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OBSERVATIONS

Relationship

Between PeriodontalDisease and DiabeticRetinopathy

Recently, various studies have re-ported that periodontal disease ad-versely affects diabetes (1). The

control of periodontal disease in elderlyindividuals has been reported to improvethe control of blood glucose (2). Severeperiodontal disease is associated with el-

evated blood lipopolysaccharide levels asa result of periodontogenic bacteria,which induce higher levels of interleu-kin-6 (IL-6) and tumor necrosis factor-(TNF-) (3,4). Control of periodontaldisease is now considered not only a den-tal problem but also an issue affecting thepatients overall quality of life. Proinflam-matory cytokines such as IL-6 have beenshown to be involved in the pathogenesisof diabetic retinopathy (DR) (5), while therelationship between diabetic retinopathyand periodontal disease remains unclear.

We investigated whether periodontal dis-ease is correlated with diabetic retinopathy.

The study was based on a prospectivereview of 73 eyes in 73 consecutive dia-betic patients. The mean duration of dia-betes was 14.3 7.1 years (range 233),and the mean HbA

1cwas 7.5 1.6%

(5.213.7). IL-6 and TNF- levels in thevitreous fluid samples from 32 eyes ob-tained during vitrectomy and in pairedplasma samples were measured by en-zyme-linked immunosorbent assay. Non-diabetic patients included 10 withmacular hole and 2 with epiretinal mem-

brane. Institutional ethics committee ap-proval was obtained, and all participantsgave informed consent. The severity of di-abetic retinopathy was quantified accord-ing to the modified Early TreatmentDiabetic Retinopathy Study (ETDRS) ret-inopathy severity scale (6). The severity ofperiodontal disease was quantified ac-cording to bone loss and then graded andevaluated (7). Patients with periodontaldisease were classified as positive or neg-ative based on median values. Diabeticpatients were classified as having nonpro-

liferative or proliferative diabetic retinop-athy. Data are presented as means SD.The Mann-Whitney U test was used tocompare IL-6 and TNF- levels. To deter-mine the relationship between the sever-ity of periodontal disease and ETDRS,retinopathy severity, or angiogenic fac-

tors, as well as between X and Y parame-ters, Spearmans rank-order correlationcoefficient and logistic regression modelwere applied.

The severity of periodontal diseasewas significantly correlated with the se-verity of diabetic retinopathy (P 0.0012), and the risk of proliferative dia-betic retinopathy was significantly higherin the presence of periodontal disease(odds ratio 2.80, P 0.036). Therewas no significant relationship betweenthe severity of periodontal disease and

HbA1c or duration of diabetes (P 0.098and 0.295, respectively). There was a sig-nificant relationship between the severityof diabetic retinopathy and duration ofdiabetes (P 0.002). The vitreous fluidlevel of IL-6 (mean 154.2 164.6 pg/ml[range 0.993597.0]) was significantly el-evated in patients with diabetic retinopa-thy compared with that in nondiabeticpatients (mean 1.34 0.91 pg/ml [0.63.68]) (P 0.0001). Furthermore, thevitreous fluid level of IL-6 was signifi-cantly correlated with the severity of peri-odontal disease (P 0.012). There was

no significant relationship between thevitreous fluid level of IL-6 and HbA

1cor

duration of diabetes (P 0.293 and0.705, respectively). In contrast, the vit-reous fluid level of TNF- was not signif-icantly correlated with the severity ofperiodontal disease. The IL-6 concentra-tion in vitreous fluid (mean 154.2 164.6 pg/ml [0.993597.0]) was signifi-cantly higher than that in plasma (mean1.89 3.47 pg/ml [0.15618.8]) (P 0.0001).

There was a significant relationship

between periodontal disease and severityof diabetic retinopathy, but it was unclearwhether periodontal disease directly af-fects the progression of diabetic retinopa-thy because this was a cross-sectionalstudy. Further prospective studies, in-cluding evaluation of systemic factors, arenecessary.

HIDETAKA NOMA, MD1

IKUO SAKAMOTO, PHD1

HIDEKI MOCHIZUKI, MD1

HIDETOSHI TSUKAMOTO, PHD2

ATSUSHI MINAMOTO, PHD1

HIDEHARU FUNATSU, PHD3

HIDETOSHI YAMASHITA, PHD4

SHIGEO NAKAMURA, PHD5

KEN KIRIYAMA, PHD4

HIDEMI KURIHARA, PHD5

HIROMU K. MISHIMA, PHD1

From the 1Department of Ophthalmology and Vi-sual Science, Hiroshima University Graduate Schoolof Biomedical Sciences, Hiroshima, Japan; the 2De-partment of Ophthalmology, Hiroshima PrefecturalHospital, Hiroshima, Japan; the 3Department ofOphthalmology, Diabetes Center, Tokyo WomensMedical University, Tokyo, Japan; the 4Departmentof Ophthalmology and Visual Science, YamagataUniversity School of Medicine, Yamagata, Japan;and the 5Department of Periodontal Medicine, Hi-roshima University Graduate School of BiomedicalSciences, Hiroshima, Japan.

Address correspondence to Hiromu K. Mishima,PhD, Hiroshima University Graduate School of Bio-medical Sciences, Department of Ophthalmologyand Visual Science, 1-2-3 Kasumi, Minami-ku, Hi-roshima 734-8551, Japan. E-mail: [email protected].

2004 by the American Diabetes Association.

References

1. LoeH: Periodontal disease: the sixth com-

plication of diabetes mellitus. DiabetesCare 16:329334, 19932. Grossi SG, Skrepcinski FB, DeCaro T,

Robertson DC, Ho AW, Dunford RG,Genco RJ: Treatment of periodontal dis-ease in diabetics reduces glycated hemo-globin. J Periodontol 68:713719, 1997

3. Grossi SG, Genco RJ: Periodontal diseaseand diabetes mellitus: a two-way relation-ship. Ann Periodontol 3:5161, 1998

4. Soolari AS, Champagne C, Punzi JS, AmarS, Van Dyke TE: Serum modulation ofneutrophil response to Porphyromonasgingivalis LPS in periodontal disease. J IntAcad Periodontol 1:101109, 1999

5. Funatsu H, Yamashita H, Shimizu E,Kojima R, Hori S: Relationship betweenvascular endothelial growth factor and in-terleukin-6 in diabetic retinopathy. Retina21:469 477, 2001

6. The Early Treatment Diabetic Retinopa-thy Study Research Group: Fundus pho-tographic risk factors for progression ofdiabetic retinopathy: ETDRS report num-ber 12. Ophthalmology 98:823833, 1991

7. Jeffcoat MK, Wang IC, Reddy MS: Radio-graphic diagnosis in periodontics. Peri-odontol 2000 7:5468, 1995

L E T T E R S

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Effect of DiabetesInterventionPrograms onPhysical Activity

Among Migrant

Mexican WomenWith Type 2Diabetes

The 2000 Dietary Guidelines for

Americans and the dietary guide-lines for the control of diabetes in

Mexico include recommendations thatadults participate in at least 30 min ofmoderate physical activity, preferablydaily (1,2). However, to our knowledge,there have been no studies that explorethe effect of diabetes intervention pro-grams on physical activity among migrantMexican women with type 2 diabetes.

All women from seven diabetes edu-cation groups from three different Mexi-can institutions located in Tijuana wereinvited to answer a previously validatedquestionnaire on physical activity. Of 111questionnaires, 100 were adequately an-swered. The mean age was 53 12 years.The majority of the sample was migrantsfrom other Mexican states, and 40% wereclassified as overweight and 31% as

obese. Of the women, 62, 45, and 15%reported 20, 30, and 60 min ofphysical activity per day, respectively.Seventy-three percent reported 80 minof weekly physical activity. Daily outdooractivity of participants was 39 4.2 min(mean SE), and daily indoor activitywas 5.72 0.27 h. Total light activity(3.0 metabolic equivalents [METs]) was5.28 0.24 h/day, total moderate activity(3 6 METs) was 55 14 min/day, andtotal vigorous activity (6.0 METs) was4.2 0.6 min/day. The average physical

activity level was 1.54 0.03. The mainindoor activities were cooking (11h/week), dishwashing and clothes wash-ing (3.2 h/week), cleaning (3.1 h/week),and shopping (1.9 h/week), and the mainoutdoor physical activities were walking(3.1 h/week), semiactive exercise andstretching (1.26 h/week), running (0.23h/we e k), a nd bic yc le r iding (0.18h/week). The main resting activity wassleeping (49.16 h/week), followed bywatching television (11.3 h/week), rest-ing in bed (2 h/week), driving or sitting in

a car (1.5 h/week), and sitting at home(1.38 h/week).

This study shows that the majority ofMexicans with diabetes who are willing toparticipate in diabetes education groupsat the primary health care clinics engagein 20 min of daily physical activity,which therefore reinforces the need forpromoting culturally based interventions(3,4). These results are better than the na-tional data for adults with type 2 diabetesin Mexico and the U.S. (5,6); however,the groups we studied were especiallymotivated subjects interested in obtainingbetter metabolic control through diabeteseducation groups. On the other hand, thepopulation from this study, which has alow socioeconomic status, usually con-fronts major environmental or economicbarriers that prevent access to safe recre-

ational areas or fitness facilities. Thus,even with economic constraints and inad-equate environmental access to physicalactivity, promoting physical activity in aculturally based intervention is a worth-while strategy that should be supported.

Although further studies in large popula-tions are still required to evaluate the ef-fectiveness at a larger scale, at the primarycare level of Mexican institutions, stron-ger emphasis should be placed on pro-moting physical activity.

MONTSERRAT BACARD-GASCON, MD

PERLA ROSALES-GARAY, MDARTURO JIMENEZ-CRUZ, MD, PHD

From the Nutrition Program, Medical School, Uni-versidad Autonoma de Baja California, Tijuana,Mexico.

Address correspondence to Montserrat Bacard-Gascon, MD, Universidad Autonoma de Baja Cali-fornia, Medical School, Nutrition, Av. Tecnologico14418, Mesa de Otay, Baja California, Tijuana22390, Mexico. E-mail: [email protected].


References

1. US Department of Agriculture/Depart-ment of Health and Human Services:Home and garden bulletin no. 232. In2000 Dietary Guidelines for Americans. 5thed. Washington, DC, U.S. Department ofAgriculture, 2000

2. Secretaria de Salud: Norma Oficial Mexi-cana Para la Prevencion, Tratamiento yControl de la Diabetes Mellitus en la Aten-cion Primaria a la Salud. Mexico, DF,Mex-ico, Secretaria de Salud, 2000 (NOM-015-SSA2-1994)

3. Jimenez-Cruz A, Bacard-Gascon M, Ro-sales-Garay P, Herrera-Espinoza J, Willis

OW: A culturally sensitive tool for Mexi-can people with diabetes: La Manzana dela Salud. Rev Biomed 14:5159, 2003

4. Clark DO: Physical activity efficacy andeffectiveness among older adults and mi-norities. Diabetes Care 20:11761182

5. Aguilar-Salinas CA, Velazquez-Monroy

O, Gomez-Perez FJ, Gonzalez-Chavez A,Esqueda AL, Molina-Cuevas V, Rull-Rodrigo JA, Tapia Conyer R, the EncuestaNacional de Salud 2000 Group: Charac-teristics of patients with type 2 diabetes inMexico: results from a large population-based nationwide survey. Diabetes Care26:20212026, 2003

6. Nelson KM, Reiber G, Boyko EJ: Diet andexercise among adults with type 2 diabe-tes. Diabetes Care 25:17221728, 2002

Alternative SiteTesting at theEarlobe Tip

Reliability of glucose measurementsand pain perception

There is growing interest in alterna-tive less painful sites for capillaryblood glucose (CBG) monitoring.

