Response to Mastrototaro and Gross

OBSERVATIONS

Comparison ofGlycemic and LipidResponse toPioglitazoneTreatment inMexican-Americansand Non-HispanicCaucasians WithType 2 Diabetes

The risk of type 2 diabetes in Mex-ican-Americans is almost twice thatof non-Hispanic Caucasians (1).

Mexican-Americans are also, in general,more likely to have insulin resistance, im-paired fasting glucose, and impaired glu-cose tolerance than non-HispanicCaucasians (1,2). Given these increasedrisks of type 2 diabetes in the Mexican-American population and the fact thatpoor glycemic control is more common indiabetic Mexican-Americans than in non-Hispanic Caucasians (3), it is important toconsider the efficacy of diabetes therapyin this specific population.

In a retrospective chart review, ourclinic identified patients with type 2 dia-betes who had been treated with pioglita-zone 45 mg/day for 6 or more monthswithout interruption. Patient charts werethen selected if HbA1c and lipids wereavailable within 4 weeks of starting treat-ment and �4 months into treatment. Pa-tients whose lipid-lowering medicationwas changed during this same time periodwere excluded. In total, data from 98 non-Hispanic Caucasians and 81 Mexican-Americans were reviewed.

The majority of patients (�75%)were taking pioglitazone in combinationwith metformin, sulfonylurea, or insulin,with the remainder of the patients receiv-ing pioglitazone as monotherapy. Thepercentage of patients on monotherapywas the same in both groups. Fifty-threepercent of non-Hispanic and 31% of Mex-ican-American patients were taking statinmedication (P � 0.002). One patient inthe Mexican-American group and three inthe non-Hispanic group were taking a fi-brate. Baseline characteristics (duration of

diabetes, BMI, C-peptide, and male-to-female ratio) for the two groups were sim-ilar with the exception of age. The meanand standard deviation for age was61.2 � 12.8 years in the non-HispanicCaucasian population and 52.7 � 15.2 inthe Mexican-American population (P �0.001). The younger age in the Mexican-American population is consistent withthe younger age of onset of diabetes thathas been reported elsewhere for this pop-ulation (4). The mean duration of treat-ment, at which time the laboratory datawere obtained, was 3.9 months in theMexican-American patients and 4.4months in the non-Hispanic Caucasians(P � 0.312).

Our analysis showed that mean re-duction in HbA1c was similar between thetwo populations. Mean baseline HbA1c

was 8.0 � 1.9% for non-Hispanics and8.2 � 1.9% for Mexican-Americans. At 3months, the mean reductions from base-line were 1.2 � 1.8% and 1.1 � 1.4%,respectively (the difference between twopopulations was not statistically signifi-cant, P � 0.616).

Similarly, there was no difference be-tween the two populations in terms oflipid effects. Baseline triglyceride levelswere 216 and 207 mg/dl, respectively;baseline HDL cholesterol levels were 41.6and 43.1 mg/dl, respectively; and base-line LDL cholesterol levels were 106 and113 mg/dl, respectively. Mean reductionsin triglycerides from baseline were 10.1 �47.1% in non-Hispanic Caucasians and8.4 � 47.3% in Mexican-Americans (P �0.802 for two populations). Mean in-creases in HDL cholesterol were 17.0 �21.0 and 16.0 � 18.8%, respectively (P �0.748), and mean increases in LDL cho-lesterol were 5.1 � 25.2 and 6.5 �48.1%, respectively (P � 0.826). In asubanalysis, there was no significant (P �0.05) difference within each ethnic groupin the lipid response to pioglitazone re-gardless of whether the patient was con-currently taking a statin.

Also of interest was the fact thatweight gain was similar in both groups.Baseline BMI was practically identical be-tween the two population groups (33.9and 33.1 kg/m2, respectively, for non-Hispanics Caucasians vs. Mexican-Americans), although overall, theCaucasians weighed more at baselinethan the Mexican-Americans (meanweight 99.6 and 89.2 kg, respectively).

Mean weight gain at 3 months was 1.64and 1.41 kg, respectively (P � 0.540).

Although Mexican-Americans have ahigher incidence of type 2 diabetes and anearlier age of onset, our analysis suggeststhat their response to treatment with pio-glitazone is similar to that seen in non-Hispanic Caucasians in terms of HbA1cand lipid changes. Such a comparison ofpioglitazone treatment between these twoethnic groups has not previously beenconducted, and thus these data providesome interesting and encouraging in-sights. Certainly, good glycemic controlcan greatly reduce the risk for diabeticcomplications in all ethnic groups; how-ever, because of the increased risk in Mex-ican-Americans, treatments that improveglycemic control potentially offer agreater benefit in this population (5). Fur-ther prospective comparative studies inMexican-American populations shouldbe conducted to confirm and expandupon our results.

ALLEN B. KING, MD, FACP, FACE, CDE

DANA U. ARMSTRONG, RD, CDE

SITHIPHOL CHINNAPONGSE, MD

From the Diabetes Care Center, Salinas, California.Address correspondence to Allen B. King, Diabe-

tes Care Center, 1260 Main St. S., Suite 201, Salinas,CA 93901. E-mail: [email protected].

A.B.K. is a member of the National Actos ProductAdvisory Committee and has received honorariafrom Takeda Pharmaceuticals.

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References1. Harris MI, Flegal KM, Cowie CC, Eber-

hardt MS, Goldstein DE, Little RR, Wied-meyer H-M, Byrd-Holt DD: Prevalence ofdiabetes, impaired fasting glucose, andimpaired glucose tolerance in U.S. adults:the Third National Health and NutritionExamination Survey 1988–1994: Diabe-tes Care 21:518–524, 1998

2. Chiu KC, Chuang L-M, Yoon C: Compar-ison of measured and estimated indices ofinsulin sensitivity and beta cell function:impact of ethnicity on insulin sensitivityand beta cell function in glucose-tolerantand normotensive subjects. J Clin Endocri-nol Metab 86:1620–1625, 2001

3. Harris MI, Eastman RC, Cowie CC, FlegalKM, Eberhardt MS: Racial and ethnic dif-ferences in glycemic control of adults withtype 2 diabetes. Diabetes Care 22:403–408, 1999

4. Stern MP, Haffner SM: Type II diabetesand its complications in Mexican Ameri-cans. Diabet Metab Rev 6:29–45, 1990

5. de Lissovoy G, Ganaczy DA, Ray NF: Re-lationship of hemoglobin A1c, age of dia-

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DIABETES CARE, VOLUME 26, NUMBER 1, JANUARY 2003 245

betes diagnosis and ethnicity to clinicaloutcomes and medical costs in a comput-er-simulated cohort of persons with type2 diabetes. Am J Manag Care 6:573–584,2000

DiabeticVasculopathy andAlcohol ToleranceTrait in Type 2Diabetes

In 1978, Pyke and Leslie (1,2) first pro-posed the hypothesis that clinical pic-tures of patients with type 2 diabetes

can be characterized by two clinical pre-sentations in response to chlorpropamideuse and tolerance to alcohol. Chlorprop-amide alcohol flushing (CPAF) is oftenobserved in diabetic patients with a familyhistory of diabetes, but among those pa-tients without CPAF, there is a high prob-ability of developing severe diabeticretinopathy. Subsequently, Barnett et al.(3) has reported that persistent protein-uria is also more commonly observed inpatients without CPAF. However, the roleand significance of CPAF and diabeticvasculopathy still remains controversial.

Aldehyde dehydrogenase-2 (ALDH2)and alcohol dehydrogenase-2 (ADH2) arethe key enzymes for alcohol metabolism.Many Asians lack enzyme activity ofALDH2 and have superactive enzyme ac-tivity of ADH2, attributed to point muta-tions within both structural genes (4).Hence, the expression of these two en-zyme mutations could determine the al-cohol tolerance among the Japanesepopulation.

We have found an increase in theprevalence of nephropathy and advanceddiabetic retinopathy among Japanese pa-tients with diabetes and a specific ADH2and ALDH2 genotype. A total of 158 pa-tients with type 2 diabetes (114 men and44 women aged 17–81 years) were exam-ined. The subjects were consecutively se-lected from our outpatient clinic and wereall unrelated. After informed consent, ablood sample was obtained from eachsubject. Genotyping of ALDH2 andADH2 was performed by the PCR-restriction fragment–length polymor-phism (RFLP) method, details describedelsewhere (4). The phenotype of ALDH2inactivity is compatible with possession of

the genotype ALDH2*1/ALDH2*2 orALDH2*2/ALDH2*2, and the phenotypeof ADH2 superactivity is compatible withpossession of the genotype ADH2*2/ADH2*2 (4). Diabetic retinopathy wasassessed and categorized by ophthalmol-ogist examination. Nephropathy was di-agnosed if proteinuria was found ontesting with CLINITEK-200� (BayerMedical) on at least three consecutiveclinic visits in the absence of other causesof proteinuria.

The results of this study showed that41 subjects have active ALDH2 and su-peractive ADH2 genotypes, which was re-garded as the alcohol tolerance (ATO)group. The other 117 subjects were re-garded as the alcohol intolerance (AIT)group, because these patients had usualADH2 and/or inactive ALDH2 genotypes,which accounts for delayed alcohol me-tabolism. There was no difference be-tween the two groups in sex, age, age ofdiabetes onset, duration of diabetes,height, BMI, fasting plasma glucose, andHbA1c level (for ATO vs. AIT, respec-tively, male/female 28/13 vs. 86/31, age59.1 � 9.6 vs. 57.7 � 11.2 years, onset ofdiabetes 47.6 � 10.4 vs. 46.5 � 12.4years, duration 11.7 � 7.3 vs. 11.0 � 7.7years, height 161.3 � 9.7 vs. 162.9 � 7.9cm, BMI 23.2 � 3.9 vs. 22.8 � 3.4 kg/m2,fasting plasma glucose 149.5 � 38.9 vs.146.5 � 42.4 mg/dl, and HbA1c 7.8 � 1.4vs. 7.8 � 1.3%). However, the ATOgroup had a higher frequency of havingpersistent proteinuria than the AIT group(ATO 15 of 41, 36.6%; AIT 24 of 117,20.5%; P � 0.05 by �2 analysis). Amongall, retinopathy was found in 31.7% (13of 41) of the ATO group and in 32.5%(38/117) of the AIT group, showing nodifference. However, among the patientswith retinopathy, the frequency of prolif-erative retinopathy was three times higherin the ATO group (5 of 13, 38.5%) than inthe AIT group (5 of 38, 13.2%) (P �0.05). Thus, the ATO group had higherfrequency of having nephropathy and ofdeveloping diabetic proliferative retinop-athy than the AIT group.

