal isimpaired by 30%, first-phase insulin isimpaired by 75%, and second-phase in-sulin is impaired by 65% comparedwith those in youth with NGT. Such

cross-sectional observations are consis-tent with longitudinal studies showing ahigher risk of progression to type 2 diabe-tes in the subjects with combined IFG/IGT compared with those with isolatedIFG or IGT (15).

The present study confirms the re-sults in some of the existing adult liter-a t ure but c ont ra dic t s ot he rs. O urfindings are consistent with observa-tions in adults demonstrating greaterimpairment in insulin secretion in indi-viduals with IFG (9,14,16,17) com-

pared with those with IGT, in that thedefect in insulin secretion involves bothfirst-phase and second-phase insulin inIFG, whereas second-phase insulin ispreserved in IGT. Moreover, adult stud-ies indicate that the loss of -cell func-tion may start at levels of FPG on thehigher end of the conventional normalrange (18). A recent longitudinal studysuggests that a defect in insulin secre-tion (evaluated by an OGTT-derived in-dex) is present in subjects with IFG andapparent 5 years before the develop-ment of fasting hyperglycemia (19). On

the other hand, other investigations inadults show greater insulin resistance inIGT groups compared with IFG or NGT

groups unlike our findings (17,18).However, a major difference betweenour study and the adult studies, besidesthe age factor, is that almost invariably,t h e r e po r te d a d ul t s w i th I G T(9,15,17,18,20) or IFG (9,15,18,20)have higher BMI and/or abdominal fatcompared with the NGT groups, whichcould contribute to the observed differ-ences in insulin action between IGT,IFG, and NGT categories. This observa-tion is supported by the fact that whensubjects have similar anthropometricmeasures (21), investigators did not

find significant differences in peripheralglucose uptake in the IFG or IFG/IGTgroups compared with the NGT group(21). In addition, controlling for bodycomposition (BMI and waist-to-hip ra-tio) eliminated differences in insulinsensitivity among NGT, IFG, and IGTsubgroups in one study (22) and be-tween IGT and NGT in another study(23). In that same study, lower insulinsensitivity is evident in the type 2 dia-betic group compared with that in theNGT group and with that in the pre-

diabetic groups after controlling foroverweight (23), consistent with ourcurrent and previous findings (12).

In this study, use of the hyperglyce-mic clamp allowed us to examine second-phase insulin secretion, information onwhich is not widely available in the pub-lished literature. The defect in first-phaseinsulin secretion in our pre-diabeticgroups is consistent with the findings ofCali et al. (11) of decreased glucose sen-sitivity of first-phase insulin secretion inthe pre-diabetic state. In their study, ab-solute values of first- and second-phase

Figure 2Relationship of GDI to FPG (A) and 2-h OGTT glucose level (B) in NGT (E), IFG (), IGT (), IFG/IGT (), and type 2 diabetes (f).




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insulin levels were not significantly differ-ent in the pre-diabetic groups comparedwith those in the NGT group, and glucosesensitivity of second-phase insulin wasnot affected except in the combined IFG/IGT group. Their study, however, did notinclude subjects with type 2 diabetes toallow them to evaluate the magnitude of

impairment across the spectrum of glu-cose tolerance. In our study, inclusion ofadolescents with type 2 diabetes allowedus to assess not only deviations from nor-mal but also differences from the extremeabnormal. Although absolute levels ofsecond-phase insulin were significantlylower in the type 2 diabetic versus IGTgroup, there was no difference betweenthe type 2 diabetic and IFG or coexistingIFG/IGT groups. Such an observationsuggests that in IFG the impairment ininsulin secretion may play a more critical

role in the progression to type 2 diabetesthan is the case with IGT. Another con-trast between the two studies is the studypopulation. Although our participantswere limited to a balanced representationof African Americans and whites, theirstudy included subjects of multiple eth-nicities with a significant number of His-panics who may differ in their metabolicresponse to perturbations in glucose ho-meostasis. In studies limited to Latino ad-olescents, investigators did not findsignificant differences in the acute insulinresponse between those with IFG and

NGT (10) or between those with IGT andNGT (24), although GDI was reduced inthe IFG and IGT groups compared withthat in the NGT group, indicating an im-pairment in -cell function relative to in-sulin sensitivity.

Several adult studies suggested thatthe IFG state is characterized by hepaticinsulin resistance measured during theeuglycemic clamp (9,15,25). However,the population in those studies consistedof Mexican American adults in one (15)and Native Americans (9) in another. In

addition, the pre-diabetic subjects hadhigher BMI and waist circumference (15)compared with those in the NGT group,which could have contributed to their he-patic insulin resistance. In a study byBock et al. (25), mild hepatic insulin re-sistance was found in white subjects withIFG compared with those with NGT,which was attributed to increased glu-coneogenesis. However, again the sub-

jects with IFG were significantly moreobese and had higher visceral fat (25).Ourstudy participantsin thefive differentgroups had comparable degrees of total

and abdominal adiposity, and thus it ispossible that with similar degrees of obe-sity, the earliest detected abnormality is in-cell function and insulin secretion, andhepatic insulin resistance develops laterand becomes more marked in individualsof certain ethnic backgrounds. Therefore,we propose that the defect in insulin se-

cretion in the IFG group in combinationwith hepatic insulin resistance (which wedid not measure during the clamp) maybe responsible for the mild fasting hyper-glycemia. On the other hand, the inter-play between impaired insulin secretionand peripheral insulin resistance in sub-

jects with coexisting IFG/IGT may pre-vent maintenance of plasma glucosewithina normalrange after a glucose load.

One limitation in our study is the rel-atively smaller sample size of the IFG andcombined IFG/IGT groups. However, the

use of the clamp, a sensitive method forassessing insulin sensitivity and secretion,allowed us to demonstrate significant dif-ferences in a five-group comparison.

In summary, all pre-diabetic states inobese youth have impaired insulin secre-tion relative to insulin sensitivity, al-though the magnitude of impairment in-cell function may be variable. Such dif-ferences potentially translate to a differen-tial in the risk of progression to type 2diabetes. Further investigations into theunderlying mechanisms/reasons areneeded. The ultimate objective from such

scientific advances is to individualize thetherapeutic/preventive approach to thespecific underlying metabolic dysfunc-tion, leading to type 2 diabetes at a youngage.

Acknowledgments This work was sup-ported by the U.S. Public Health Service(grants R01-HD-27503 and K24-HD-01357to S.A.A.), Richard L. Day Endowed Chair(S.A.A.), Department of Defense (F.B., S.L.,and S.A.A.), Thrasher Research Fund (F.B.and N.G.), General Clinical Research Center

(grant M01-RR-00084), and Clinical andTranslational Science Award (UL1-RR-024153).

No potential conflicts of interest relevant tothis article were reported.

F.B. conducted the study, obtained fund-ing, acquired data, analyzed data, and wrotethe manuscript. S.L. contributed analyticaltools for body composition. N.G. initiated theproject and acquired data. S.A.A. contributedthe study concept and design, acquired data,obtained funding, provided administrativetechnical and material support, supervised thestudy, and reviewed/edited the manuscript.

These studies would not have been possible

without the nurses and staff of the PediatricClinical and Translational Research Center,the efforts of the past fellows who partici-pated in performing clamp experiments, theresearch team (Sabrina Kadri, Lori Bednarz,RN, CDE, and Nancy Guerra, CRNP), thelaboratory expertise of Theresa Stauffer andKatie McDowell, and most importantly thecommitment of the study volunteers and

their parents.

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From Pre-Diabetes to Type 2 Diabetes In

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