The earlobe tip is a potential site (1) that

has been occasionally used by nurseswhen fingertip testing is refused or diffi-cult. We investigated the clinical valueand accuracy of earlobe CBG measure-ments as an alternative to fingertip andforearm testing.

A total of 50 patients with type 2 di-abetes (aged 42 82 years, 28% with neu-ropathy) were enrolled in the study. Theduration of diabetes was 9.5 8.3 years(means SD). Testing sites (lateral aspectof the fingertip, earlobe tip, and flexorsurface of the forearm) were rubbed and

cleaned before lancing was performed bya physician using Lifescan Unistick-2 lan-cets (Lifescan, Milpitas, CA). The forearmwas lanced using the Microlet-Vaculancedevice (Bayer, Tarrytown, NY). The orderof site testing was randomized. Pain wasimmediately assessed after the first at-tempt using a 100-mm graphic visualscale (2). CBG was measured with an

Accu-Check Advantage glucose meter(Roche, Indianapolis, IN).

First-attempt sampling success rateswere 88% (fingertip), 74% (earlobe), and

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62% (forearm). After earlobe pricking,bleeding lasted for 60 s in all subjects(30 s in 90%). Earlobe pain (medianscore 5.5 mm) was less uncomfortablethan fingertip pain (17 mm, P 0.01,

Wilcoxon test) but not statistically differ-entfrom forearm (8.0 mm). Although ear-lobe pain was more tolerable, a limitationin this study is that it did not evaluate painperception after repeated testing on mul-tiple days, when skin soreness might be-come relevant.

CBG measurements from the earlobedeviated from the fingertip by 9.5 1.0%(mean SE). The correlation coefficientbetween these two sites was 0.97 (P 0.01). Of earlobe measurements, 97.8%were within clinically acceptable zones

AB by error grid analysis (3). When ear-lobe was compared with forearm, CBG

deviation was 10 1.4%, correlation co-efficient 0.96 (P 0.01), and 95.3% ofmeasurements were within zones AB byerror grid analysis.

In contrast to other sites that requirevacuum-assisted lancing devices or so-phisticated glucose meters, our observa-tions demonstrate that CBGmonitoring atthe earlobes is attainable with regularstandard lancets and that earlobe CBGconcentrations correlate well and deviateminimally from either fingertip or fore-arm values. Earlobe testing was also clin-

ically accurate by the error grid analysismethod, which takes into account the ef-fects on the clinical decision that wouldhave been made if the CBG had been mea-sured in the reference site. These datasupport the notion that earlobe CBG con-centrations can be used in substitution offingertip values. However, one limitationin our data series is that glucose values70 mg/dl were not observed. Therefore,earlobe testing should be avoided if hypo-glycemia is suspected.

For many patients, the earlobe prick-ing technique may be less convenient be-cause it requires a second person to lancethe skin and collect the blood. This cer-tainly limits the applicability of the tech-n i q u e i n t h e o u t p a t i e n t s e t t i n g .Nevertheless, earlobe testing seems to bea useful alternative that could minimizecosts and discomfort in patients assistedby a relative or nurse in hospitals andnursing homes.

FREDERICO G.S. TOLEDO, MD1,2

ANDREW TAYLOR, MD2

From the 1Department of Medicine, Division of En-docrinology and Metabolism, University of Pitts-burgh Medical Center, Pittsburgh, Pennsylvania;and the 2Department of Internal Medicine, Divisionof Endocrinology and Metabolism, University of Mi-amiSchoolof Medicine andMiamiVA Medical Cen-ter, Miami, Florida.

Address correspondence to Frederico G.S. To-

ledo, MD, University of Pittsburgh Medical Center,Department of Medicine, Division of Endocrinologyand Metabolism, E1140 Biomedical Science Tower,200 Lothrop St., Pittsburgh, PA 15261. E-mail:[email protected].


References1. Carley SD, Libetta C, Flavin B, Butler J,

Tong N, Sammy I: An open trial to reducethe pain of blood glucose testing: ear ver-sus thumb. BMJ321:20, 2000

2. Huskisson EC: Measurement of pain.Lan-cet 9:11271131, 1974

3. Clarke WL, Cox D, Gonder-Frederick LA,Carter W, Pohl SL: Evaluating clinical ac-curacy of systems for self-monitoring ofblood glucose. Diabetes Care 10:622628,1987

Needle Reuse andTip Damage

Questions about needle reuse areraised in recommendations by the

American Diabetes Association (1)and by practitioners and manufacturingcompanies (2). As an initial approach toexamining these questions, we investi-gated whether multiple insertions of nee-dles through the rubber stoppers oninsulin vials would cause damage to nee-dle tips (3). New needles were selected,attached to a precision manipulator, andinserted into insulin vials attached to atransducer that measured the force neces-sary to insert and remove a needle

through the stopper. If needles were dam-aged by multiple insertions, an increase inforce required to penetrate the rubberstopper would be expected.

In five experiments, we found thatthere was no significant difference in themean force required to penetrate the rub-ber stopper of an insulin vial between 17initial (41.5 g) and 17 subsequent (42.0 g)insertions. This suggests that needle tipsare not dulled or damaged by multipleinsertions to a degree that more forcewould be required to penetrate a vial

stopper. Light micrographs and scanningelectron micrographs supported the con-clusion that little or no damage to needletips occurred as a result of multiple inser-tions. We observed no hooks, bending, orother needle tip damage, although therewas some evidence for deterioration of thesilicon lubricant coating of needles.

At the same time, our examination ofnew, unused needles revealed imperfec-tions when observed at high magnifica-tion. Our observations make it clear thatdamage attributed to reuse must be dis-tinguished from inherent imperfectionsassociated with the manufacturingprocess.

Clinical and manufacturer recom-mendations that discourage reuse of nee-dle s be c a use of a ssume d dul l ing,bending, and/or fragmenting of needle

tips are at variance with our findings, inwhich repeated penetration of insulin vialstoppers did not damage needle tips (2).

Although we found no evidence of needledamage when penetrating the rubberstopper on insulin vials, there is need toascertain the effect of cutaneous tissuepenetration on needle tips. The reuse ofneedles by a significant number of pa-tients with diabetes as a matter of conve-nience, or out of concern for cost and/orthe creation of nonbiodegradable waste,indicates that further examination of nee-dle reuse in vial stoppers and cutaneoustissue is warranted.

DOUGLAS KLINE, PHD1

TERRY KUHN, PHD2

From the 1Department of Biological Sciences, KentState University, Kent, Ohio; and the 2Division ofUndergraduate Studies, Kent State University, Kent,Ohio.

Address correspondenc e to Terry Kuhn, KentState University,Division of Undergraduate Studies,P.O. Box 5190, Kent, OH 44242-0001. E-mail:[email protected].


References1. American Diabetes Association: American

Diabetes Association Complete Guide to Di-abetes. 3rd ed. American Diabetes Associ-ation, Alexandria, VA, 2002, p. 106, 480

2. Effect of multiple insulin vial insertions onneedle tips [article online], 2003. Availablefrom http://www.diabetesneedlereuse.org.Accessed 8 December 2003

3. The Editors: Questions and answers (Let-ter). Diabetes Self Manag 17:9495, 2000

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The DiabetesTreatmentSatisfactionQuestionnaire

A cross-cultural South Africanperspective

Reliable and valid multicultural in-struments are important in multi-cultural societies that are typical of

modern cities, and clinicians, using psy-chosocial assessments, need to ensurethat their diagnostic and screening toolsare appropriate. This study was con-ducted with 176 diabetic outpatientsfrom two culturally distinct groups (95

Bantu-speaking and 81 Afrikaans-speaking subjects) to 1) ascertain the un-de rlying dime nsions of t re a t me ntsatisfaction as measured by the DiabetesTreatment Satisfaction Questionnaire(DTSQ status) (1), 2) determine the reli-ability (internal consistency) of the mea-sures, and 3) investigate the effects ofobjective (HbA

1cresults) and subjective

metabolic control, health (2), and well-being (3) on satisfaction with diabetestreatment.

Principal components analysis wasconducted on the 8-item DTSQ (1). All

communality estimates exceeded the cri-terion of 0.30 (4) for both Bantu-speakingand Afrikaans-speaking patients (range0.62 0.79 and 0.55 0.76, respectively).Two factors explained 71% of the vari-ance for Bantu-speaking patients and68% of the variance for Afrikaans-speaking patients. The first factor con-sisted of the six treatment satisfactionitems, and the second factor consisted ofthe two subjective metabolic controlitems. Reliability (internal consistency)coefficients were excellent (5) and very

similar for both groups (0.80 on allmeasures).Treatment satisfaction was associated

with fewer incidents of hyperglycemia(r 0.58, P 0.01) and hypoglycemia(r 0.32, P 0.01), higher generalwell-being (r 0.56, P 0.01), and bet-ter health (r 0.44, P 0.01) for Bantu-spe a king pa t ie nt s. For Afr ika a ns-speaking patients, greater treatmentsatisfaction was associated with fewer in-cidents of hyperglycemia (r 0.29, P 0.01), higher general well-being (r

0.54, P 0.01), and better health (r 0.50, P 0.01). Language, sex, age, andemployment status were not related totreatment satisfaction or general well-being (P 0.05), confirming the con-struct validity of the measures. HbA

1c

results were not significantly related totreatment satisfaction, subjective meta-bolic control, general well-being, or gen-eral health for either group (P 0.05).

For Bantu-speaking patients, fewerincidents of hyperglycemia significantlypredicted 33% of the variance (P 0.001) in treatment satisfaction; an addi-tional 11% of the variance (P 0.001)was explained by general well-being. For

Afrikaans-speaking patients, generalwell-being predicted 29% of the variance(P 0.001) in treatment satisfaction; an

additional 7% of the variance (P

0.001)was explained by general health.In conclusion, the study demon-

strated that the underlying dimensions ofthe DTSQ for both groups were treatmentsatisfaction and hyper- and hypoglyce-mia, all measures had excellent reliability(5), and well-being is an important pre-dictor of treatment satisfaction for bothgroups of patients. These findings wereconsistent with those reported in the U.K.and Sweden (6 7) and support the ideathat the DTSQ can be used in multicul-

tural settings.