It has been noted that activation ofprotein kinase C (PKC)-� under hyper-glycemia can lead to a number of down-stream sequelae, which are potentiallydamaging to the vascularity of glomerulusand retina in diabetes (5). ADH andALDH are the enzymes not only for alco-hol metabolism, but also for degradationof 4-hydroxy-2-nonenal (4-HNE) and

other aldehydes (6–8). 4-HNE is a by-product of lipid peroxidation and has arole in pathophysiological conditions byacting as a signal molecule able to modu-late relevant biological events, such as cellsignaling, gene expression, cell prolifera-tion, and cell differentiation. Interest-ingly, Chiarpotto et al. (9) has reported ondifferential regulation of protein PKC iso-forms by a concentration of 4-HNE that isactually detectable in specific biologicalfluids or tissues. PKC-�1 and PKC-�II ac-tivities are markedly increased by 0.1mol/l 4-HNE, whereas they are unaffectedor even inhibited by 1–10 mol/l 4-HNE.Decreased tissue levels of 4-HNE couldresult from active ALDH2 and superactiveADH2 expression, as represented by sub-jects of the ATO group (6–8). Therefore,we speculate, in the ATO group, that the4-HNE in the low micromolar range isable to have an influence on cell functionthrough upregulation of PKC-� isoforms,which aggravates the damaging effects ofPKC-� isoforms induced by hyperglyce-mia. Then, in the chronic situation, thelower concentration trait of 4-HNE in theATO group may account for the long-term development of diabetic nephropa-thy and severe retinopathy.

In conclusion, we suggest that in Jap-anese individuals, the alcohol tolerancegenetic trait is associated with the occur-rence of diabetic vasculopathy. Our find-ing seemingly has a similar importance tothat of the CPAF hypothesis, in terms of asuggestion for a relationship between al-cohol tolerance and diabetic vasculopa-thy (2,3).

Acknowledgments— The authors thank Dr.R. Arakaki for help in preparation of themanuscript.

YOSHIHIKO SUZUKI, MD1,2,3

MATSUO TANIYAMA, MD2

TAROU MURAMATSU, MD4

SUSUMU HIGUCHI, MD5

SHIGEO OHTA, PHD3

YOSHIHITO ATSUMI, MD1

KEMPEI MATSUOKA, MD1

From 1Saiseikai Central Hospital, Tokyo, Japan;2Fujigaoka Hospital, Showa University, Kanagawa,Japan; the 3Department of Biochemistry and CellBiology, Institute of Gerontology, Nippon MedicalSchool, Kanagawa, Japan; the 4Department of Neu-ropsychiatry, Keio University, Tokyo, Japan; and the5National Institute of Alcoholism, Kurihama Na-tional Hospital, Kanagawa, Japan.

Address correspondence to Y. Suzuki, MD, Sai-

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246 DIABETES CARE, VOLUME 26, NUMBER 1, JANUARY 2003

seikai Central Hospital, 1-4-17, Mita, Minato-ku,Tokyo, 108 Japan. E-mail: [email protected].

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References1. Pyke DA, Leslie RDG: Chlorpropamide-

alcohol flushing: a definition of its rela-tion to non-insulin-dependent diabetes.BMJ 2:1521–1522, 1978

2. Leslie RDG, Pyke DA: Chlorpropamide al-cohol flushing and diabetic retinopathy.Lancet 12:997–999, 1979

3. Barnett AH, Leslie RDG, Pyke DA: Chlor-propamide-alcohol flushing and protein-uria in non-insulin-dependent diabetics.BMJ 282:522–523, 1981

4. Muramatsu T, Wang Zu-Cheng, Fang Yi-Ru, Hu B, Yan H, Yamada K, Higuchi S,Harada S, Kono H: Alcohol and aldehydedehydrogenase genotypes and drinkingbehavior of Chinese living in Shanghai.Hum Gene 96:151–154, 1995

5. Koya D, King GL: Protein kinase C activa-tion and the development of diabeticcomplications. Diabetes 47:859–866, 1998

6. Hartly DP, Petersen DR: Co-metabolismof ethanol, ethanol-derived acetaldehyde,and 4-hydroxynonenal in isolated rathepatocytes. Alcohol Clin Exp Res 21:298–304, 1997

7. Vasiliou V, Pappa A: Polymorphisms ofhuman aldehyde dehydrogenases. Phar-macology 61:192–198, 2000

8. Esberbauer H, Zolliner H, Lang J: Metab-olism of the lipid peroxidation product4-hydroxynonenal by isolated hepato-cytes and by liver cytosolic fractions. Bio-chem J 228:363–373, 1985

9. Chiarpotto E, Domenicotti C, Paola D, Vi-tali A, Nitti M, Pronzato MA, Biasi F, Cot-talasso D, Marinari UM, Dragonetti A,Cesaro P, Isidoro C, Poli G: Regulation ofrat hepatocyte protein kinase C betaisoenzymes by the lipid peroxidationproduct 4-hydroxy-2,3-nonenal: a signal-ing pathway to modulate vesicular trans-port of glycoproteins. Hepatology 29:1565–1572, 1999

Screening UsingCompressed DigitalRetinal ImagesSuccessfullyIdentifiesRetinopathy

D igital retinal photographs can be in-tegrated into a computerized net-work that more easily enables

communication and quality assurance(1). Image compression overcomes the

difficulty of transmitting and storing largefile sizes. Concern has been raised thatmajor compression of �70% results inclinically significant loss of retinal detailwith inadequate screening sensitivities(2). It is unclear whether low levels ofcompression result in loss of screeningsensitivity compared with the original bit-map image.

We used a Topcon TRC-NW6S non-mydriatic fundus camera with a SonyDXC950P to photograph 171 patientswith diabetes (one eye each for the study),without the use of mydriasis. Original bit-map images (768 576 pixels, 1.27 MB)were stored and compressed to make aJPEG image (104 KB) of the highest qual-ity using Paintshop Pro (Jasc Software,Eden Prairie, MN) with standard encod-ing. All images were anonymized and pre-sented to the grader in random order.Images were graded on a 17-inch Cathoderay tube monitor with 1,024 768 pixelresolution in a darkened room by a singlegrader. Severe and very severe nonprolif-erative retinopathy, proliferative retinop-athy, and maculopathy were defined asvision-threatening retinopathy.

On the original bit-map images, 80patients had normal retina (46.7%), 35had background retinopathy (20.5%), 38had vision-threatening retinopathy(22.2%, 5 proliferative and 33 maculopa-thy), 8 had non–diabetes-related changes(4.7%), and 10 were unreadable (5.8%).Compared with bit-map images, gradingusing the JPEG images achieved a sensi-tivity of 95.8% (�5.1%, 95% CI) and aspecificity of 95.0% (�4.2%) in the de-tection of any identifiable disease. Thisyields a positive predictive value of 94.6%and a negative predictive value of 96.2%.In terms of identifying vision-threaten-ing retinopathy, the sensitivity of usinghighest-quality compressed JPEG imageswas 97.4% (�2.4%) with a specificity of100%. The positive predictive value was100%, and the negative predictive valuewas 99.3%. The difference between JPEGimages and bit-map images in the detec-tion of vision-threatening referable dis-ease amounted to a disagreement aboutthe presence of one microaneurysm inone image, which did not require subse-quent laser photocoagulation.

Using highest-quality compressedJPEG images (Paintshop Pro) does not ap-pear to result in any loss of sensitivitywhen compared with uncompressed bit-map images for detecting potentially vi-

sion-threatening disease. This findinghelps confirm earlier pilot studies (3,4).JPEG files compressed to highest-qualityimages result in file sizes that are 8% ofthe original bit-map image file size, whichallows them to be more readily stored,more easily transferred across a web-interface, and transmitted at a faster rate.

GRAHAM P. LEESE, MD, FRCP1,2

ANGELA ELLINGFORD, BSC3

ANDREW D. MORRIS, MD, FRCP1,2

JOHN D. ELLIS, MPH, FRCOPHTHAL3

SCOTT CUNNINGHAM, BSC1

From the 1Department of Diabetes, Ninewells Hos-pital and Medical School, Dundee, U.K.; the 2De-partment of Medicine, Ninewells Hospital andMedical School, Dundee, U.K.; and the 3Depart-ment of Ophthalmology, Ninewells Hospital andMedical School, Dundee, U.K.

Address correspondence to Dr. Graham Leese,Ward 1 and 2 Ninewells Hospital, Dundee DD19SY, U.K. E-mail: [email protected].

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References1. Jackson W: Improving diabetic retinopa-

thy screening (Editorial). Diabetes Care25:1477–1478, 2002

2. Newsom RS, Clover A, Costen MT, SadlerJ, Newton J, Luff AJ, Canning CR: Effect ofdigital image compression on screeningfor diabetic retinopathy. Br J Ophthalmol85:799–802, 2001

3. Eikelboom RH, Yogesan K, Barry CJ, Con-stable IJ, Tay-Kearney ML, Jitskaia L,House PH: Methods and limits of digitalimage compression of retinal images fortelemedicine. Invest Ophthalmol Vis Sci 41:1916–1924, 2000

4. Zeimer R, Zou S, Meeder T, Quinn K, Vi-tale S: A fundus camera dedicated toscreening of diabetic retinopathy in theprimary-care physicians office. InvestOphthalmol Vis Sci 43:1581–1587, 2002

Indications ThatPhototherapy Is aRisk Factor forInsulin-DependentDiabetes

In a previous study (1), we found thatthe diagnosis of maternal-child bloodgroup incompatibility appeared as a

risk factor for type 1 diabetes, but we werenot able to disentangle possible treatmenteffects from that of diagnosis. A Europeanpopulation-based multicenter study con-firmed the association of type 1 diabetes

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with jaundice and blood group immuni-zation (2). Since our previous study, thenumber of infants recorded in the Swed-ish Childhood Diabetes Registry has al-most doubled. We therefore repeated ourstudy with special stress on the possiblerisk associated with phototherapy.