Acknowledgments We thank Novo Nor-disk (South Africa) for funding the interview-ers salaries. We also thank Professor ClareBradley for permission to use her measuresand Rosalind Plowright for constructive com-ments on the application of the DTSQ in mul-ticultural settings.

MARGARET SANDRA WESTAWAY, PHD1,2

JOHN R. SEAGER, PHD1,3

From the 1South Africa Medical Research Council,Health and Development Research Group, Pretoria,Gauteng, South Africa; the 2School of Health Sys-tems and Public Health, University of Pretoria, Pre-toria, Gauteng, South Africa, and the 3Faculty ofCommunity and Health Sciences, University of the

Western Cape, Cape Town, Western Cape, SouthAfrica.

Address correspondence to Prof. Margaret San-dra Westaway, SA Medical Research Council, Healthand Development Department, Private Bag X385,Pretoria, Gauteng, 0001 South Africa. E-mail:[email protected].


References1. Bradley C: Diabetes treatment satisfaction

questionnaire. In Handbook of Psychologyand Diabetes: A Guide to Psychological Mea-surement in Diabetes Research and Practice.Bradley C, Ed. Chur, Switzerland, Har-

wood Academic, 1994, p. 1111322. Stewart AL, Hays RD, Ware JE: The MOSShort-Form General Health Survey: reli-ability and validity in a patient popula-tion. Med Care 26:724 735, 1988

3. Bradley C: The well-being questionnaire.In Handbook of Psychology and Diabetes: AGuide to Psychological Measurement in Dia-betes Research and Practice. Bradley C, Ed.Chur, Switzerland, Harwood Academic,1994, p. 89 109

4. Child D: The Essentials of Factor Analysis.London, Holt, Rinehart & Winston,1970, p. 3334

5. Arias E, de Vos S: Using housing items to

indicate socio-economic status: LatinAmerica. Soc Indic Res 38:53 80, 19966. Petterson T, Young B, Lee P, Newton P,

Hollis S, Dornan T: Well-being and treat-ment satisfaction in older people with di-abetes. Diabetes Care 21:930 935, 1998

7. Wredling R, Stalhammar J, Adamson U,Berne C, Larsson Y, Ostman J: Well-beingand treatment satisfaction in adults withdiabetes: a Swedish population-basedstudy. QualLife Res 4:515522, 1995

Depression,Diabetes, andGlycemic Control inPima Indians

Few studies have addressed the rela-tionship of depression and diabetesin ethnic minority groups, especially

Native Americans (1). We examined therelationship between depression and dia-betes in a community-based sample of

541 Pima Indians aged 18 years (192with and 349 without diabetes) examinedfrom September 2002 through February2003.

Depression was defined by five ormore depressive symptoms lasting 2weeks, as assessed with PRIME-MD(Mood Module in the Primary Care Eval-uation of Mental Disorders) (2). Diabeteswas defined by a glucose tolerance test(fasting plasma glucose 7.0 mmol/l or2-h plasma glucose 11.1 mmol/l) orprevious clinical diagnosis.

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The prevalence of depression was16.3% (18.7% in women and 12.6% inmen, P 0.06). In both sexes, the prev-alence of depression was higher in dia-betic individuals (men 17.2 vs. 10.9%,women 20.2 vs. 17.6%), although thesedifferences were not statistically signifi-cant (for total sample: age- and sex-adjusted odds ratio 1.3 [95% CI 0.72.1]). In diabetic individuals, HbA

1cwas

higher by 1.2% in those with depression(9.3 vs. 8.1%, P 0.01), although de-pression was not related to HbA

1cin non-

diabetic individuals (5.2 vs. 5.3%, P 0.2). This association remained signifi-cant in a multivariate linear regressionmodel that included age, sex, duration ofdiabetes, and BMI (HbA

1chigher by 1.1%

in depressed persons, P 0.01). Fastingplasma glucose was also higher, but not

significantly so, in depressed diabetic in-dividuals (10.2 vs. 9.5 mmol/l, P 0.3).Although studies of depression in Na-

tive-American communities are limited,our findings are consistent with previoussuggestions that depression is severaltimes more prevalent among Native

Americans than in the general U.S. popu-lation (3). Our finding that the prevalenceof depression was somewhat higher in di-abetic individuals is also consistent withprevious studies (1,4 6). Ourstudy lacksprecision to estimate the association ofdepression with diabetes because of therelatively small sample size (541, as com-pared with 21,513 to 1.3 million in otherrecent reports [4 6]). The high preva-lence of depression in our study suggeststhat certain social, cultural, or economicfactors may overshadow the influence ofdiabetes on depression in this population.

The higher HbA1c

in depressed dia-betic individuals is consistent with previ-ous findings in other populations (7).Treatment of depression reportedly im-proves glycemic control in diabetic pa-tients, although the long-term effects are

not known (8,9). This study adds to thesparse literature on depression and diabe-tes in ethnic minority groups. Identifica-tion and treatment of depression may bean important aspect of treating diabetes inNative Americans.

PUNEET K. SINGH, BAHELEN C. LOOKER, MBBS

ROBERT L. HANSON, MD, MPHJONATHAN KRAKOFF, MD

PETER H. BENNETT, MB, FRCPWILLIAM C. KNOWLER, MD, DRPH

From the National Institute of Diabetes and Diges-tive and Kidney Diseases, National Institutes ofHealth, Phoenix, Arizona.

Address correspondence to Helen C. Looker, Na-tional Institutes of Health, 1550 E. Indian SchoolRd., Phoenix, AZ 85014. E-mail: [email protected].


Acknowledgments We thank Dr. RichardRubin, Dr. Patrick Lustman, and Dr. Maryde Groot for advice; Dr. Diane Montella andPriscilla Foote, MSW, of Gila River HealthCare; andthe members of theGila River IndianCommunity for their participation.

References1. Anderson RJ, Freedland KE, Clouse RE,

Lustman PJ: The prevalence of comorbiddepression in adults with diabetes: a

meta-analysis. Diabetes Care 24:10691078, 20012. Spitzer RL, Williams JB, Kroenke K, Lin-

zer M, deGruy FV III, Hahn SR, Brody D,Johnson JG: Utility of a new procedure fordiagnosing mental disorders in primarycare: the PRIME-MD 1000 study. JAMA272:1749 1756, 1994

3. US Department of Health and HumanServices: Mental health. A supplement toMentalHealth: A Report of the Surgeon Gen-eral: Culture, Race, and Ethnicity. Rock-ville, MD, U.S. Department of Health andHuman Services, 2001

4. Egede LE, Zheng D, Simpson K: Comor-

bid depression is associated with in-creased health care use and expendituresin individuals with diabetes. Diabetes Care25:464 470, 2002

5. Nichols GA, Brown JB: Unadjusted andadjusted prevalence of diagnosed depres-sion in type 2 diabetes. Diabetes Care 26:744749, 2003

6. Finkelstein EA, Bray JW, Chen H, LarsonMJ, Miller K, Tompkins C, Keme A,Manderscheid R: Prevalence and costs ofmajor depression among elderly claim-ants with diabetes. Diabetes Care 26:415420, 2003

7. Lustman PJ, Anderson RJ, Freedland KE,

de Groot M, Carney RM, Clouse RE: De-pression and poor glycemic control: ameta-analytic review of the literature. Di-abetes Care 23:934 942, 2000

8. Lustman PJ, Freedland KE, Griffith LS,Clouse RE: Fluoxetine for depressionin diabetes: a randomized double-blindplacebo-controlled trial. Diabetes Care 23:618 623, 2000

9. Lustman PJ, Griffith LS, Freedland KE,Kissel SS, Clouse RE: Cognitive behaviortherapy for depression in type 2 diabetesmellitus: a randomized, controlled trial.Ann Intern Med 129:613 621, 1998

Improper InsulinCompliance MayLead toHepatomegaly andElevated Hepatic

Enzymes in Type 1Diabetic Patients

We have encountered hepatomeg-aly and pronounced elevation ofliver enzymes AST and ALT in

four patients with type 1 diabetes. Thesepatients shared similar clinical features.They were all female (aged 1114 years)with poor glycemic control. All had fre-quent hyperglycemia and intermittenthypoglycemia related to their history of

poor compliance. Most of them had mul-tiple hospital admissions for severe hy-perglycemia and/or diabetic ketoacidosis.In addition to their high daily doses ofinsulin (1.32.2 units kg1 day1),most were receiving extra doses of insulinto correct their frequent hyperglycemia.

A1C levels were all higher than normal(ranging from 9.2 to 14.5%). Their initial

AST and ALT levels were at least 30- and14-fold higher than the normal limits, re-spectively, but the other liver functiontests, such as alkaline phosphatase, pro-

thrombin/partial prothrombintime, andtotal bilirubin, were normal except foronepatient who hada minimal increase inalkaline phosphatase and total billirubin.The degree of hepatomegaly did not cor-relatewith theliver enzyme levels, nor didit correlate with glycemic control orHbA

1clevels.

Upon admission to the hospital,proper insulin dosing was established.Three of the four patients were able tolower their insulin dose to 0.9 1.2 units kg1 day1 and achieve normal glyce-

mic control. The AST and ALT levels werequickly decreased in just a few days afterthe patients obtained better glycemic con-trol during hospitalization. Except for onepatient, who was admitted for diabetic ke-toacidosis, the patients had no apparentsymptoms of liver disease before the admis-sion. Their hepatomegaly was an inciden-tal finding. Other than poorly controlleddiabetes, the investigations did not revealany other causes for hepatomegaly andincreased liver enzymes. The normal cre-atine phosphokinase level and negative

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myoglobinuria from one patient ruled outthe possibility of rhabdomyolysis. Theliver biopsy obtained in one patient re-vealed abundant glycogen deposits inhepatocytes that were consistent with theabdominal computed tomography find-ing offatty appearance of those enlargedlivers in all four patients. There were alsosome features that these patients did notshare. One patient with the most pro-found hepatomegaly had significant delayin growth and puberty consistent withMauriac syndrome as previously de-scribed (1), whereas the other three pa-tients had normal growth and puberty.One patient, who was found to have hep-atomegaly and elevated hepatic enzymesduring one of her admissions to the hos-pital for diabetic ketoacidosis, had somenonspecific gastrointestinal symptoms

that might have been related to her dia-betic ketoacidosis rather than the hepaticdisorder. Although all of our cases weregirls, similar cases have been identified inboys (2).

Hepatomegaly and elevated hepaticenzymes, reported in both adult and pe-diatric patients with type 1 diabetes (2,3),could be relatively common but may beunder-recognized or misidentified as themore common nonalcoholic steatohepa-titis (NASH) because of similar clinicalfeatures. NASH is commonly seen inobese type 2 diabetic patients with insulinresistance. The hepatic enzyme elevationis slow to resolve. Our patients, however,were all nonobese type 1 diabetic pa-tients. Their pronounced elevation of he-patic enzymes was resolved in just a fewdays once they achieved reasonable glyce-mic control at insulin dosages that werelower than what they were prescribed athome. Though the mild hepatomegalyand abnormal liver enzymes were be-lieved to be associated with liver steaticchange in NASH, whether the pro-nounced elevation of the liver enzymes

was directly caused by liver glycogen de-posit is not known. The pathogenesis forthese problems has not been well studied.Nevertheless, both the increased hepaticenzymes and glycogen deposits may berelated to poor glycemic control. Most ofour patients received relatively high dosesof insulin at home. We question the pos-sible role of insulin over-treatment thatmight contribute to the pathogenesis ofhepatomegaly because insulin is clearly apromoting agent for glycogenesis. Similarcases of hepatomegaly and elevated

hepatic enzymes have been reportedin children and adolescents who werechronically over-treated with insulin(4,5).

We therefore advocate the high vigi-lance in promoting patient compliance toinsulin dosing rather than simply increas-ing insulin dosage in response to hyper-glycemia. The swift reduction of hepaticenzymes in our cases after achieving rea-sonable glycemic control suggests thatliver biopsy and other extensive work-upmay be unnecessary in managing similarpatients.

Y. MILES YU, MDCAMPBELL P. HOWARD, MD

From the Section of Endocrinology, Children sMercy Hospital, University of Missouri at KansasCity School of Medicine, Kansas City, Missouri.

Address correspondence to Miles Yu, Section ofEndocrinology, Childrens Mercy Hospital, 2401Gillham Rd., Kansas City, MO 64108. E-mail:[email protected].


References1. Lee RGG, Bode HH: Stunted growth and

hepatomegaly in diabetes mellitus. J Peds91:82 84, 1977

2. Chatila R, West AB: Hepatomagely andabnormal liver tests due to glycogenesisinadults with diabetes. Medicine 75:327333, 1996

3. Olssen R, Wesslau C, William-Olsen T,Zettergren L: Elevated aminotransferasesand alkaline phosphatases in unstable di-abetes mellitus without ketoacidosis orhypoglycemia. J Clin Gastroenterol 11:541545, 1989

4. Asherov J, Mimouni M, Varsano I, LubinE, Laron Z: Hepatomegaly due to self-in-duced hyperinsulinism.Arch Dis Child 54:148149, 1979

5. Rosenbloom AL, Giordano BP: Chronicovertreatment with insulin in childrenand adolescents. Am J Dis Child 131:881885, 1977

Acute Hyperglycemia

Implications for contrast-inducednephropathy during cardiaccatheterization

Acute hyperglycemia exacerbatesischemic injury of the brain andheart (1,2). Renal contrast agents

are nephrotoxic, largely due to acute isch-

emia secondary to renal artery vasocon-striction (3). Historically, diabeticpatients have been identified as a high-risk group for the development of con-trast-induced nephropathy followingcardiac catheterization; however, themechanism for this increased risk is un-clear (4). The purpose of this study was todetermine whether acute hyperglycemiais an independent risk factor for the de-velopment of contrast-induced nephrop-a t hy a ft e r c a rdia c c a t he t e riz a t ionprocedures.

A prospective, observational studywas performed on all patients with diabe-tes (insulin dependent and independent)or any patient with a baseline serum cre-atinine 1.2 mg/dl receiving a cardiaccatheterization procedures in a universi-ty-affiliated cardiac catheterization facil-

ity between June 2001 and January 2002.Patients with a diagnosis of acute renalfailure or patients on dialysis were ex-cluded. Patients were divided into twogroups, hyperglycemic (AHG) (serumglucose 150 mg/dl) and nonhypergly-cemic (NHG) (serum glucose 150 mg/dl), at the time of cardiac catheterizationprocedures. Contrast-induced nephropa-thy was defined as an increase in serumcreatinine 0.3 mg/dl or 25% abovethe patients baseline, determined 35days following cardiac catheterizationprocedures.

The mean age, baseline creatinine,presence or absence of diabetes, hydra-tion status, type and dose of contrastagent received, and use of specific medi-cations, including acetylcysteine, werenot different between groups. The per-centage of inpatients was greater in the

AHG group (74%) than in the NHG(26%), P 0.049. Ventricular function,as measured by left ventricular end-diastolic pressure, was the same betweengroups (AHG 17 10 mmHg vs.NHG 13 3 mmHg, P 0.21), and

left ventricular ejection fraction was sig-ni ficantly lower in the AHG group(AHG 45 13% vs. NHG 59 14%, P 0.023). A total of 38 patientswere studied, including 33 diabetic sub-

jects (87%). One-half of the study group(19 patients) was found to have hypergly-cemia at the time of their cardiac catheter-ization procedure. Mean serum glucosewas 217 78 mg/dl for the AHG groupvs. 124 15 mg/dl for the NHG group,P 0.001. The incidence of contrast-induced nephropathy for the entire study

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population was 24% (9 of 38). The inci-dence of contrast-induced nephropathyin the AHG group was 42% (8 of 19) andwas significantly greater than that for theNHG group, 5.3% (1 of 19), P 0.01.

Acute hyperglycemia is a potential in-dependent risk factor for the develop-ment of contrast-induced nephropathy indiabetic patients undergoing cardiaccatheterization procedures. The glucosemolecule has been shown to be a potentialcytotoxin in the context of hyperglycemia(5). Acute hyperglycemia in patients withor without diabetes can detract from clin-ical outcomes in cardiovascular disease(1). The mechanism by which acute hy-perglycemia worsens ischemic myocar-dial injury is currently under study.Conceivably, hyperglycemia may exacer-bate acute renal ischemia associated with

administration of radiographic contrastagents. The observational design of thisstudy limits the relationship betweenacute hyperglycemia and contrast-induced nephropathy to that of a tempo-ral association and does not addresscausality. Confounding variables, such asthe slightly worse left ventricular ejectionfraction in the AHG group, may have con-tributed to the development of contrast-induced nephropathy; however, thehyperglycemia in the AHG group mayhave contributed to poorer ventricularfunction. The relationship between acutehyperglycemia and contrast-induced ne-phropathy reported here will require arandomized controlled clinical trial fordefinitive characterization. This reportsuggests that a temporal association existsbetween acute hyperglycemia and con-trast-induced nephropathy at the time ofcardiac catheterization procedures in dia-betic patients with mild renal dysfunc-tion, and this topic bears further study.

DIANE B. TURCOT, MD1

FRANCIS J. KIERNAN, MD, FACC1

RAYMOND G. MCKAY, MD, FACC1

NEIL J. GREY, MD, FACP2

WILLIAM BODEN, MD, FACC1

GEORGE A. PERDRIZET, MD, PHD, FACS3

From the 1Division of Cardiology, Hartford Hospi-tal, University of Connecticut School of Medicine,Hartford, Connecticut; the 2Division of Endocrinol-ogy, Hartford Hospital, University of ConnecticutSchool of Medicine, Hartford, Connecticut; and the3Division of Trauma, Hartford Hospital, Universityof Connecticut School of Medicine, Hartford, Con-necticut.

Address correspondence to George A. Perdrizet,MD, PhD, FACS, Hartford Hospital, Division of

EMS/Trauma, 80 Seymour St., P.O. Box 5037, Hart-f o r d , C T 0 6 1 0 2 - 5 0 3 7 . E - m a i l : g p e r d r i @harthosp.org.


References

1. Malmberg K, for the DIGAMI (DiabetesMellitus, Insulin Glucose Infusion inAcute Myocardial Infarction) StudyGroup: Prospective randomized study ofintensive insulin treatment on long-termsurvival after acute myocardial infarctionin patients with diabetes mellitus. BMJ314:15121515, 1997

2. Weir CJ, Murray GD, Dyker AG, Lees KR:Is hyperglycemia a predictor of poor out-come after acute stroke? BMJ 314:13031306, 1997

3. Brezis M, Rosen S: Hypoxia of the renalmedulla: its implication for disease.N Engl J Med 332:647 655, 1995

4. Parfrey PS, Griffiths SM, Barrett BJ, PaulMD, Genge M, Withers J, Farid N, Mc-Manamon PJ: Contrast material-inducedrenal failure in patients with diabetes mel-litus, renal insufficiency, or both: a pro-spective controlled study. N Engl J Med320:143149, 1989

5. Porte D Jr, Schwartz MW: Diabetes com-plications: why is glucose potentiallytoxic? Science 272:699700, 1996

Influence of thePolymorphisms

Tpr64Arg in the 3-Adrenergic ReceptorGene and Pro12Alain the PPAR2 Geneon MetabolicSyndromeRelatedPhenotypes in anIndigenousPopulation of theBrazilian Amazon

Metabolic syndrome is a cluster ofrisk factors for type 2 diabetes andcardiovascular disease. Multiple

mechanisms, including genetic factors,may contribute to this condition. TheTrp64Arg variant in the 3-adrenergic re-ceptor has been associated with featuresof the metabolic syndrome (1). A rela-tively common gene variant, Pro12Ala ofthe peroxisome proliferatoractivated re-ceptor-2 (PPAR2) has been previously

studied for association with obesity andtype 2 diabetes (2,3).

The Parkataje Indians, from the Bra-zilian Amazon region, remained largelyisolated. Recently, they underwent arapid and intensive process of accultura-tion, with important changes in their life-style. Accompanying these changes, anincreasing prevalence of obesity and otherfeatures of the metabolic syndrome havebeen observed. This study examines therelevanceof theTrp64Arg mutation in the3-adrenergic receptor gene and thePro12Ala mutation in the PPAR2 geneasa susceptibility factor to features of themetabolic syndrome in this population.

Participants were individuals aged20 years; those with admixture andpregnant women were excluded. Thestudy population comprised 85 (52 men

and 33 women) individuals (mean age41 14.9 years). The degree of related-ness among the individuals was deter-mined, and 37 nuclear families from sixpedigrees were verified. Polygamy, in-cluding polyandry, occurs in this popula-tion. BMI, waist-to-hip ratio, systolic anddiastolic blood pressures, and serum li-poproteins were studied. Fasting and 2-hblood samples were drawn for glucoseand insulin measurements. Changes inbody weight were analyzed in 80 individ-uals for a 3-year period. Genotypes weredetermined by PCR/restriction fragmentlength polymorphism, as previously de-scribed (1,2).

A principal component analyses fromthe correlation matrix of the variablesmeasured was performed. Statistical anal-yses (ANOVA and family-based associa-tion test) were done with the first twoprincipal components because the mea-sured variables are all related to the met-a b o l i c s y n d r o m e . T h e p r i n c i p a lcomponent, therefore, reflects the vari-ance common to these variables andavoids corrections for multiple indepen-

dent tests.Obesity rates were higher in women

than in men (27.2 vs. 3.8% at baseline,P 0.006 and 45.2 vs. 16.3% at 3-yearfollow-up, P 0.01), and for both sexes,there was an increase in these rates duringthe follow-up period (12.94 vs. 27.5%,P 0.03). Diabetes was diagnosed in oneindividual, impaired glucose tolerance inanother, and the remaining were classi-fied as normal glucose tolerant accordingto World Health Organization criteria.