The Childhood Diabetes Registry,containing information on 7,343 chil-dren with diabetes and born duringthe period 1973–1997, was linked withthe Medical Birth Registry to get individ-ual and diabetes-independent informa-tion on neonatal events. No linkageoccurred for 327 (4.5%) diabetic chil-dren. We excluded twins, infants born ofdiabetic mothers, and infants whosecounty of birth was unknown, leaving6,487 cases for analysis and 2.8 millionbirths for comparison. We used Mantel-Haenszel’s weighted estimates of odds ra-tios (ORs), stratifying for year of birth. Alogistic multiple regression analysis wasalso made with further adjustments forputative confounders.

A diagnosis of jaundice gave an OR of1.13 (95% CI 1.01–1.26). The OR fortherapy, irrespective of diagnosis, was3.79 (3.13–4.59). Therapeutic traditionsand coding habits may vary by county andover time; the OR was relatively constantover time but varied between counties.We selected three counties with morethan five treated infants who developedtype 1 diabetes and added the other 21counties into one group (0 –5 treatedcases per county, 54 total). The OR fortherapy and type 1 diabetes was 2.41(1.36 – 4.17) in the first county, 6.03(3.29–10.8) in the second county, 4.80(2.64–8.53) in the third county, and 2.62in the remaining counties. The heteroge-neity was significant between the groups(P � 0.015). The ORs for a jaundice di-agnosis for the two high-risk counties was1.30 (0.79–2.16) and thus not differentfrom the rest (1.01 [0.57–1.53]). We an-alyzed the type 1 diabetes risk in the twohigh-risk counties with enough recordedevents and in the remaining counties inlogistic multiple regression analyses, en-tering year of birth, preterm birth, respi-ratory symptoms in the newborn, bloodgroup immunization, and phototherapyas explanatory variables. The photother-apy OR was 1.95 (1.19–3.20) in the twoselected counties and 1.06 (0.78–1.43) inthe other counties.

Our findings indicate that previousobservations that neonatal jaundice

and/or blood group incompatibility syn-dromes are associated with type 1 diabe-tes risk may be due to phototherapytreatment independent of diagnosis. Thedifference in OR between the counties in-dicates that actual treatment regimescould be of importance, and a medicalrecord study could pinpoint such differ-ences. The mechanism behind the associ-ation is unknown; however, effects on theneonatal gut and gut immune responseare possible, and the frequent use of thistreatment combined with the increasingincidence of childhood type 1 diabetes re-quires further study.

Acknowledgments— This study was sup-ported by grants from the Swedish MedicalResearch Council (project no. 07531), theSwedish Diabetes Association, and the NordicInsulin Foundation.

The authors thank all members of the Swed-ish Childhood Diabetes Study Group whocontributed to the Swedish Childhood Diabe-tes Registry and the National Board of Healthand Welfare for providing access to the Medi-cal Birth Registry.

GISELA DAHLQUIST, MD, PHD1

BENGT KALLEN, MD, PHD2

From the 1Department of Clinical Sciences, Paediat-rics Umeå University, Umeå, Sweden; and the2Tornblad Institute, Lund University, Lund, Swe-den.

Address correspondence to Prof. Gisela Dahl-quist, Umeå University, Department of Clinical Sci-ences—Paediatrics, S-901 85 Umeå, Sweden.E-mail: [email protected].

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References1. Dahlquist G, Kallen B: Maternal-child

blood group incompatibility and otherperinatal events increase the risk for early-onset type I (insulin-dependent) diabetesmellitus. Diabetologia 35:671–675, 1992

2. Dahlquist G, Petterson C, Soltesz G: Peri-natal risk factors for childhood type 1diabetes in Europe: the EURODIAB Sub-study 2 Study Group. Diabetes Care 22:1698–1702, 1999

Celiac Disease andType 1 Diabetes

T ype 1 diabetes is a chronic autoim-mune disorder with varying degreesof insulin deficiency resulting from

an immune-mediated destruction of pan-

creatic �-cells, usually starting in youngindividuals with an acute onset (1).

Type 1 diabetes can be associatedwith other clinical, subclinical, or poten-tial organ-specific autoimmune diseases,mainly of thyroid, stomach, adrenals, andintestine, contributing to depict the con-stellation of autoimmune polyglandularsyndromes (2,3).

Celiac disease is an autoimmune en-teropathy characterized by small intesti-nal lesions of variable severity (4). Ingenetically predisposed individuals, thedisease is triggered by ingestion of gluten.Celiac disease is diagnosed by small-bowel biopsy and is associated with anti-gliadin antibodies (AGAs), endomysial(EmA), and tissue transglutaminase auto-antibodies (tTGAs) of IgA class (4). It iswell known that clinical celiac diseaserepresents only the tip of the iceberg. Thesubclinical disease is not infrequent in thegeneral population, and AGAs associatedto EmA can be used as markers for theidentification of these asymptomatic indi-viduals (5).

Coexistence of type 1 diabetes and ce-liac disease was first suspected in 1954(6). The recognition of celiac disease inasymptomatic patients with type 1 diabe-tes is important. From 1984 to 2001, apopulation of 15,712 patients with type 1diabetes has been examined in 38 pub-lished articles. Using different screeningprocedures for autoantibodies, the re-ported prevalence of celiac disease rangedfrom 0.6 to 16.4%.

Recently, tTGAs were measured in305 patients from Germany with newlydiagnosed type 1 diabetes: 11 (3.6%) and12 (3.9%) subjects were positive fortTGA-IgA and IgG, respectively. Of 12 pa-tients, 5 gave informed consent for small-bowel biopsy and all showed either partialor total villous atrophy (7).

A total of 200 patients with type 1diabetes at onset (107 men, 93 women;mean age 21.5 years, range 9 months to72 years) were screened for celiac disease,testing tTGAs of IgA class by commercialkit Quanta Lite tTG ELISA (INOVA Diag-nostic, San Diego, CA) with purified anti-gen from guinea pig liver. The sera withvalues �20 units were considered nega-tive. One of them had a known history ofceliac disease.

Of the 200 patients who underwenttTGA-IgA testing, 8 (6 women and 2 men)(4%) were positive; levels ranged from20.7 to �200 units. One of them was the

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patient with known celiac disease, whodid not maintain the diet. Of the sevenpatients who remained tTGA-IgA posi-tive, four (with titers of 34.9 units, 36.8units, 159.6 units, and �200 units, re-spectively) gave informed consent forsmall-bowel biopsy. All showed eitherpartial or total villous atrophy, thus con-firming the diagnosis of celiac disease.

This study shows that the appearanceof tTGA-IgA represents a specific markerto identify subjects with silent celiac dis-ease. This is important because the treat-ment of asymptomatic patients with type1 diabetes with a gluten-free diet has apositive effect on glycemic control (8) andon the growth. Furthermore, it can pre-vent osteoporosis and the development ofother autoimmune diseases.

FRANCESCA LAZZAROTTO, MD1

DANIELA BASSO, MD2

MARIO PLEBANI, MD2

ALESSANDRO MOSCON, TCH1

RENATO ZANCHETTA, MD1

CORRADO BETTERLE, MD1

From the 1Dipartimento di Scienze Mediche eChirurgiche, Universita di Padova, Padova, Italy;and the 2Dipartimento Interaziendale di Medicina diLaboratorio, Azienda Ospedale-Universita diPadova, Padova, Italy.

Address correspondence to Corrado Betterle, Di-partimento di Scienze Mediche e Chirurgiche, Uni-versita di Padova, Via Ospedale 105, Padova, 35100,Italy. E-mail: [email protected].

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References1. Atkinson MA, Eisenbarth GS: Type 1 dia-

betes: new perspectives on disease patho-genesis and treatment. Lancet 358:221–229, 2001

2. Drell DW, Notkins AL: Multiple immuno-logical abnormalities in patients with type1 (insulin-dependent) diabetes mellitus.Diabetologia 30:132–143, 1987

3. Presotto F, Betterle C: Insulin-dependentdiabetes mellitus: a constellation of auto-immune diseases. J Pediatr Endocr Met 10:455–469, 1997

4. Maki M, Collin P: Coeliac disease. Lancet349:1755–1759, 1997

5. Catassi C, Ratsch I-M, Fabiani E, RossiniM, Bordicchia F, Candela F, Coppa GV,Giorgi PL: Coeliac disease in the year2000: exploring the iceberg. Lancet 343:200–203, 1994

6. Payne WW: Coeliac disease and diabetesmellitus in the same patient. Gt OrmondStr J 8:118–122, 1954

7. Seissler J, Schott M, Boms S, Wohlrab U,Ostendorf B, Morgenthaler NG, Scher-baum WA: Autoantibodies to human tis-

sue transglutaminase identify silentcoeliac disease in type I diabetes. Diabeto-logia 42:1440–1441, 1999

8. Mohn A, Cerruto M, Iafusco D, Prisco F,Tumini S, Stppoloni O, Chiarelli F: Celiacdisease in children and adolescents withtype 1 diabetes: importance of hypoglyce-mia. J Pediatr Gastroenterol Nutr 32:37–40, 2001

Influence of AlcoholIntake and AldehydeDehydrogenase 2Phenotype onPeripheralNeuropathy ofDiabetes

In Asians, the differences of alcohol tol-erance are mainly determined by apolymorphism of aldehyde dehydro-

genase 2 (ALDH2), which metabolizes ac-etaldehyde produced from ethanol intoacetate (1). To examine whether the inac-tive ALDH2 influences the peripheralneuropathy in diabetes, 194 Japanese pa-tients with type 2 diabetes (135 men and58 women, aged 59.1 � 11.7 years) weredivided by ALDH2 phenotype and alco-hol consumption and then the correlationof NCV (nerve conduction velocity in tib-ial motor nerve) with clinical parameterswas compared. It was found that 99 and95 patients had the active and inactiveALDH2 phenotype, respectively. In thefirst set of patients, 22 were nondrinkers(group 1) and 77 were drinkers (group 2).In the second set, 42 were nondrinkers(group 3) and 53 were drinkers (group 4).As determined by regression analysis,NCV was inversely correlated with diabe-tes duration and HbA1c in the nondrink-ers (group 1: r � 0.433, P � 0.05 forHbA1c; group 3: r � 0.509, P � 0.01 forduration). In the drinkers, alcohol con-sumption was calculated as amounts ofalcohol weight (in grams) per week. NCVwas inversely correlated with the pastmaximum alcohol consumption per weekin group 4 only (r � 0.502, P � 0.001),not in group 2. These results suggest thatperipheral neuropathy in diabetes is re-lated to alcohol consumption, especiallyin drinkers who are genetically alcohol in-tolerant.