Frequencies of the 3-adrenergic re-

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ceptor Arg and the PPAR2 Ala variantswere 0.33 and 0.31, respectively. Thesefrequencies are in the Hardy-Weinbergequilibrium. The 3-adrenergic receptor

Arg allele frequency (0.33) is much higherthan those reported in other populations,except for Pima Indians (4). Similarly, thePPAR2 Ala allele was more prevalent inthe Parkateje Indians than in the otherpopulations, whose frequency rangesfrom 0.12 among Caucasians to 0.01 inChinese (5). ANOVA (with Welchs cor-rection) showed that the first principalcomponent was heterogeneous amongthe genotypic classes of the PPAR2 lo-cus; the AlaAla genotype was differentfrom the others (F 3.51, P 0.035).The 3-adrenergic receptor locus showedno differences among the genotypes. TheFBAT analyses showed that the PPAR2

locus presented a significant segregationdistortion with the recessive model (P 0.032) but not with the additive or dom-inant models.

Among the Parkateje Indians, thePro12Ala variant in the PPAR2 gene, butnot the Trp64Arg variant in the 3-adrenergic receptor, was associated withfeatures of the metabolic syndrome.

JOAO PAULO B. VIEIRA-FILHO, MD, PHD1

ANDRE F. REIS, MD, PHD1

TERESA S. KASAMATSU, BSC1

EDELWEISS F. TAVARES, MD, PHD1

LAERCIO J. FRANCO, MD, PHD2

SERGIO R. MATIOLI, PHD3

REGINA S. MOISES, MD, PHD1

From the 1Division of Endocrinology, Departmentof Medicine, Federal University of Sao Paulo, SaoPaulo, Brazil; the 2Department of Social Medicine,Faculty of Medicine of Ribeirao Preto-University ofSao Paulo, Sao Paulo,Brazil; andthe 3DepartmentofBiology, University of Sao Paulo, Sao Paulo, Brazil.

Address correspondence to Regina S. Moises,MD, PhD, Universidade Federal de Sao Paulo, Es-cola Paulista de Medicina, Disciplina de Endocrino-logia, Rua Botucatu, 740-2o, andar, 04034-970 SaoP au lo , S P, B ra zi l. E -m ai l: r mo is es @

endocrino.epm.br. 2004 by the American Diabetes Association.

References1. Widen E, Lehto M, Kanninen T, Walston

J, Shuldiner AR, Groop LC: Association ofa polymorphism in the B3-adrenergic-re-ceptor gene with features of the insulinresistance syndrome in Finns. N EnglJ Med 333:348351, 1995

2. Ek J, Urhammer SA, Sorensen TIA,Andersen T, Auwerx J, Pedersen O: Ho-mozygosity of the Pro12Ala variant of the

peroxisome proliferation-activated recep-tor-2 (PPAR-2): divergent modulatingeffects on body mass index in obese andlean Caucasian men. Diabetologia 42:892895, 1999

3. Altshuler D, Hirschhorn JN, KlannermarkM, Lindgren CM, Vohl MC, Nemesh J,

Lane CR, Schaffner SF, Bolk S, Brewer C,Tuomi T, Gaudet D, Hudson TJ, Daly M,Groop L, Lander ES: The common PPARgamma Pro12Ala polymorphism is asso-ciated with decreased risk of type 2 dia-betes. Nat Genet 26:76 80, 2000

4. Walston J, Silver K, Bogardus C, KnowlerWC, Celli FS, Austin S, Manning B, Stros-berg AD, Stern MP, Raben N, Sorkin JD,Roth J, Shuldiner AR: Time of onset ofnon-insulin-dependent diabetes mellitusand genetic variation in the B3-adrener-gic-receptor gene. N Engl J Med 333:347347, 1995

5. Yen CJ, Beamer BA, Negri C, Silver K,

Brown KA, Yamall DP, Burns DK, Roth J,Shuldiner AR: Molecular scanning of thehuman peroxisome proliferator activatedreceptor gamma gene in diabetic Cauca-sians: identification of a Pro12Ala PPARgamma 2 missense mutation. Biochem Bio-phys Res Commun 241:270274, 1997

Elevated SerumFerritinConcentrations in aGlucose-ImpairedPopulation and inNormal GlucoseTolerant First-Degree Relatives inFamilial Type 2Diabetic Pedigrees

Two large epidemiological studieshave recently reported a strong as-sociation between elevated serum

ferritin concentration and increased riskfor diabetes (1,2). Moreover, other stud-ies have revealed the relationship amongexcess ferritin, coronary heart disease,and insulin resistance and have thereforerenewed interest in ferritin as a risk factorfor diabetes.

This study further investigates the as-sociation between ferritin metabolismand different status of glucose tolerance,including 121 type 2 diabetic subjects, 86impaired glucose tolerant (IGT) subjects,58 normal glucose tolerant (NGT) first-

degree relatives in type 2 diabetic pedi-grees, and 85 healthy control subjects. Allpatients underwent an oral glucose toler-ance test (OGTT) and insulin release testsafter 8 h of fasting, and blood levels offerritin, HbA

1c, glucose, insulin, C-

peptide, and lipids were measured. Se-rum ferritin levels were measured withthe radioimmunoassay kit (Beijing NorthInstitute of Biological Technology). Nor-mal ranges for ferritin concentration are12245 ng/ml for adult men and 5130 ng/ml for women. We defined ele-vated concentrations of ferritin as 295ng/ml for men and 155 ng/ml forwomen.

Levels of fasting and postprandialplasma glucose in the NGT group wereremarkably higher than in the healthycontrol subjects. Fasting insulin concen-

trations in the NGT group were alsohigher than those of the other groups,while postprandial insulin concentrationsincreased significantly when comparedwith healthy control subjects. Ferritinconcentrations were the highest in type 2diabetic subjects, followed by the IGTgroup, the NGT group, and the healthyc ontrol group (412.88 155.58,354.19 173.03, 231.31 130.32 [P 0.05 compared with healthy control sub-

jects], and 164.69 110.54 ng/ml, re-spectively). In the type 2 diabetic group,the newly diagnosed patients had higherferritin concentrationsthan previously di-agnosed (461.72 132.41 vs. 354.19 173.03 ng/ml, P 0.05).

We also compared concentrations ofserum ferritin in men andwomen for eachgroup. In general, concentrations of fer-ritin in men were higher than in women(P 0.05) except for in the healthy con-trol group. In male subjects, ferritin con-centrations of both newly and previouslydiagnosed type 2 diabetic, IGT, NGT, andhealthy control groups showed the sametrend as the whole group (494.30

142.6, 425.01 136.77, 390.07 125.09, 284.74 112.04 [P 0.001compared with the healthy control sub-

jects], and 197.93 110.41 ng/ml, re-spectively). However, in female subjects,f e r r i t i n c o n c e n t r a t i o n s i n n e w l y(425.65 137.5 ng/ml) and previously(295.37 150.98 ng/ml) diagnosed type2 diabetes and IGT (330.72 131.03 ng/ml) were higher than the NGT (174.06 123.45 ng/ml) and healthy contol(137.28 89.63 ng/ml) groups (P 0.001). No significant difference was

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found between female NGT and femalehealthy control subjects. Moreover, innewly diagnosed type 2 diabetes, the con-centrations of ferritin were significantlyhigher than in the previously diagnosedtype 2 diabetic and IGT patients.

Using multiple regression analysis,we found an association between ferritinconcentration and BMI, waist-to-hip ra-tio, systolic blood pressure, diastolicblood pressure. HbA

1c, FPG, 2-h plasma

postprandial glucose, triglycerides, andtotal cholesterol were positively related toferritin concentrations, while HDL cho-lesterol levels were inversely related toferritin concentrations.

In recent years, the issue of the poten-tial pathology of serum ferritin in type 2diabetes has gained remarkable interest(3). In this study, we found that serum

ferritin concentrations were remarkablyincreased in type 2 diabetes, especially innewly diagnosed patients. Subjects withhigher concentrations of ferritin conse-quently had higher HbA

1c, glucose, and

insulin concentrations. These results fur-ther proved a positive association be-tween type 2 diabetes and high plasmaferritin concentrations.

The exact mechanism through whichelevated ferritin promotes the develop-ment of type 2 diabetes is unknown.Some investigations argued that abnor-malities in ferritin metabolism might be aprimary cause of type 2 diabetes (4 6). Inour study, ferritin concentration in IGTsubjects, the high-risk populationfor type2 diabetes, already significantly increasedwhen compared with normal control sub-

jects, implying that hyperferritinemia oc-curs before elevation of plasma glucoseconcentrations. This observation was fur-ther substantiated by evidence that NGTfirst-degree relatives in the type 2 diabeticpedigrees had higher ferritin concentra-tions than normal control subjects.

YAN REN, MD, PHD1HAOMING TIAN, MD1

XIUJUN LI, MD1

JINZHONG LIANG, MD1

GUIZHI ZHAO,2

From the 1Division of Endocrinology, Departmentof Internal Medicine, West China Hospital, SichuanUniversity; and the 2Laboratory of Endocrinologyand Metabolism, WestChina Hospital, Sichuan Uni-versity, Chengdu, China.

Address correspondence to Haoming Tian, MD,Division of Endocrinology, Department of InternalMedicine, West China Hospital of Sichuan Univer-

sity, 37 Guoxue Lane, Chengdu, Sichuan China610041. E-mail: [email protected].


References1. Tuomainen TP, Nyyssonen K, Salonen R,

Tervahauta A, Korpela H, Lakka T,Kaplan GA, Salonen JT: Body iron storesare associated with serum insulin andblood glucose concentration: populationstudy in 1,013 eastern Finnish men. Dia-betes Care 20:426 428, 1997

2. Ford ES, Cogswell ME: Diabetes and serumferritin concentration among U.S. adults.Diabetes Care 22:1978 1983, 1999

3. Salonen JT, Tuomainen TP,Nyyssonen K,Lakka HM, Punnonen K: Relation be-tween iron stores and non-insulin depen-dent diabetes in men: case-control study(Abstract). BMJ317:727, 1998

4. Moczulski DK, Grzeszczak W, Gawlik B:Role of hemochromatosisC282YandH63Dmutations in HFE gene in development oftype 2 diabetes and diabetic nephropathy.Diabetes Care 24:11871191, 2001

5. Van Lerberghe S, Hermans MP, Dahan K,Buysschaert M: Clinical expression andinsulin sensitivity in type 2 diabetic pa-tients with heterozygous for haemochro-matosis. Diabetes Metab 28:3338, 2002

6. Salonen JT, Tuomainen TP, Kontula K:Role of C282Y mutation of in haemochro-matosis gene in development of type 2diabetes in healthy men: prospective co-hort study. BMJ24:17061707, 2000

SimultaneousBilateral Facial Palsyin a Diabetic Patient

Unilateral facial paralysis is a rela-tively common condition with anincidence of 20 25 per 100,000

population. However, simultaneous bilat-eral facial palsy (facial diplegia) is an ex-tremely rare clinical entity and occurs in0.32% of facial paralysis patients (1).

The annual incidence is approximately 1per 5 million (2).

A 78-year-old diabetic patient pre-sented to the emergency room of our hos-pit a l wit h dysa rt hry a nd bi la t e ra lsymmetrical facial weakness. He was un-able to show his teeth, close his eyelids, ordilate his cheeks. From the neurologic ex-amination, there were no other importantfindings, except for a minor instabilityduring walking. The patient did not referhead injury or febrile viral infection in therecent past. We made the presumptive di-

agnosis of bilateral peripheral facial paral-ysis. Five weeks after his admission to ourhospital, he made a full recovery. We haveto note that glucocorticoids were not ad-ministered to him.

His full blood count, erythrocyte sed-imentation rate, liver function tests, tu-mor markers, thyroid hormones, serumprotein immunoelectrophoresis, serum

ACE levels, C-reactive protein, and rapidprotein reagent (RPR) were all within nor-mal limits. HbA

1cwas 7.0%, and the au-

toantibody screen was negative. Purifiedprotein derivative was 5 mm. Serologicaltests for varied infectious agents, includ-ing herpes simplex virus (HSV)-I and -II,

Varicella-Zoster virus (VZV), Epstein-Barr, Coxsackie, HIV-I and -II, cytomeg-alovirus (CMV), and hepatitis B viruses,as well as Mycoplasma and Borrelia Burg-

dorferi, were all negative.Lumbar puncture revealed a normalpressure. Glucose, protein, and whiteblood count of the cerebrospinal fluid(CSF) were all within normal limits. Fur-thermore, stains and cultures for micro-organisms were negative, as were tests forviruses (HSV and HSV-II, VZV, amdCMV), Borrelia Burgdorferi, and syphilis(venereal disease reaction level [VDRL]test).

Magnetic resonance imaging (MRI) ofthe brain and computed tomography(CT) scans of the head, thorax, and abdo-men were all normal.

Facial diplegia may have diverse eti-ologies and may prove to be a diagnosticdilemma. The most common causes arebilateral Bells palsy, Lyme disease, Guil-lain-Barre syndrome, sarcoidosis, Moebi-ous syndrome, leukemia, viral infections,syphilis, basilar skull fractures, and pon-tine gliomas.

The most common infectious cause offacial diplegia is Lyme disease, caused byBorrelia Burgdorferi (3). Regarding thecase presented, the IgG antibodies against

this agent in serum, as well as in CSF, werenegative. Other rare infectious causes in-clude syphilis and Mycoplasma (4). How-ever, VDRL tests in CSF and RPR in serumwere negative, whileantibody titer againstMycoplasma was negative.

Guillan-Barre syndrome is thought tobe a postinfectious inflammatory polyra-diculoneuritis. Up to 50% of the fatalcases have bilateral facial paralysis (5).The diagnosis is made on lumbar punc-ture (with a typically elevated protein inthe absence of a raised number of cells)

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and peripheral areflexia. Our patient hadneither peripheral muscle weakness norareflexia, and the CSF examination wasnormal.

Basilar skull fractures and pontine gli-omas were excluded by means of bothbrain CT and MRI. Because there was nohilar adenopathy on chest CT and be-cause serum ACE levels were normal, sar-coidosis was rejected.

Bilateral Bells palsy does not seem tobe a plausible diagnosis because our pa-tient had neither a preceding viral infec-tion nor the characteristic symptoms ofthis condition (facial numbness or pain,change in taste, numbness of the tongue,hyperacusis, etc.).

Diabetes has previously been associ-ated with facial diplegia (4,6,7). Accord-ing to Adour, Wingerd, and Doty (7),

diabetes was present in 28.4% of 67 pa-tients with recurrent or bilateral facialpalsy. A plausible explanation could bethat diabetic patients are more prone tonerve degeneration. In another series of43 patients with bilateral seventh nervepalsy, there was one case associated withdiabetes (4). Thus, having excluded allthe other possible causes of this disorderafter extensive evaluation, we could as-sume that the most likely cause of facialdiplegia in the case presented is diabetes.

In conclusion, bilateral facial paraly-sis may be due to a life-threatening condi-tion and, therefore, the practitioner shouldbe aware of the diagnostic possibilitiesthat cause this extremely rare condition. Areview of the literature reveals that diabe-tes is associated with facial diplegia andshould always be included in the differ-ential diagnosis of this condition.

ALEXANDER KAMARATOS, MD, PHD1

STELIOS KOKKORIS, MD1

JOHN PROTOPSALTIS, MD, PHD1

DIMITRIOS AGORGIANITIS, MD2

HARIS KOUMPOULIS, MD2

JOHN LENTZAS, MD1

ANDREAS MELIDONIS, MD, PHD3

GREGORY GIANNOULIS, MD, PHD1

From the1SecondDepartment of Internal Medicine,Tzanio Hospital, Piraeus, Greece; the 2NeurologyDepartment, Tzanio Hospital, Piraeus, Greece; andthe 3Diabetologic Center, Tzanio Hospital, Piraeus,Greece.

Address correspondence to Alexander Kamara-tos, MD, PhD, Tzanio General Hospital of Piraeus,Second Department of Internal Medicine,Tzani and

Afe nto uli 1, Pir aeu s 185 36, Gre ece . E-m ail :[email protected].


References1. Stahl N, Ferit T: Recurrent bilateral pe-

ripheral facial palsy. J Laryngol Otol 103:117119, 1989

2. George MK, Pahor AL: A cause for bilat-eral facial palsy. Ear Nose Throat J 70:

4923, 19913. Clark JR, Carlson RD, Pachner AR: Facialparalysis in Lyme disease. Laryngoscope95:13411345, 1985

4. Keane JR: Bilateral seventh nerve palsy:analysis of 43 cases and review of the lit-erature. Neurology 44:11981202, 1994

5. Arias G, Nogues J, Manos M, Amilibia E,Dicenta M: Bilateral facial nerve palsy:four case reports. ORL J OtorhinolaryngolRelat Spec 60:227229, 1998

6. Hattori T, Schlagenhauff RE: Bilateral fa-cial palsy: occurrence with diabetes mel-litus. NYStateJMed 77:14921494, 1977

7. Adour K, Wingerd J, Doty HE: Prevalence

of concurrent diabetes mellitus and idio-pathic facial paralysis (Bells palsy). Dia-betes 24:449 451, 1975

Reduced Fear ofHypoglycemia inSuccessful IsletTransplantation

T

he recent dramatic improvement inclinical outcomes in islet transplan-tation in type1 diabetes withthe Ed-

monton Protocol has led to considerableexcitement in the field of diabetes (1,2).The unprecedented 1-year success ratesprovide considerable evidence of the clin-ical effectiveness of the procedure (2,3).However, the benefits of freeing or reduc-ing insulin requirements for these pa-tients must be weighed against the risks ofthe procedure itself, as well as the life-long immunosuppression. Before makingthis treatment available to a larger num-ber of people with type 1 diabetes, mea-

sures of quality of care and of clinicaleffectiveness must be incorporated tofully evaluate the benefit of this treatment.

Episodes of severe hypoglycemia, acommon occurrence in patients with la-bile type 1 diabetes andhypoglycemiaun-awareness, result in considerable fear andanxiety (4,5). When these concerns be-come an overwhelming burden for pa-t i e n t s w i t h t y p e 1 d i a b e t e s , i s l e ttransplantation with the Edmonton Pro-tocol is a potential solution (13). To de-termine the potential impact of islet

transplantation on self-reported health-related quality of life (HRQL) outcomes,we compared islet-transplanted patientswith pretransplant patients on measuresof fear of hypoglycemia and anxiety.

Patients were asked to self-complete abattery of measures, including the Hypo-glycemia Fear Survey (HFS) (4,5) and theHealth Utilities Index Mark two (HUI2)(6). The HFS contains 23 questions thatassess patients concerns and worriesabout hypoglycemia and the behaviors inwhich patients may engage to avoid lowblood glucose. The emotion attribute ofthe HUI2 can be used as an index of anx-iety (6). Ourstandardprotocol for admin-istration of HRQL questionnaires occursat baseline (pretransplant); midtransplant(i.e., between the first and second); 1, 3,6, and 12 months posttransplant; and an-

nually thereafter. Because islet-transplantedpatients may have completed multiplesurveys during follow-up, we initiallyused only the last available HRQL assess-ment. Surveys were completed by 81 (46pretransplant and 35 islet-transplanted)patients. Among the islet-transplantedpatients, questionnaires were completeda median of 11.9 months (range 136)after transplant. Scores between the twogroups of patients were compared usingnonparametric statistical tests.

Fear of hypoglycemia was signifi-cantly lower in islet-transplanted (median5.0) compared with pretransplant (me-dian 47.0) patients for the HFS total score(P 0.001). The magnitude of the differ-ence in HUI2 emotion scores betweenpretransplant and islet-transplanted pa-tients would be considered clinically im-portant (6) (1.00 vs. 0.86, respectively),although the difference was not staticallysignificant (P 0.96). Among all islet-transplanted patients, the small number(n 3) without C-peptide secretion andrequiring exogenous insulin had substan-tially more fear about hypoglycemia (P

0.041) and reported more anxiety on theHUI2 emotion attribute (P 0.023) thanislet-transplanted patients with successfultransplants.

Because anxiety pre- and posttrans-plant could be related to the procedureitself, we also compared HFS and HUI2emotion scores between pretransplantand islet-transplanted patients in the im-mediate posttransplant period; for thesecomparisons, we used all available HRQLassessments at 1 and 3 months posttrans-plant. We found that fear of hypoglyce-

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mia was lower, with a median HFS totalof 30.0 for islet-transplanted patients(n 20)at 1 monthand 6.5(n 18) at 3months, both of which were significantlylower (P 0.01) than pretransplant.Conversely, the HUI2 emotion scorewas not significantly different frompretransplant at either 1 or 3 monthsposttransplant.

These initial evaluations of self-reported HRQL outcomes of in islet trans-plant recipients demonstrate that clinicalsuccess is associated with substantial re-duction in emotional burden through re-duced fear of hypoglycemia. Generalanxiety in islet-transplanted patients is re-duced overall, which seems to be relatedto the freedom from requirement of exog-enous insulin rather than to recoveringfrom the transplant procedure itself. Al-

though the interpretation of our initialdata is interesting and informative, sev-eral limitations and questions remain.These initial data were collected cross-sectionally and on a relatively small butgrowing sample of islet-transplanted pa-tients; even with the small sample sizes,the observed differences were statisticallysignificant. Longitudinal assessments tomeasure within-person change over timeare required to fully assess the impact onHRQL.