Because the ALDH2 gene is tran-scribed in the nervous system, the ALDH2

deficiency may directly contribute to ex-cess acetaldehyde accumulation after al-cohol ingestion. Alternatively, nerve lipidperoxidation increases in experimentaldiabetic neuropathy (2). Among lipid-peroxidative-derived toxic aldehydes,4-hydroxynonenal (4-HNE) is one of themost reactive aldehydes under physiolog-ical conditions. 4-HNE inhibits Na/K AT-Pase and has multiple deleterious effectson nerve (3). Aldehydes, including4-HNE and acetaldehyde, are cometabo-lized by ALDH isozymes (4). Therefore, ingroup 4, due to the increased needs ofacetaldehyde oxidation after alcohol in-gestion, the patients with inactive ALDH2may have a high nerve tissue concentra-tion of toxic aldehydes such as 4-HNE,thereby developing neuropathy and slow-ing NCV.

Acknowledgments— The authors thank Dr.R. Arakaki for reviewing the manuscript.

YOSHIHIKO SUZUKI, MD1

MATSUO TANIYAMA, MD2

TANIYAMA MURAMATSU, MD3

SHIGEO OHTA, PHD4

YOSHITO ATSUMI, MD1

KEMPEI MATSUOKA, MD1

From 1Saiseikai Central Hospital, Tokyo, Japan;2Fujigaoka Hospital, Showa University, Kanagawa,Japan; the 3Department of Neuropsychiatry, KeioUniversity, Tokyo, Japan; and the 4Department ofBiochemistry and Cell Biology, Institute of Geron-tology, Nippon Medical School, Nippon, Japan.

Address correspondence to Yoshihiko Suzuki,MD, Saiseikai Central Hospital, 1-4-17, Mita, Mi-nato-ku, Tokyo 108, Japan. E-mail: [email protected].

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References1. Crabb DW, Edenberg HJ, Bosron WF, Li

TK: Genotypes for aldehyde dehydroge-nase deficiency and alcohol sensitivity:the inactive ALDH2*2 allele is dominant.J Clin Invest 83:314–316, 1989

2. Low PA, Nichander KK, Tritschler HJ:The role of oxidative stress and antioxi-dant treatment in experimental diabeticneuropathy. Diabetes 46 (Suppl. 2):S38–S42, 1997

3. Siems WG, Hapner SJ, Kuuk FJGM: 4-Hydroxynonenal inhibits Na�-K�-ATPase.Free Radic Biol Med 20:215–223, 1996

4. Hartly DP, Petersen DR: Co-metabolismof ethanol, ethanol-derived acetaldehyde,and 4-hydroxynonenal in isolated rathepatocytes. Alcohol Clin Exp Res 21:298–304, 1997

Letters


High Prevalence ofInsulin Resistanceand MetabolicSyndrome inOverweight/ObesePreadolescent HongKong ChineseChildren Aged 9–12Years

During the past decade, the risingprevalence of childhood obesity hasbeen accompanied by a rapid in-

crease in young-onset type 2 diabetes (1).The associations among obesity, insulinresistance, hypertension, and dyslipide-mia are not well defined in preadolescentchildren. Furthermore, the impact of fam-ily history of diabetes, low birth weight,and non–breast-feeding on the clusteringof features of insulin resistance syndromein children remained to be determined. Ina cross-sectional study of 271 primaryschool children between 9 and 12 years ofage, we compared the effects of family his-tory of diabetes, breast-feeding, and ex-tremes of birth weight on obesity, insulinresistance, and cardiovascular risk factorsbetween an obese/overweight (n � 129)and a nonobese group (n � 142). Anthro-pometric indexes, blood pressure, fastingplasma lipids, glucose, and insulin weremeasured. Family history of diabetes,birth weight, and feeding mode in the first3 months of life were obtained from par-ents.

Overweight/obese children weretaller and had higher systolic blood pres-sure, fasting triglycerides, fasting seruminsulin, and insulin resistance index (ho-meostasis model assessment) but lowerHDL cholesterol level than nonobese chil-dren (Table 1). The odds ratios for a fam-ily history of diabetes and formula feedingin overweight/obese children were 4.37-(95% CI 2.25– 8.52, P � 0.001) and2.20-fold (1.29–3.76, P � 0.004). Over-weight/obese children had increased riskof high blood pressure (3.21 [1.60 –6.45], P � 0.001), dyslipidemia (2.72[1.58–4.66], P � 0.001), and hyperinsu-linemia (defined as insulin level above theage- and sex-specific 85th percentile;14.1 [7.75–25.48], P � 0.001). Nearly50% of overweight/obese children had atleast two of the three cardiovascular riskfactors of dyslipidemia, high blood pres-sure, and hyperinsulinemia, and 8% hadall three risk factors. Seventy-seven per-cent of overweight/obese children had in-sulin resistance, which was best predictedby waist circumference (� � 0.52, P �0.001) and HDL cholesterol level (� ��0.19, P � 0.001) on multivariate anal-ysis.

Clustering of cardiovascular risk fac-tors is common in overweight/obese pre-adolescent children in Hong Kong.Overweight/obese children are morelikely to have a positive family history ofdiabetes and formula milk-feeding in in-fancy. Our findings support the notionthat breast-feeding may be associatedwith a reduction in childhood obesity risk(2). In agreement with the recent report

by Sinha et al. (3), �77% of overweight/obese children in the present study hadhyperinsulinemia. Given the predictivevalue of insulin resistance on future de-velopment of type 2 diabetes and coro-nary heart disease (4,5), the highprevalence of insulin resistance in thesepreadolescent children is an importantpublic health issue.

Acknowledgments— This study was sup-ported by funding From the Research GrantsCouncil of the Hong Kong Special Administra-tive Region (project no. CUHK 4060/00M)and the Hong Kong Foundation for Researchand Development in Diabetes.

RITA Y.T. SUNG, MD, FRCP1

PETER C.Y. TONG, PHD, MRCP2

CHUNG-WAH YU, MB, BS, MPHIL1

PATRICK W.C. LAU, PHD3

GEOFFREY T.F. MOK, MB, BS, MRCP1

MAN-CHING YAM, MB, BS, MRCP1

PEGGO K.W. LAM, MPHIL4

JULIANA C.N. CHAN, MD, FRCP2

From the 1Department of Pediatrics, the ChineseUniversity of Hong Kong, the Prince of Wales Hos-pital, Shatin, Hong Kong; the 2Department of Med-icine & Therapeutics, the Chinese University ofHong Kong, the Prince of Wales Hospital, Shatin,Hong Kong; the 3Department of Physical Education,Hong Kong Baptist University, Kowloon, HongKong; and the 4Centre for Clinical Trials and Epidemi-ological Research, the Chinese University of HongKong, the Prince of Wales Hospita, Shatin, Hong Kong.

Address correspondence to Dr. Peter Tong, De-partment of Medicine & Therapeutics, The ChineseUniversity of Hong Kong, The Prince of Wales Hospi-tal, Shatin, Hong Kong. E-mail: [email protected].

Table 1—Clinical characteristics and cardiovascular risk profiles in overweight/obese and nonobese Chinese preadolescent children

Boys Girls

Nonobese Obese P Nonobese Obese P

n 67 84 75 45Age (years) 10.5 � 1.1 10.4 � 0.9 NS 10.4 � 1.0 10.5 � 1.1 NSBMI (kg/m2) 16.7 � 1.7 24.7 � 3.1 �0.001 16.5 � 1.7 23.4 � 2.4 �0.001Birth weight (kg) 3.26 � 0.50 3.39 � 0.52 NS 3.18 � 0.46 3.26 � 0.46 NSWaist circumference (cm) 61.1 � 5.6 80.6 � 8.0 �0.001 60.5 � 4.8 75.2 � 7.9 �0.001Systolic blood pressure (mmHg) 98 � 10 107 � 9 �0.001 99 � 10 107 � 11 �0.001Diastolic blood pressure (mmHg) 63.5 � 11 67 � 13.0 NS 64 � 11 67 � 11 NSFasting triglycerides (mmol/l)* 0.72/�1.38 0.96/�1.51 �0.001 0.77/�1.46 0.99/�1.53 �0.01Fasting HDL cholesterol (mmol/l) 1.80 � 0.37 1.41 � 0.37 �0.001 1.65 � 0.42 1.40 � 0.33 �0.01Fasting plasma glucose (mmol/l) 4.8 � 0.3 4.8 � 0.4 NS 4.7 � 0.3 4.7 � 0.4 NSFasting serum insulin (pmol/l)* 41.7/�1.9 110/�2.1 �0.001 57/�2.1 102.1/�1.8 �0.001Insulin resistance index (HOMA)* 1.22/�1.9 3.22/�2.2 �0.001 1.66/�2.2 2.94/�1.8 �0.001

Data are means � SD or *geometric means /� antilog SD. HOMA, homeostasis model assessment; NS, not significant.

Letters


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References1. Rosenbloom AL, Joe JR, Young RS, Winter

WE: Emerging epidemic of type 2 diabetesin youth. Diabetes Care 22:345–354, 1999

2. Armstrong J, Reilly JJ: Breastfeeding andlowering the risk of childhood obesity.Lancet 359:2003–2004, 2002

3. Sinha R, Fisch G, Teague B, TamborlaneWV, Banyas B, Allen K, Savoye M, RiegerV, Taksali S, Barbetta G, Sherwin RS,Caprio S: Prevalence of impaired glucosetolerance among children and adolescentswith marked obesity. N Engl J Med 346:802–810, 2002

4. Larsson B, Svardsudd K, Welin L, Wil-helmsen L, Bjorntorp P, Tibblin G: Ab-dominal adipose tissue distribution,obesity, and risk of cardiovascular diseaseand death: 13 year follow up of partici-pants in the study of men born in 1913. BrMed J (Clin Res Ed) 288:1401–1404,1984

5. Boyko EJ, Fujimoto WY, Leonetti DL,Newell-Morris L: Visceral adiposity andrisk of type 2 diabetes: a prospective studyamong Japanese Americans. Diabetes Care23:465–471, 2000

Effect of StructuredGroup Education onGlycemic Control andHypoglycemia inInsulin-TreatedPatients

W e investigated the effect of astructured group diabetes edu-cation program (1) on insulin-

treated patients who had receivedindividual counseling (at the time of diag-nosis and insulin initiation). A total of1,369 type 1 and insulin-treated type 2diabetic patients with mean disease dura-tion of 11.7 and 13.7 years, respectively,were allocated to receive or not receivestructured group education, which wasdelivered in 10 45-min sessions over 3–5days.