JEFFREY A. JOHNSON, PHD1,2

MARIA KOTOVYCH, MA2

EDMOND A. RYAN, MD, FRCPC3,4

A.M. JAMES SHAPIRO, MBBS, BMEDSCI,PHD, FRCSC

4,5

From the 1Department of Public Health Sciences,University of Alberta, Edmonton, Alberta, Canada;the 2Institute of Health Economics, Edmonton, Al-berta, Canada; the 3Division of Endocrinology andMetabolism, Department of Medicine, University of

Alberta, Edmonton, Alberta, Canada; the 4ClinicalIslet Transplant Program, University of Alberta, Ed-monton, Alberta, Canada; and the 5Department ofSurgery, University of Alberta, Edmonton, Alberta,Canada.

Address correspondence to Jeffrey A. Johnson,PhD, Institute of Health Economics, 1200-10405

Jasper Ave., Edmonton, Alberta, Canada T5J 3N4.E-mail: [email protected].


References1. Shapiro AMJ, Lakey JRT, Ryan EA, Kor-

butt GS, Toth E, Warnock GL, KnetemanNM, Rajotte RV: Islet transplantation inseven patients with type 1 diabetes melli-tus using a glucocorticoid-free immuno-suppressive regimen. N Engl J Med 343:

230238, 20002. Ryan EA, Lakey JR, Rajotte RV, Korbutt

GS, Kin T, Imes S, Rabinovitch A, ElliottJF, Bigam D, Kneteman NM, WarnockGL, Larsen I, Shapiro AM: Clinical out-comes and insulin secretion after islettransplantation with the Edmonton Pro-

tocol. Diabetes 50:710719, 20013. Ryan EA, Lakey JRT, Paty BW, Imes S,Korbutt GS, Kneteman NM, Bigam D, Ra-jotte EV, Shapiro AMJ: Successful islettransplantation:continuedinsulin reserveprovides long-term glycemic control. Di-abetes 51:21482157, 2002

4. Cox D, Irvine A, Gonder-Frederick L,Nowacek G, Butterfield J: Fear of hypo-glycemia: quantification, validation, andutilization. Diabetes Care 10:617 621,1987

5. Irvine A, Cox D, Gonder-Frederick L:Thefear of hypoglycemia scale. In Hand-book of Psychology and Diabetes. Bradley C,

Ed. Amsterdam, Hardwood Academic,1994, p. 133155

6. Feeny DH, Torrance GW, Furlong WJ:Health utilities index. In Quality of Life andPharmacoeconomics in Clinical Trials. 2nded. Spilker B, Ed. Philadelphia, Lippin-cott-Raven, 1996, p. 239 251

A Case ofLipoatrophy With

Lispro InsulinWithout InsulinPump Therapy

Localized lipoatrophy occurring inthe subcutaneous insulin injectionarea in diabetic patients was a phe-

nomenon practically forgotten after theintroduction of human insulin in medicalpractice. In recent years, there have beenvery few publications in relation to thismatter.

Three cases of patients with type 1diabetes who presented with subcutane-ous localized lipoatrophy areas and whowere in treatment with Lispro insulinwere recently reported (1,2). The threepatients used a continuous subcutaneousinsulin infusion (CSII) system; therefore,the authors posed the doubt of whethersuch an administration system locallyplayed a determinant role in the occurrenceof subcutaneous localized lipoatrophy.

We present a case of localized lipoat-rophy associated with treatment with

Lispro insulin administered in a multipledose regimen that disregards the role ofCSII as a necessary factor for its genesis.

Our patient is a 35-year-old womandiagnosed in January of 1992 at 22 yearsof age. From the start, she was treatedwith recombinant DNA human insulin(Humulin Regular and Humulin NPH;Lilly) in a regimen of three daily doses.She always exhibited a good degree ofmetabolic control, with HbA

1cbetween 6

and 7%. Seven years after diagnosis, shebegan to exhibit episodes of hypoglyce-mia not perceived with accompanyingneuroglycopenia, which persisted in spiteof several changes of her prior insulin reg-imen. For that reason, in November of2000 it was decided that she wouldchange to LisPro insulin administered be-fore breakfast, lunch, snack, and dinner,

and NPH insulin administered beforebreakfast and dinner. With the new regi-men, metabolic control remained similarto the previous control and the episodesof neuroglycopenia persisted. Anti-insulin antibody (IAA) levels were mea-sured and were high (49.6%, referencevalue 8.5%). In October of 2002, 23months after beginning with LisPro, thepatient consulted the physician becauseshe had a circumscribed localized lipoat-rophy area of 3 cm in diameter on theanterior aspect of the right thigh, one ofher normal injection areas. Six monthslater, a period in which injection in saidarea was avoided, the lesion remained un-changed, but an incipient localized lipoat-rophy area could be observed in the samearea of the contralateral thigh. For thisreason, it was decided to change fromLispro to Aspart insulin.

Six months after said change of insu-lin, which was when this letter was sent,neither progression nor improvement ofthe localized lipoatrophy lesions had beenobserved. IAA levels were 30.5%, slightlylower than the previous levels.

The development of localized lipoat-rophy in the insulin injection area is apractically exclusive complication of type1 diabetic patients, although cases havebeen reported in patients with type 2 di-abetes (3). From the etiopathogenic pointof view, it is considered an immunologicalphenomenon. Although this has not beensufficiently clarified, a strong associationbetween the lesions and high IAA plasmalevels and the presence of insulin and im-munoglobulin G deposits in subcutane-ous tissue of the affected areas (4) have

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been reported. The consequences of thisimmunological activation are the local in-hibition of adipocyte differentiation,probably mediated by the local hyperpro-duction of tumor necrosis factor- (5).

In affected patients, the pharmacoki-netic variations of insulin due to high IAAlevels and the erratic absorption of thedrug when it is injected in the areas af-fected with localized lipoatrophy imply aglycemic variability making it very diffi-cult to achieve suitable metabolic control.

Although the immunogenic profile ofthe patients treated with Lispro insulinand recombinant human insulin are com-parable (6), the recent occurrence of de-scriptions of localized lipoatrophyassociated to this analogue can decreasethe therapeutic alternatives of this com-plication when, especially in recent years,

in the few published cases of human in-sulininduced localized lipoatrophy theattempted solution to the problem was tochange to Lispro. It is possible that the useof CSII may favor the occurrence of local-ized lipoatrophy but, as can be seen in thecase we present, it is not a factor sine quanon for its development. Curiously, severecases of human insulininduced localizedlipoatrophy have been previously re-ported that responded satisfactorily afterthe introduction of CSII (7).

The association of localized lipoatro-phy and Lispro insulin without the con-course of CSII has not been reportedpreviously. We therefore believe it is in-teresting to disclose our case and toencourage publishing for other diabetolo-gists who have observed similar cases forthe purpose of clarifying its pathogenesisand therapeutic approach.

ALFONSO ARRANZ, MDVICTOR ANDIA, MD

ANTONIO LOPEZ-GUZMAN, MD

From the Endocrinology Unit, Hospital Nuestra Se-nora de Sonsoles, Avila, Spain.

Address correspondence to Dr. Alfonso Arranz,Endocrinology Unit, Ntra. Sra. De Sonsoles, Car-retera de Madrid, km 109, Avila, Spain 05071. E-mail: [email protected].


References1. Griffin ME, Feder A, Tamborlane WV: Li-

poatrophy associated with lispro insulinin insulin pump therapy (Letter). DiabetesCare 24:174, 2001

2. Ampudia-Blasco FJ, Hasbum B, CarmenaR: A new case of lipoatrophy with lispro

insulin in insulin pump therapy (Letter).Diabetes Care 26:953954, 2003

3. Mu L, Goldman JM: Human recombinantDNA insulin-induced lipoatrophy in pa-tient with type 2 diabetes mellitus. EndocrPract 6:151152, 2000

4. Reeves WG, Allen BR, Tattersall RB: Insu-

lin induced lipoatrophy evidence for animmune pathogenesis. BMJ 1:15001506, 1980

5. Atlan-Gepner C, Bondgrand P, FarnarierC, Xerri L, Choux R, Gauthier JF, Brue T,Vague P, Grob JJ, Vialettes B: Insulin-in-duced lipoatrophy in type 1 diabetes: apossible tumor necrosis factor-medi-ated dedifferentiation of adipocytes. Dia-betes Care 19:12831285, 1996

6. Fineberg SE, Huang J, Brunelle R, GulliyaKS, Anderson JH: Effect of long-term ex-posure to insulin Lispro on the inductionof antibody response in patients with type1 or type 2 diabetes. Diabetes Care 26:89

96, 20037. Chantelau E, Reuter M, Schotes S, Starke

AA: Severe lipoatrophy with human insu-lin: successfully treated by CSII (Letter).Diabet Med 10:580 581, 1993

Diabetes In ANonpancreatectomizedChild WithNesidioblastosis

Persistent hyperinsulinemic hypogly-cemia of infancy (PHHI) (OnlineMendelian Inheritance in Man

[OMIM] 256450), formerly known as ne-sidioblastosis, is a glucose metabolismdisorder characterized by profound hy-poglycemia and inappropriate secretionof insulin (1). Affected children run therisk of severe neurological damage unlessimmediate and adequate steps are taken(2). Treatment with diazoxide and/or so-

matostatin analogue is the first line oftherapy. However, it not always effective,especially in familial cases, which may ne-cessitate an alternative intervention suchas pancreatectomy (3).

Several studies have suggested thatpartial pancreatectomy endangers futureislet cell function (4,5). The incidence ofdiabetes increases with age and correlateswith the extent of surgical resection (6,7).However, there was no report of occur-rence of overt diabetes in medicallytreated patients (8). In this report, we de-

scribed an adolescent female with neona-tal nesidioblastosis who developeddiabetes after medical treatment with dia-zoxide/octreotide. To our knowledge,thisis the first nesidioblasosis case subjectwho developed diabetes following medi-cal therapy.

A 14-year-old Saudi female presentedwith severe persistent hypoglycemiaduring the first few days of life. She wasdiagnosed with hyperinsulinemic hypo-glycemia of infancy based on her intrave-nous glucose requirement of 14 mg kg1 min1, an insulin-to-glucose ratioof0.3(her insulin level was 98 U/ml ata serum glucose of 32 mg/dl), negativeurinary ketones, a 30-min glucose incre-ment of30 mg/dl in response to intra-muscular 0.5 mg glucagon, and normalblood spot acylcarnitine profile deter-

mined by tandem mass spectrometry. Shealso had a normal growth hormone levelof20 mU/l and a normal cortisol level of500 nmol/l during hypoglycemia. Shewas treated initially with frequent feedingsupplemented with complex carbohy-drates (polycose/corn starch) and thenstarted on diazoxide 15 mg kg1 day1

divided three times a day, which kept hereuglycemic with occasional hypoglyce-micepisodes. In 1992,octreotide wasfirstintroduced in our hospital as an adjunc-tive therapy to diazoxide. She was startedon 25 g kg1 day1 of subcutaneousoctreotide divided four times a day. Sheresponded to medical treatment with nohypoglycemic episodes. She was contin-ued on diazoxide and octreatide until theage of 10 years, when she became eugly-cemic and these two medications werestopped. At the age of 14, she developedhyperglycemia associated with weightgain. Her blood glucose ranged from 200to 300 mg/dl, and her weight was 75 kg(95%). She had an insulin level of 10U/ml and C-peptide level of 0.16 nmol/lat a serum glucose level of 350 mg/dl. An-

tiglutamic acid decarboxylase, insulin,and islet cell antibodies were negative.She responded to metformin 250 mgtwice a day with a serum mean glucoselevel of 109 mg/dl and HbA

1cof 7.5%.