Baseline GHb levels of type 1 diabeticpatients were 9.3% for the educationgroup and 9.13% for the control groupand decreased at 6 months by �0.82 and�0.22%, respectively (P � 0.0005). Thenumber of injections per day and self-monitoring increased, while the total in-sulin dose remained unchanged. Theincidence of severe hypoglycemia was re-duced by 0.18 events/6 months in the ed-

ucation group, whereas it increased by0.03 events/6 months in the controlgroup (P � 0.003).

In type 2 diabetic patients, baselineGHb was 9.1% in the education and 8.7%in the control group, with a significantdifference in the changes after 6 monthsin favor of the education group: �0.48 vs.0.17%, respectively (P � 0.0005). Atrend of reduced incidence of hypoglyce-mic episodes was observed.

Education for people with diabetes isa prerequisite for an understanding andacceptance of their condition and its suc-cessful self-management (2). A recentstudy found that group education was aseffective as individual tuition in achievingimprovements in glycemic control (3). Inour study, structured group education af-ter initial individual counseling at diagno-sis and insulin initiation resulted inimproved glycemic control and reductionof hypoglycemia. This observation is inline with results from previous publica-tions (4,5). These improvements could beattributed to better self-care (increasedfrequency of self-monitoring in both type1 and insulin-treated type 2 diabetic pa-tients) and the increase in the number ofinsulin injections (in type 1 diabetic pa-tients). It should be noted that there wasnot a significant difference in the meaninsulin doses at the 6-month follow-upvisit compared with baseline in both type1 and type 2 diabetic patients; therefore, itwas not the amount of injected insulin butthe educational intervention that contrib-uted to the improved glycemic control.

It can be suggested that a group edu-cation program following individualcounseling could be an effective tool indiabetes management.

DRAGOMIR J. KOEV, MD, DMSC1

TZVETALINA I. TANKOVA, MD, PHD1

PLAMEN G. KOZLOVSKI, MD2

From the 1Diabetic Clinic, Medical University, Sofia,Bulgaria; and 2Novo Nordisk A/S, Bagsværd, Den-mark.

Address correspondence to Plamen Kozlovski,MD, Novo Nordisk A/S, Novo Alle, 2880 Bagsvaerd,Denmark. E-mail: [email protected].

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References1. Diabetes Education Program in Bulgaria

(DEPB) Project Group: Diabetes educa-tion program in Bulgaria. Patient EducCounsel 43:111–114, 2001

2. Assal JP, Muhlhauser I, Pernet A, GfellerR, Jorgens V, Berger M: Patient education

as the basis for diabetes care in clinicalpractice and research. Diabetologia 28:602–613, 1985

3. Rickeim PL, Weaver TW, Flader JL, Ken-dall DM: Assessment of group versusindividual diabetes education: a random-ized study. Diabetes Care 25:269–274,2002

4. Tilly KF, Belton AB, McLachlan JF: Con-tinuous monitoring of health statusoutcomes: experience with diabetes edu-cation. Diabetes Educ 21:413–419, 1995

5. Pieber TR, Brunner GA, Schenedl WJ,Schattenberg Kaufmann P, Krejs GJ: Eval-uation of a structured outpatient groupeducation program for intensive insulintherapy. Diabetes Care 18:625–630, 1995

Relationship of �2-Adrenergic ReceptorPolymorphism WithObesity in Type 2Diabetes

Adrenergic receptor genes are candi-date genes for obesity and type 2diabetes because they regulate lipid

mobilization. An association has been re-ported between the frequently occurringGly27Gln polymorphism of the �2-adrenergic receptor (B2ADR) gene withobesity (1,2) and triglycerides (3) in non-diabetic subjects.

We studied 542 unrelated type 2 di-abetic subjects to assess the possible rela-tionship of the Glu27Gln polymorphismof the B2ADR gene with obesity, as well aswith plasma lipids. The Medical EthicsCommittee of the University MedicalCenter Utrecht approved the study, andall participants signed an informed con-sent. The Glu27Gln polymorphism wasexamined by a modification of a PCR/restriction fragment–length polymor-phism– based method (3) in duplicateand included sequence-verified controls.

After exclusion of PCR failures, geno-types were obtained for 502 type 2 dia-betic patients. Subjects were subdividedaccording to three genotype groups: 109subjects were Gln27Gln, 225 wereGlu27Gln, and 168 were Glu27Glu.ANOVA of age at diagnosis of type 2 dia-betes (61 � 10, 60 � 9, and 61 � 9 yearsfor the Gln27Gln, Glu27Gln, andGlu27Glu genotype groups, respective-ly), BMI (27.2 � 3.8, 27.9 � 4.4, and28.2 � 4.0 kg/m2), HbA1c (7.2 � 1.4,

Letters


7.4 � 1.3, and 7.2 � 1.2%; normal values�6.1%), plasma cholesterol (5.3 � 1.2,5.3 � 1.0, and 5.3 � 1.0 mmol/l), plasmaHDL cholesterol (1.2 � 0.3, 1.1 � 0.3,and 1.2 � 0.3 mmol/l), and plasma tri-glycerides (1.8 � 1.1, 1.9 � 0.9, and1.9 � 0.1 mmol/l) showed no statisticallysignificant differences (all P � 0.26). Afterexclusion of the insulin-treated subjects,the differences were also not statisticallysignificant. We also found no significantdifferences for men or women separately.

We conclude that, at least in our co-hort of subjects with type 2 diabetes, theGlu27Gln polymorphism of the �2-adrenergic receptor has no important ef-fect on BMI, age at diagnosis of diabetes,metabolic control, or plasma lipids.

Acknowledgments— This work was sup-ported by the Dutch Diabetes Research Foun-dation (Amersfoort, the Netherlands, DFNgrant 97.114 to C.W. and T.W.v.H.).

JONATHAN H. VAN TILBURG, PHD1

CISCA WIJMENGA, PHD1

HARM VAN BAKEL, MSC1

LEIDA ROZEMAN, MSC1

PETER L. PEARSON, PHD1

TIMON W. VAN HAEFTEN, MD2

From the 1Department of Medical Genetics, Univer-sity Medical Center, Utrecht, the Netherlands; andthe 2Department of Internal Medicine, UniversityMedical Center, Utrecht, the Netherlands.

Address correspondence to Timon W. vanHaeften, MD, Department of Internal Medicine, G02.228, P.O. Box 85500, NL 3508 GA Utrecht, TheNetherlands. E-mail: [email protected]

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References1. Large V, Hellstrom L, Reynisdottir S, Lon-

nqvist F, Eriksson P, Lannfelt L, Arner P:Human beta-2 adrenoceptor gene poly-morphisms are highly frequent in obesityand associate with altered adipocytebeta-2 adrenoceptor function. J Clin Invest100:3005–3013, 1997

2. Ehrenborg E, Skogsberg J, Ruotolo G,Large V, Eriksson P, Arner P, HamstraA: The Q/E27 polymorphism in thebeta2-adrenoceptor gene is associatedwith increased body weight and dysli-poproteinaemia involving triglyceride-rich lipoproteins. J Intern Med 247:651–656, 2000

3. Rosmond R, Ukkola O, Chagnon M,Bouchard C, Bjorntorp P: Polymor-phisms of the beta2-adrenergic receptorgene (ADBR2) in relation to cardiovas-

cular risk factors in men. J Intern Med248:239 –244, 2000

Decreased Glucagon-Like Peptide 1Fasting Levels inType 2 Diabetes

The significance of over- or under-production of glucagon-like peptide1 (GLP-1) (7–36) amide in diabetes

remains controversial (1,2). Although ithas been proposed that at least one factorcontributing to the pathogenesis of type 2diabetes is desensitization of the GLP-1receptor on �-cells (2), exogenous ad-ministration of GLP-1 in patients withtype 2 diabetes fully normalizes fastinghyperglycemia and reduces postprandialglycemic increments (3). Also, the GLP-1response to oral glucose is not altered inpostmenopausal women with impairedglucose tolerance (2). The purpose of thepresent study was to establish any differ-ence in the fasting state concentration ofGLP-1 in type 2 diabetes as comparedwith the normal state.

We examined 26 subjects (12 menand 14 women) with type 2 diabetes whowere aged 67.6 � 10.09 years (means �SD) and had a BMI of 29.2 � 3.5 kg/m2

and a diabetes duration of 137.0 � 23.7months. As a control group, we included15 normal subjects (9 women and 6 men)who were aged 65.8 � 8.01 years and hada BMI of 28.1 � 3.7 kg/m2. Patients withtype 2 diabetes were treated by diet andwere on metformin and/or sulfonylureatherapy with HbA1c 6.81 � 1.37% andfasting glucose 87.30 � 5.20 mg/dl. Writ-ten consent was obtained from all partic-ipants. Blood samples were obtained atrest between 8:00 and 9:00 A.M. after anovernight fast and 24 h alcohol absten-tion. Insulin and GLP-1 were measuredusing an enzyme-linked immunosorbentassay (AxSYM; Abbott Lab, North Abbott,IL) and competitive radioimmunoassay(Peninsula Lab, Belmont, CA), respectively.

Interestingly, GLP-1, displaying anormal distribution, exhibited a statisti-cally significant decrease (P � 0.001) intype 2 diabetic patients (23.8 � 3.17 pg/ml) compared with control subjects(76.4 � 4.47), whereas the plasma insu-lin concentration was higher in type 2 di-

abetic subjects (20.9 � 13.4 IU/ml) thanin control subjects (9.8 � 1.3), with thedifference being statistically significant(P � 0.03).

Using linear regression analysis, wefound that GLP-1 was more negativelycorrelated with insulin in the type 2 dia-betic patients than in the normal subjects(r � �0.64, P � 0.001 vs. r � �0.43,P � 0.040). In addition, GLP-1 was alsonegatively correlated with HbA1c in type2 diabetic subjects at a statistical level(r � �0.43, P � 0.037). Interestingly,the results were independent of diabetesduration.

The physiological importance of thedecreased fasting level of GLP-1 in type 2diabetic patients requires further clarifi-cation. If it is a reflection of increasedsensitivity of �-cell responsitivity tosecretagogues, then this study furtherconfirms previous findings on the exis-tence of a negative feedback loop betweenGLP-1 and insulin secretion and providesfurther evidence for the importance of theentero-insular axis in the regulation of in-sulin secretion. Moreover, the dissocia-tion of GLP-1 levels with the duration ofthe disease suggests an early impairmentof the entero-insular axis.

IOANNIS N. LEGAKIS, MD

COSTAS TZIORAS, MD

COSTAS PHENEKOS, MD

From the Endocrinology Unit, Red Cross Hospital,Athens, Greece.

Address correspondence to Dr. Ioannis N. Le-gakis, 27 Navarinou St., Cholargos 155 62 Athens,Greece. E-mail: [email protected].

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References1. Orskov C, Jeppesen J, Madsbad Holst JJ:

Proglucagon products in plasma of non-insulin-dependent diabetics and nondia-betic controls in the fasting state and afteroral glucose and intravenous arginine.J Clin Invest 87:415–423, 1991

2. Kieffer TJ, Habener JF: The glucagon-likepeptides. Endocr Rev 20:876–913, 1999

3. Toft-Nielsen MB, Madsbad S, Holst JJ:Continuous subcutaneous infusion ofglucagon-like peptide 1 lowers plasmaglucose and reduces appetite in type 2 di-abetic patients. Diabetes Care 22:1137–1143, 1999

Letters


DocosahexaenoicAcid But NotEicosapentaenoicAcid Increases LDLParticle Size inTreatedHypertensive Type 2Diabetic Patients

The dyslipidemia of type 2 diabetesincludes the accumulation of smalldense LDL particles in plasma that

have an increased propensity to glycationand oxidation and may contribute to theendothelial dysfunction in type 2 diabeticpatients. We recently reported that botheicosapentaenoic acid (EPA) and docosa-hexaenoic acid (DHA), the two majordietary long-chain n-3 fatty acids, signifi-cantly reduced triglycerides and in-creased HDL2 cholesterol withoutchanging total, LDL, or HDL cholesterolin a group of type 2 diabetic subjects (1).We now report additional data on the dif-ferential effects of EPA and DHA on LDLparticle size in the same subjects.

Nonsmoking treated hypertensive di-abetic men and postmenopausal women,aged 40–75 years, were stratified by sex,age, and BMI and randomized to receive 4g/day purified EPA, DHA, or olive oil (pla-cebo) for 6 weeks in a double-blindedtrial. LDL particle diameter was deter-mined by gradient gel electrophoresis (2).

At baseline there were no significantdifferences among the olive oil, EPA, andDHA groups in plasma LDL cholesterollevel and LDL particle size (25.69 � 0.13nm, 26.0 � 0.16 nm, and 25.74 � 0.16nm, respectively). Relative to placebo,LDL particle size was decreased by 0.12 �0.10 nm (P � 0.49) with EPA and in-creased by 0.26 � 0.10 nm (P � 0.02)with DHA after adjusting for multiplecomparisons (Bonferroni).

These data support our previousstudy in overweight hypercholester-olemic subjects, in whom LDL particlesize increased after supplementation withDHA but not EPA (2). While the increasein LDL particle size with DHA supple-mentation seen in our present study ap-pears relatively small, a significantdifference in size of 1.02 nm distin-guished between middle-aged healthymen with no risk factors and men with the

metabolic syndrome (3). The differentialeffects on LDL particle size after EPA andDHA cannot be explained by the reduc-tion in triglycerides alone, since both EPAand DHA significantly decreased serumtriglycerides by a similar extent relative toplacebo (19 and 15%, respectively) (1).Additionally, the association between thechange in LDL size and triglycerides wasonly weak (r � �0.30, P � 0.04).

Supplementation with purified DHAincreases LDL particle size, reduces se-rum triglycerides, and increases HDL2cholesterol (1), as well as improves vascu-lar function (4) and blood pressure (5).Therefore, for subjects with type 2 diabe-tes, DHA may have more therapeuticvalue than EPA as a food additive, butlonger-term prospective studies areneeded to address this issue.

RICHARD J. WOODMAN, MMEDSCI1

TREVOR A. MORI, PHD1

VALERIE BURKE, MD1

IAN B. PUDDEY, MD1

GERALD F. WATTS, MD, PHD1

JAMES D. BEST, MD2

LAWRENCE J. BEILIN, MD1

From the 1Department of Medicine, the Universityof Western Australia, the West Australian Institutefor Medical Research and West Australian Heart Re-search Institute, Royal Perth Hospital, Perth, West-ern Australia; and the 2Department of Medicine,University of Melbourne and St. Vincents Hospital,Melbourne, Australia.

Address correspondence to Richard Woodman,Department of Medicine, University of WesternAustralia, P.O. Box x2213, Perth, WA, Australia6847. E-mail: [email protected].

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References1. Woodman RJ, Mori TA, Burke V, Puddey

IB, Watts GF, Beilin LJ: Effects of purifiedeicosapentaenoic acid and docosahexae-noic acid on glycemic control, blood pres-sure and serum lipids in treated-hyper-tensive type 2 diabetic patients. Am J ClinNutr 76:1007-1015, 2002

2. Mori TA, Burke V, Puddey IB, Watts GF,O’Neal DN, Best JD, Beilin LJ: Purified ei-cosapentaenoic and docosahexaenoic ac-ids have differential effects on serumlipids and lipoproteins, LDL particle size,glucose, and insulin in mildly hyperlipid-emic men. Am J Clin Nut 71:1085–1094,2000

3. Hulthe J, Bokemark L, Wikstrand J, Fag-erberg B: The metabolic syndrome, LDLparticle size, and atherosclerosis: the Ath-erosclerosis and Insulin Resistance (AIR)study. Arterioscler Thromb Vasc Biol 20:2140–2147, 2000

4. Mori TA, Watts GF, Burke V, Hilme E,Puddey IB, Beilin LJ: Differential effects ofeicosapentaenoic acid and docosahexae-noic acid on vascular reactivity of the fore-arm microcirculation in hyperlipidemic,overweight men. Circulation 102:1264–1269, 2000

5. Mori TA, Bao DQ, Burke V, Puddey IB,Beilin LJ: Docosahexaenoic acid but noteicosapentaenoic acid lowers ambulatoryblood pressure and heart rate in humans.Hypertension 34:253–260, 1999

The Human InsulinAnalogue Aspart IsNot the AlmightySolution for InsulinAllergy

A lthough human insulin is beneficialfor most diabetic patients, some pa-tients suffer from an allergy to

exogenous insulin. Human insulin ana-logues, lispro or aspart, have been welltolerated in cases of insulin allergy. How-ever, we report herein the first case of al-lergy to both lispro and aspart.

A 53-year-old woman with a historyof type 2 diabetes for the past 3 years con-sulted our hospital for management ofuncontrolled diabetes. Her postprandialblood glucose level was 12.9 mmol/l, andher HbA1c level was 10.2%. She was ini-tially treated with oral hypoglycemicagents (voglibose, glimepiride, met-formin, and pioglitazone), which led to adecrease in her HbA1c to 6.8%. However,her hyperglycemia became difficult tocontrol over the next year (HbA1c 7.6%),and treatment with intermediate-actinghuman insulin (Novolet N; Novo Nor-disk, Bagsværd, Denmark) was begun.Two months after starting insulin injec-tions, the patient noticed a skin rash anditching at the injection sites, so her insulinwas changed to the analogues aspart andlispro, in succession. The local reactionscontinued, however, and the insulin ana-logue injections were suspended.

The patient had no previous historyof any allergy. The percentage of eosino-phils in her peripheral white blood cellcount was 8.0%. She showed a high levelof total IgE (748 IU/ml; normal, �400IU/ml) and human insulin-specific IgE(19.80 IU/ml; normal, �0.34) measuredby radioallergosorbent test. She had apositive test for anti-insulin antibodies(52%; normal, �7%). Prick tests were

Letters


positive for lispro, aspart, human insulin,and porcine insulin, as well as for an ad-ditive of insulin preparations, protamine,using the Novo insulin allergy kit (NovoNordisk), for which in vitro drug-induced lymphocyte stimulation testswere all positive. A biopsied specimen ofthe skin with prick tests revealed subcu-taneous edema with infiltrated cells, in-cluding eosinophils. Her illness wasdiagnosed as insulin allergy.

Because the anti-allergenic drug ebas-tine did not reduce the allergic reaction,insulin and insulin analogues had to bediscontinued. Since the patient’s hospital-ization, administration of oral hypoglyce-mic agents with intensification ofnutrition therapy and exercise has conve-niently led to an HbA1c of 5.5%.

The human insulin analogues aspart(B28Asp human insulin) and lispro(B28Lys-B29Pro human insulin) havebeen reported to be beneficial for the re-duction of allergic reactions to insulin be-cause of less antigenicity due to increasedclearance of insulin analogue monomersfrom injection sites. Aspart has been con-firmed to be less immunogenic for devel-opment of antibodies against humaninsulin (1). Lispro and aspart have beenavailable internationally since 1996 and1999, respectively; and both analogues,especially aspart, certainly seem to bebeneficial for patients with insulin allergy(2,3). To our knowledge, there has beenno report that aspart is intolerable in casesof insulin allergy. However, our patientshowed an allergic reaction to both insu-lin analogues. Therefore, these analoguesare not necessarily tolerated as alterna-tives when insulin allergy has already de-veloped. We need follow-up of patientstreated with insulin analogues that fo-cuses on the evocation of insulin allergy.

HIROSHI TAKATA, MD

YOSHITAKA KUMON, MD

FUMIAKI OSAKI, MD

CHIZURU KUMAGAI, MD

KAORU ARII, MD

YUKIO IKEDA, MD

TADASHI SUEHIRO, MD

KOZO HASHIMOTO, MD

From the Second Department of Internal Medicine,Kochi Medical School, Kochi, Japan.