The long-term outcome of PHHI isnot well documented. Previous reportssuggested that subtotal or near total pan-createctomy in infants will endanger thefuture islet function (4 8). Long-termfollow-up studies in medically treated pa-tients with diazoxide or octreotideshowed that some of these patients re-

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sponded to medical therapy and becameeuglycemic (9 11). Some patients wereweaned off medical therapy and contin-ued to be euglycemic; however, none ofthem became hyperglycemic or diabetic.Leibowitz et al. (8) followed six conserva-tively treated patients with PHHI. Intra-venous glucose tolerance was performedin all patients and showed a blunted in-sulin response in two with no overt hy-perglycemia. Histologically, Kassem et al.(12) showed that -cell proliferation andapoptosis, which normally occurrs in thenormal developing human pancreas, alsooccurs in thePHHI pancreas with a higherfrequency of apoptosis. They suggestedthat this phenomenon will result in aslow, progressive, and complete loss of-cell mass. This histological report andthe development of diabetes in our non-

pancreatectomized PHHI patient maysuggest that patients with PHHI will nat-urally develop diabetes whether theywere treated medically or surgically oreven if they are left untreated. This hy-pothesis was further raised when the nat-ural history of this disease was discussedin knockout mouse models. Transgenicmice engineered to express a dominant-negative form of Kir6.2 or mice with ATP-sensitive K channel deficiency devel-oped hyperinsulinemic hypoglycemiafollowed by hypoinsulinemic hyperglyce-mia. Diabetes in these transgenic micewas thought to be due to sustained unreg-ulated Ca influx and premature -cell ap-optosis (burn-out phenomenon) (13,14).Seino et al. (15,16) reported another pos-sible predisposing factor to hyperglyce-mia in PHHI patients. They showed thathyperglycemia in Kir6.2 knockout micewas more evident with age and increasingweight. They suggested that the Kir6.2knockout mouse provides a model of type2 diabetes, and that both the genetic de-fect in glucose-induced insulin secretionand the acquired insulin resistance due to

environmental factors are necessary to de-velop diabetes in the Kir6.2 knockoutmouse.

We hypothesized that diabetes wasinduced by weight gain and obesity in ourpatient. She responded to metformin,which may suggest that her diabetes isdue to insulin resistance induced by bothweight gain and insulin insufficiency.Simple type 2 diabetes is still a possibility,although there was no history of diabetesin the family. This patient could be thehuman example of the Kir6.2 knockout

mouse model. We recommend, based onthis human clinical evidence, weight con-trol in aged PHHI patients to decease theincidence of diabetes.

BASSAM S. BIN-ABBAS, MDABDULLAH A. AL-ASHWAL, MD

Fromthe Department of Pediatrics, King Faisal Spe-cialist Hospital and Research Center, Riyadh, Saudi

Arabia.Address correspondence to Bassam Saleh Bin-

Abbas, MD Consultant, Section of Pediatric Endo-crinology Department of Pediatrics, MBC 58 KingFaisal Specialist Hospital and Research Center, P.O.Box 3354 Riyadh 11211 Saudi Arabia. E-mail:[email protected].


References1. Aynsley-Green A: Nesidioblastosis of the

pancreas in infancy. Dev Med Child Neurol23:372379, 19812. Schwitzgebel VM, Gitelman SE: Neonatal

hyperinsulinism. Clin Perinatol 25:10151038, 1998

3. Shilyansky J, Fisher S, Cutz E, Perlman K,Filler RM: Is 95% pancreatectomy theprocedure of choice for the treatment ofpersistent hyperinsulinemic hypoglyce-mia of the neonate?J Pediatr Surg 32:342346, 1997

4. Dunger DB, Burns C, Ghale GK, MullerDP, Spitz L, Grant DB: Pancreatic exo-crine and endocrine function after subto-tal pancreatectomy for nesidioblastosis.

J Pediatr Surg 23:112115, 19885. Mahachoklertwattana P, Suprasongsin C,

Teeraratkul S, Preeyasombat C: Persistenthyperinsulinemic hypoglycemia of infan-cy: long-term outcome following subtotalpancreatectomy. J Pediatr EndocrinolMetabol 13:37 44, 2000

6. De Lonlay- Debeney P, Poggi-Travert F,Fournet JC, Sempoux C, Vici CD,Brunelle F, Touati G, Rahier J, Junien C,Nihoul-Fekete C, Robert JJ, SaudubrayJM: Clinical features of 52 neonates withhyperinsulism. N Engl J Med 340:11691175, 1999

7. Dacou-Voutetakis C, Psychou F, Maniati-

Christidis M: Persistent hyperinsulinemichypoglycemia of infancy: long term re-sults.J Pediatr Endocrinol Metabol 11:131141, 1998

8. Leibowitz G, Glaser B, Higazi AA,Salameh M, Cerasi E, Landau H: Hyper-insulinemic hypoglycemia of infancy (ne-sidioblastosis) in clinical remission: highincidence of diabetes mellitus and persis-tent beta-cell dysfunction at long termfol-low-up.J Endocrinol Metabol 80:386392,1995

9. Tuoati G, Poggi-Travert F, Ogier deBaulny H, Rahier J, Brunelle F, Nihoul-

Fekete C, Czernichow P, Saudubray JM:Long-term treatment of persistent hyper-insulinemic hypoglycemia of infancy withdiazoxide: a retrospective review of 77cases and analysis of efficacy-predictingcriteria. Eur J Pediatr157:628 633, 1998

10. Glaser B, Landaw H: Long-term treatment

with somatostatin analogue SMS 201995: alternative to pancreatectomy in per-sistent hyperinsulinemic hypoglycemia ofinfancy. Digestion 45:2735, 1990

11. Darendeliler F, Bundak R, Bas F, Saka N,Gunoz H: Long term diazoxide treatmentin persistent hyperinsulinemic hypogly-cemia of infancy: a patient report.J PediatrEndocrinolo Metabol 10:79 81, 1997

12. Kassem SA, Ariel I, Thornton PS, Scheim-berg I, Glaser B: -Cell proliferation andapoptosis in the developing normal hu-man pancreas and in the hyperinsulin-ism of infancy. Diabetes 49:13251333,2000

13. Miki T, Tashiro F, Iwanaga T, NagashimaK, Yoshitomi H, Aihara H, Nitta Y, GonoiT, Inagaki N, Miyazaki JI, Seino S: Abnor-malities of pancreatic isletsby targeted ex-pression of a dominant-negative KATPchannel. Proc Natl Acad Sci U S A94:1196911973, 1997

14. Miki T, Nagashima K, Tashiro F, KotakeK, Yoshitomi H, Tamamoto A, Gonoi T,Iwanaga T, Miyazaki JI, Seino S: Defect ininsulin secretion and enhanced insulinaction in KATP deficient mice. Proc NatlAcad Sci U S A 95:1040210406, 1998

15. Seino S, Iwanaga T, Nagashima K, Miki T:Diverse roles of K

ATPchannels learned

from Kir6.2 genetically engineered mice.Diabetes 49:311318, 2000

16. Winarto A, Miki T, Seino S, Iwanaga T:Morphological changes in pancreatic is-lets of KATP channel-deficient mice: theinvolvement of KATP channels in the sur-vival of insulin cells and the maintenanceof islet architecture. Arch Histol Cytol 64:59 67, 2001

Oral GlucoseTolerance Test

Evaluation WithForearm andFingertip GlucoseMeasurements inPregnant Women

It is known that glucose levels in capil-lary blood in the fingertip after a liquidglucose load are constantly higher

when compared with venous blood mea-surements (1). Recently alternative sites

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for capillary blood drawing (e.g., fore-arm) have been proposed (2) that are lesspainful compared with fingertip. Datahave shown that there was no significantdifference between the capillary blooddrawn from forearm and fingertip in dia-betic patients with glucose values in awide range (3). Nevertheless, some datahave shown that glucose results from al-ternative sites and fingertip were notidentical. This difference was more pro-nounced when there was a rapid increaseor decrease of blood glucose values (4). Itseemed that significant differences ap-peared when glucose values declined at amean rate 2 mg dl1 min1 (5), butnot at a lower rate (6). All the above-mentioned reports compared capillaryblood drawn from either the forearm orfingertip, but so far, it appears that no

direct comparison has been made be-tween venous plasma blood and capillaryforearm blood.

Thus, the purpose of this investiga-tion is to study the pattern of capillaryforearm blood and that of capillary finger-tip blood glucose using the same glucom-eter (FreeStyle; Therasense) and tocompare both with venous blood labora-tory measurements during a 100-g oralglucose tolerance test (OGTT) in preg-nant women. A total of 47 pregnantwomen (age 31 3 years, BMI 24 3kg/m2, and gestational age 24 28 weeks)underwent a 100-g OGTT. Half of thesewomen (n 23) had simultaneous glu-cose samples drawn from the forearm af-ter rubbing (7) using FreeStyle in 0, 60,120, and 180, whereas the other half(n 24) underwent the same procedurewith blood drawn from the fingertip. Thetwo groups were matched for age, BMI,and gestational age. Glucose difference inpercentage (GDP) was calculated for bothgroups separately. Mean GDP betweenfinger glucose and venous glucose sam-ples was significantly higher at 60

(14.6 20.4%), 120 (25.2 34.7%),and 180 (26.4 26.7%) than at 0(3.1 14.1%) (P 0.01). Mean GDPbetween forearm glucose and venous glu-cose samples was significantly higher at120 (16.3 21.5%) and 180 (16.3 21.5%) than at 0 (2.5 16.3%) (P 0.01). On the contrary, mean GDP at 60(6.7 20.9%) was not found signifi-cantly different.

These findings confirmed the alreadyreported observation that up to 3 h after aliquid glucose load, capillary finger glu-

cose levels are constantly higher (1526%) than venous glucose levels. On thecontrary, forearm glucose levels werecloser to venous plasma glucose levels:There was no significant difference be-tween them after 1 h, whereas a signifi-cant increase of 16% appeared at 2 and3 h.These findings are in accordance withthe concept of slower glucose kinetics atthe forearm than the fingertip due tolesser arteriovenous anastomoses (4). Tobe sure, this physiological differenceneeds to be taken into consideration inthe detection of hypoglycemia in diabeticpatients. However, it is precisely thisphysiological difference that supports thesuggestion that capillary f

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