Address correspondence to Dr. Yoshitaka Ku-mon, Second Department of Internal Medicine, Ko-chi Medical School, Kohasu Okoh-Cho, Nankoku,Kochi 783-8505, Japan. E-mail: [email protected].

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References1. Ottensen JL, Nilsson P, Jami J, Weilguny

D, Duhrkop M, Bucchini D, Havelund S,Fogh JM: The potential immunogenicityof human insulin and insulin analoguesevaluated in transgenic mouse model.Diabetologia 37:1178–1185, 1994

2. Airaghi L, Lorini M, Tedeschi A: The in-sulin analog aspart: a safe alternative ininsulin allergy. Diabetes Care 24:2000,2001

3. Yasuda H, Nagata M, Moriyama H, Fuji-hira K, Kotani R, Yamada K, Ueda H,Yokono K: Human insulin analog insulinaspart does not cause insulin allergy. Di-abetes Care 24:2008–2009, 2001

Intensive DiabetesManagement MayImprove Pregnancy

Outcomes in Chinese gravidas withimpaired glucose tolerance

In a study of diabetes in pregnancy inTianjin, China (1,2), gravidas with im-paired glucose tolerance (IGT) were

found to have poor pregnancy outcomes(3). We studied the effect of an intensivediabetes management plan (IDMP) onpregnancy outcomes in 150 gravidas whodeveloped IGT during pregnancy.

Women were randomized to receiveeither intensive care (IC; n � 95) or usualobstetric care (UC; n � 55). Of the 95women randomized to the IC group, 48(50%) completed the IDMP. All 55women of the UC group completed thestudy. Comparisons of pregnancy out-comes were performed by intention totreat. The IDMP consisted of diet and ex-ercise advice, self–home blood glucosemonitoring, and/or insulin treatment ifindicated, as well as a fortnightly clinicalreview of glycemic status and other inter-vention goals. Low intake of calories wasprescribed according to pregravid BMI(4), with subjects consuming six evenlyspaced meals per day. The goal of theIDMP was fasting capillary whole bloodglucose �5.5 mmol/l and a 1.5-h post-prandial glucose �7.0 mmol/l. Glucosetests were carried out 1.5 h postprandial.Fasting glucose tests were also performedwhen the fasting glucose level at the diag-nostic OGTT was elevated.

The IC and UC groups were compa-rable in age, pregravid BMI, weight gain

during pregnancy, gestational age at de-livery, and fasting and 2-h OGTT glucoselevels. The rate of premature rupture ofmembranes (P-ROM) was significantlylower in the IC group than in the UCgroup (4.21% [4/95] vs. 20% [11/55],P � 0.0034). The reduced risk for P-ROMin the IC group persisted after control-ling for age, stature, pregravid body weight,fasting and 2-h OGTT glucose levels, ges-tational weeks at the OGTT, caesareandelivery status, and hospital levels (sec-ondary versus tertiary) (odds ratio [OR]0.135 [95% CI 0.032–0.559]). The fre-quency of caesarean delivery was also sig-nificantly lower in the IC group than inthe UC group (64.2% [61/95] vs. 80.0%[44/55], P � 0.0445); the reduced riskwas marginally significant after control-ling for covariates (0.479 [0.211–1.084]).

Differences in preterm birth, birthweight, perinatal morbidity and mortal-ity, and deformations between the twogroups were not statistically significant.No birth trauma or shoulder dystocia oc-curred in either group. Before the currentstudy, gravidas in Tianjin were notscreened for diabetes in pregnancy andIGT was not treated.

This study investigated the effect ofan established IDMP on pregnancy out-comes in order to provide evidence for(or indicate the lack of) public healthplanning toward improved populationobstetric care in Tianjin, China. Not-withstanding the inherent limitations inintroducing the intensive diabetes man-agement and a small sample size, thecurrent study shows that intensive dia-betes management can result in statisti-cally detectable and clinically importantimprovements in pregnancy outcomes.The challenge for developing countries,such as China, who faces the risingprevalence of type 2 diabetes (5), is todevelop evidence-based health servicesthat integrate a traditional beliefs sys-tem and century-old practice and thatconsider economic rationale and, mostimportantly, the health of women andtheir children.

XILIN YANG, PHD1,2

BRIDGET HSU-HAGE, PHD1

LING DONG, MD3

PING SHAO, MD3

HUA WANG, MD3

HUIGUANG TIAN, PHD4

YUE CHEN3

HONG ZHANG, MD3

Letters


From the 1Department of Rural Health, University ofMelbourne, Melbourne, Australia; the 2Tianjin Cen-ter for Disease Control and Prevention, Tianjin, Chi-na; the 3Tianjin Institute for Women’s Health,Tianjin, China; and the 4Tianjin Public Health Bu-reau, Tianjin, China.

Address correspondence to Bridget Hsu-Hage,School of Rural Health, Faculty of Medicine, Univer-sity of Melbourne, PO Box 6500, Shepparton, Vic-toria 3632, Australia. E-mail: [email protected].

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References1. Yang X, Hsu-Hage B, Zhang H, Yu L,

Dong L, Li J, Shao P, Zhang C: Gestationaldiabetes mellitus in women of single gra-vidity in Tianjin City, China. DiabetesCare 25:847–851, 2002

2. Yang X, Hsu-Hage B, Yu L, Simmons D:Selective screening for gestational diabe-tes in Chinese women (Letter). DiabetesCare 25:796, 2002

3. Yang X, Hsu-Hage B, Zhang H, Zhang C,Zhang Y, Zhang C: Women with impairedglucose tolerance during pregnancy havesignificantly poor pregnancy outcomes.Diabetes Care 25:1619–1624, 2002

4. Fagen C, King JD, Erick M: Nutritionmanagement in women with gestationaldiabetes mellitus: a review by ADA’s Dia-betes Care and Education Dietetic Prac-tice Group. J Am Diet Assoc 95:460–467,1995

5. Pan X-R, Yang W-Y, Li G-W, Liu J: Prev-alence of diabetes and its risk factors inChina, 1994. Diabetes Care 20:1664–1669, 1997

COMMENTS ANDRESPONSES

Thyroid StimulatingHormone ScreeningIs More Sensitive forDetecting ThyroidAbnormalities inChildren andAdolescents WithType 1 Diabetes

Kordonouri et al. (1) provide interest-ing information regarding the fre-quency of thyroid autoimmunity in

pediatric-aged patients with type 1 dia-betes. Their recommendations of “yearlyexaminations of thyroid antibodies” and

“in cases of thyroid antibody positivity,thyroid function tests and ultrasound as-sessment” “to minimize the risk of undi-agnosed hypothyroidism in youngpatients with type 1 diabetes” are not sup-ported by the data. If the goal is to detectsubjects with hypothyroidism, then asshown in Table 1 of their study, 15.8%(241) of 1,530 patients who were thyroidantibody positive had an elevated thyroidstimulating hormone (TSH) and would beconsidered true positives; 7.8% (434) of5,567 thyroid antibody–negative patientshad an elevated TSH and would be con-sidered false negatives. Thus, the sensitiv-ity [true positives/(true positives � falsenegatives)] for thyroid antibody testingequals 35%. There were 5,133 antibody-negative patients with normal TSH values(true negatives) and 1,289 thyroid anti-body–positive TSH-normal patients.Thus, the specificity [true negatives/(truenegatives � false positives)] for thyroidantibody testing in their study was 80%.In regard to patients requiring thyroxinetreatment, 10.6% (162) of the antibody-positive patients were true positives (an-tibody positive and thyroxine treated)and 0.6% (33) of the antibody-negativepatients were false negatives (antibodynegative and thyroxine treated). In addi-tion, there were 5,534 true negatives (an-tibody negative, no treatment) and 1,388false positives (antibody positive, notreatment). Thus, antibody testing was83% sensitive and 80% specific.

Since there is no proven benefit intreating antibody-positive patients withnormal TSH levels (2), and since screen-ing tests should be highly sensitive, thedata actually support yearly primary TSHscreening with possible secondary anti-body testing.

ROBERT P. HOFFMAN, MD

From The Ohio State University College of Medicineand Public Health, Department of Pediatrics, Co-lumbus, Ohio.

Address correspondence to Robert P. Hoffman,MD, Children’s Hospital ED541, 700 Children’s Dr.,Columbus, OH 43205. E-mail: [email protected].

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References1. Kordonouri O, Klinghammer A, Lang EB,

Gruters-Kieslich A, Grabert M, Holl RW:Thyroid autoimmunity in children andadolescents with type 1 diabetes: a multi-center survey. Diabetes Care 25:1346–1350, 2002

2. Rother KI, Zimmerman D, Schwenk WF:Effect of thyroid hormone treatment on-thyromegaly in children and adolescentswith Hashimoto disease. J Pediatr 124:599–601, 1994

Thyroid AntibodyScreening in Childrenand AdolescentsWith Type 1Diabetes

Response to Hoffman

W e thank Dr. Hoffman for his crit-ical comments (1). According tohis calculations, based on our

cross-sectional study data, he found aspecificity of 80% and only a low sensitiv-ity of 35% for the thyroid antibody–screening test. Thus, he does not supportour recommendation for yearly examina-tions of thyroid antibodies (2).

We agree with him that screeningtests should be highly sensitive, but thedata of our multicenter study do not allowa true estimation of the sensitivity, sincepatients have not been followed longitu-dinally and since we missed those patientswho will develop hypothyroidism later onduring their course of diabetes. Indeed,we examined patients with type 1 diabe-tes at the Pediatric Diabetes OutpatientClinic of the Otto-Heubner-Center,Charite, Berlin, and found that 8 of 16patients with positive antibodies devel-oped thyroid stimulating hormone (TSH)elevation after an observation time of 2–6years (median 3.5) (3). Therefore, patientswith positive antibodies should be moni-tored for TSH elevation at yearly intervals.

In addition, the German Associationof Pediatric and Adolescent Medicinerecommends that patients with positivethyroid antibodies and concomitant thy-roid gland enlargement with a typical hy-poechogenic pattern in ultrasoundstudies should receive treatment with L-thyroxine.

For these reasons, we have been per-forming thyroid antibody–screening testsat our institution in all patients with dia-betes since 1998.

OLGA KORDONOURI, MD1

REINHARD HARTMANN, MD1

REINHARD W. HOLL, MD2

Letters


From the 1Clinic for General Pediatrics, Otto-Heubner Centrum, Charite, Campus Virchow-Klinikum, Humboldt University, Berlin, Germany;and the 2Department of Biomedical Engineering,Ulm University, Ulm, Germany.

Address correspondence to Olga Kordonouri,MD, Klinik fur Allgemeine Padiatrie, Otto-Heubner-Centrum, Charite, CVK, Augustenburger Platz 1,13353 Berlin, Germany. E-mail: [email protected].

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References1. Hoffman RP: Thyroid stimulating hor-

mone screening is more sensitive for de-tecting thyroid abnormalities in childrenand adolescents with type 1 diabetes (Let-ter). Diabetes Care 26:255, 2003

2. Kordonouri O, Klinghammer A, Lang EB,Gruters-Kieslich A, Grabert M, Holl RW,on behalf of the DPV-Initiative of the Ger-man Working Group for Pediatric Diabe-tology: Thyroid autoimmunity in childrenand adolescents with type 1 diabetes: amulticenter survey. Diabetes Care 25:1346–1350, 2002

3. Kordonouri O, Deiss D, Danne T, DorowA, Bassir C, Gruters-Kieslich A: Predictiv-ity of thyroid autoantibodies for the devel-opment of thyroid disorders in childrenand adolescents with type 1 diabetes. Dia-bet Med 19:518–521, 2002

Reproducibility ofthe ContinuousGlucose MonitoringSystem MatchesPrevious Reportsand the IntendedUse of the Product

A recent article by Metzger et al. (1)questioned the reproducibility ofthe continuous glucose monitoring

system (CGMS; Medtronic MiniMed). Wewere surprised by the authors’ conclu-sions, as their results were consistent withpreviously published reports. We believethe authors’ expectations for the CGMSdid not coincide with its intended use.We were also puzzled by their use of asubjective assessment of clinical decisionmaking when a validated tool, i.e., theClarke error grid, is available (2). Finally,Metzger et al. dismissed the impact of anupdate to the CGMS software (Solutions3.0) that does in fact improve the repro-ducibility evident in their data.

Although Metzger et al. reported re-

sults based on a limited number of sub-jects (n � 11), the results are quite similarto those reported in a large postmarketingstudy (n � 235) (3). Correlation was 0.93mg/dl (vs. 0.91), and bias was 0.0 mg/dl(vs. �3.91). Metzger et al. also reportedthat 69% of sensor-sensor pairs had�10% difference, which comparesclosely with the previously reported me-dian difference of 12.6% between sensor-meter pairs. Even the meters used tocalibrate the CGMS provide only 56 to69% of self-monitored blood glucose val-ues within 10% of corresponding labora-tory results (4).

As stated in the instructions for use,information provided by the CGMS “is in-tended to supplement, not replace, bloodglucose information using standard homeglucose monitoring devices” by providingglucose pattern and trend information for24–72 h. Metzger et al. stated, “Clinicaldecisions should not be made on the solebasis of glucose sensor data” (1). Whenused with self-monitored blood glucoseand HbA1c values, clinical decisionsbased on CGMS profiles are designed tohelp the diabetes team optimize manage-ment.

Metzger et al. included several figuresdepicting discrepancies between sensor-sensor profiles, the most obvious beingpatient K. The authors failed to note thatthe sensor software labeled the depressedtracing as not meeting optimal accuracycriteria and that it therefore should havebeen further investigated by the clinicianbefore use. The authors further report a35% discrepancy in the clinical interpre-tation of sensor-sensor profiles. Thismethod of assessment is subjective andhas not been validated. Moreover, basedon a Clarke error grid analysis, �93% ofthe CGMS readings are clinically accurateor acceptable.

Metzger et al. report technical prob-lems in 18% of the profiles generated bySolutions 2.0 software. The upgraded So-lutions 3.0 software resolves many of thetechnical reasons for which data were dis-carded in their analysis, corrects theabrupt shift in value at midnight, im-proves the accuracy and reproducibilityof the data downloads, and improves theagreement between sensor and meter val-ues as measured by mean absolute per-cent difference (18.4 vs. 16.1%) andcorrelation (0.91 vs. 0.92) (5).

An established body of literature, in-cluding a supplement to the journal Dia-

betes Technology & Therapeutics (6),supports the performance and utility ofthe CGMS to guide therapy adjustmentsbased on glycemic excursions and to im-prove and predict HbA1c. The results re-ported by Metzger et al. should beweighed against the encouraging resultsand conclusions of both evolving and pre-viously reported research.

JOHN J. MASTROTOTARO, PHD

TODD M. GROSS, PHD

From Medtronic MiniMed, Northridge, CA.Address correspondence to Dr. John J. Mastroto-

taro, Medtronic MiniMed, 18000 Devonshire St.,Northridge, CA 91325-1219. E-mail: [email protected].

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References1. Metzger M, Leibowitz G, Wainstein J, Gla-

ser B, Raz I: Reproducibility of glucosemeasurements using the glucose sensor.Diabetes Care 25:1185–1191, 2002

2. Bland JM, Altman DG: Statistical methodsfor assessing agreement between twomethods of clinical measurement. Lancet8:307–310, 1986

3. Gross TM, Bode BW, Einhorn D, KayneDM, Reed JH, White NH, Mastrototaro JJ:Performance evaluation of the MiniMedcontinuous glucose monitoring systemduring patient home use. Diabetes TechnolTher 2:49–56, 2000

4. Poirier J-Y, Le Prieur N, Campion L, Guil-hem I, Allannic H, Maugendre D: Clinicaland statistical evaluation of self-monitor-ing blood glucose meters. Diabetes Care21:1919–1924, 1998

5. Shin JJ, Dangui ND, Kanderian S Jr, GrossTM, Mastrototaro JJ: A new retrospectivecalibration algorithm (New-RA) for con-tinuous glucose monitoring providesmore complete and more accurate CGMSdata (Abstract). Diabetes 51(Suppl. 2):A207, 2002

6. Skyler JS, Klonoff DC, Grodsky GM(Eds.): Advances in continuous glucosemonitoring in diabetes mellitus. DiabetesTechnol Ther 2 (Suppl. 1):1–97, 2000

Response toMastrototaro andGross

W e thank Mastrototaro et al. (1) fortheir comments. For more than30 years, development of a reli-

able ambulatory continuous glucosemonitor has appeared to be an insur-

Letters


mountable technological challenge. TheMedtronic MiniMed continuous glucosemonitoring system (CGMS), the firstcommercially available system, providesretrospective analysis of glucose levels,making confirmation of unexpected find-ings difficult. As stated by Mastrototaro etal., when our sensor data were evaluatedusing correlation tests, a high degreeof correlation with capillary blood mea-surements was found, confirming severalprevious reports. However, simple corre-lation tests do not identify potentially im-portant clinical discrepancies. The toolsto evaluate the clinical efficacy of newmonitoring systems are limited. We didnot use the Clarke error grid because theboundaries used in the published version(2) are not consistent with the require-ments of tight glycemic control. For ex-ample, reference/sensor glucose valuepairs such as 200 vs. 90 or 80 vs. 160would fall into the acceptable “B” zone,although today such differences are unac-ceptable. Indeed, in the data reported byGross et al. (3), many points falling in theB zone may not be considered clinicallyacceptable today. Therefore, pending thepublication of a validated modern versionof the Clarke error grid or another vali-dated tool, we used an admittedly moresubjective tool, the clinical judgment of adiabetologist blinded to the subject’sidentity.

Our profiles were generated using So-

lutions version 2 software, which was theversion available at the time of the studyand the one used in most previously pub-lished reports. Recalculation of our datawith the newer software showed signifi-cant improvement, particularly in cor-recting the “midnight shift.” However,other discrepancies apparent in ourstudy, and our ultimate conclusions, wereunchanged.

Recently, McGowan et al. (4) used adifferent technique to validate CGMSreadings in seven patients and found thatin four, falsely low sensor readings “mighthave resulted in inappropriate reductionof overnight insulin dose,” a findingthat supports our results. They concludethat many hypoglycemic episodes identi-fied by the sensor may be spurious, thusquestioning recent reports that showedan unexpectedly high incidence ofasymptomatic nocturnal hypoglycemia.

We recognize the importance of thisnew technology and its inherent technicaldifficulties. We applaud Medtronic Mini-Med for producing the first commercialsystem and for their continuing efforts toimprove its reliability. The need for con-tinued development is obvious, andclearly this technology will greatly im-prove our ability to treat diabetes. How-ever, the current model has limitationsthat must be recognized, and new toolsare needed to critically evaluate the clini-cal reliability of future devices.

MURIEL METZGER, MD1

GIL LEIBOWITZ, MD1

JULIO WAINSTEIN, MD2

BENJAMIN GLASER, MD1

ITAMAR RAZ, MD1

From the 1Diabetes Center, Endocrinology and Me-tabolism Service, Hadassah University Hospital,Jerusalem, Israel, and the 2Diabetes Unit, WolfsonHospital, Holon, Israel.

Address correspondence to Dr. Muriel Metzger,Diabetes Unit, Hadassah University Hospital, P.O.Box 12000, Jerusalem, Israel. E-mail: [email protected].

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References1. Mastrototaro JJ, Gross TM: Reproducibil-

ity of the continuous glucose monitoringsystem matches previous reports and theintended use of the product (Letter). Dia-betes Care 26:256, 2002

2. Clarke WL, Cox D, Gonder-Frederick LA,Carter W, Pohl SL: Evaluating clinical ac-curacy of systems for self-monitoring ofblood glucose. Diabetes Care 10:622–628,1987

3. Gross TM, Bode BW, Einhorn D, KayneDM, Reed JH, White NH, Mastrototaro JJ:Performance evaluation of the MiniMedcontinuous glucose monitoring systemduring patient home use. Diabetes Tech-nology & Therapeutics 2:49–56, 2000

4. McGowan K, Thomas W, Moran A: Spu-rious reporting of nocturnal hypoglyce-mia by CGMS in patients with tightlycontrolled type 2 diabetes. Diabetes Care25:1499–1503, 2002

Letters


Documents

Response to Mastrototaro and Gross