LETTERS

After 2 years off , HbA1c has re- Hospital for Children, Epsom and St. Helier Univer- OBSERVATIONS mained normal (5.4–5.5%). sity Hospitals National Health Service Trust, Car- shalton, Surrey, U.K.; and the 2Department of The cause of diabetes resolution in Diabetes, School of Postgraduate Medicine, Royal these boys remains unexplained. Tran- Devon and Exeter, National Health Service Health- sient hyperglycemia can occur during in- care Trust, Exeter, U.K. Remitting Diabetes tercurrent illness, is of very short Address correspondence to Dr. Christine P. Bur- duration, and is not associated with ele- ren, Queen Mary’s Hospital for Children, St. Helier Hospital, Wrythe Lane, Carshalton, Surrey SM5 A new genetic subgroup? vated HbA1c. Although type 1 diabetes 1AA, U.K. E-mail:christine@cpburren. was the initial diagnosis, their subsequent freeserve.co.uk. clinical course and absence of autoimmu- © 2004 by the American Diabetes Association. nity markers make this unlikely. Type 1 e describe a previously unre- diabetes may have an extended honey- ●●●●●●●●●●●●●●●●●●●●●●● ported clinical scenario of remit- moon (i.e., partial remission), sometimes ting diabetes in two young References W up to 2 years, but normal HbA1c off treat- 1. Stride A, Hattersley AT: Different genes, brothers who do not fit existing diagnos- ment 4 years after diagnosis is very un- different diabetes. Annal Med 34:207– tic classifications. They may represent a usual. IGT in the father and type 2 216, 2002 new genetic subgroup of diabetes. diabetes in the paternal grandmother is 2. Winter WE, Maclaren NK, Riley WJ, Clarke Case 1 presented at 3.6 years with consistent with autosomal-dominant in- DW, Kappy MS, Spillar RP: Maturity- poor linear growth, polyuria, and poly- heritance suggesting maturity-onset dia- onset diabetes of youth in black Ameri- dipsia. Diabetes was diagnosed based on a betes of the young (MODY); however, no cans. N Engl J Med 316:285–291, 1987 blood glucose value of 11.5 mmol/l and MODY subgroups remit (1). While glu- an elevated HbA1c of 7.0% (normal 3.8– cokinase mutations could explain the 6.0). During 3 months’ observation, hy- adults’ hyperglycemia, neither child had Seroconversion of Ͼ perglycemia and an elevated HbA1c fasting blood glucose ( 5 mmol/l) effec- GAD Antibody in persisted. Working diagnosis was very tively excluding MODY2. Case 1 tested early type 1 diabetes, and insulin was negative for hepatocyte nuclear factor-␣ “Unclassified” Ϫ1 Ϫ1 commenced (0.2 units kg day ). (HNF-1␣) mutations. Transient neonatal Diabetes With Long HbA1c improved from 7.0 to 5.3%. How- diabetes remits but is excluded as they Duration of Disease ever, linear growth did not improve. presented after age 3 months (1.5 and 3.6 The family also tested asymptomatic years). A remitting form of atypical diabe- siblings and identified hyperglycemia in tes is described in black adolescent Amer- atent autoimmune diabetes in adults the 18-month-old brother. Diabetes was icans (2) but not in whites or young (LADA) (1), or slowly progressive in- diagnosed on repeated blood glucose val- children. sulin-dependent diabetes mellitus Ͼ L ues 11 mmol/l and HbA1c 9.0%. Al- In summary, disappearance of diabe- (SPIDDM) (2), is a subtype of type 1 dia- though thriving, there was concern of tes in these young boys is unusual and betes with a slowly progressive course. early type 1 diabetes, and he commenced does not fit clinically recognized syn- LADA, or SPIDDM, is diagnosed by the Ϫ1 Ϫ1 insulin (0.2 units kg day ). HbA1c dromes. Two affected siblings suggest a detection of islet-associated autoantibod- normalized to 5.5% after 16 months. Two novel genetic syndrome probably altering ies such as islet cell antibody (ICA) or additional family members had glucose ␤-cell function. This could be a recessive GAD antibody (GADA) in the serum; abnormalities: the 44-year-old father had condition with coincidental hyperglyce- moreover, patients with LADA are usually impaired glucose tolerance (IGT) (glu- mia in adults. Alternatively, it may repre- originally diagnosed as having type 2 di- cose 6.4 mmol/l [0 min] and 10.4 mmol/l sent different stages in a dominant abetes. If islet-associated autoantibodies [120 min] in an oral glucose tolerance test disorder, with adults having undetected are not detected in the serum, these pa- [OGTT]; BMI 29 kg/m2), and the 74-year- hyperglycemia during childhood, sug- tients who are originally diagnosed as old paternal grandmother was diagnosed gesting that the children may later re- having type 2 diabetes cannot be diag- with type 2 diabetes at age 60 years and is lapse. This cyclical pattern of diabetes nosed as having LADA and are followed as on (not overweight, no diabe- remission and relapse occurs in transient “unclassified” diabetes at present. tes complications). The mother’s OGTT neonatal diabetes, and we hypothesize a In clinical situations, if islet- was normal. novel genetic mutation causing a similar associated autoantibodies are not initially No evidence of autoimmunity was process. We would welcome reports of detected in the serum, these cases are usu- found in either child (insulin, islet cell, further cases of remitting diabetes, as they ally followed as type 2 diabetes or “un- and GAD antibodies). After age 1.6 and could provide further insights into this classified diabetes” without reevaluation 2.3 years, respectively, insulin was potential new genetic form of diabetes. of autoantibodies because it is unknown ceased, as requirements had remained whether islet-associated autoantibodies low with normal HbA1c and blood glu- CHRISTINE P. BURREN, MBBS, MD, will appear later in the disease course. It 1 cose. Both boys had OGTTs showing nor- FRACP, FRCPCH has been reported that islet-associated au- 2 mal glucose tolerance. Interestingly, the ANDREW T. HATTERSLEY, DM, FRCP toantibodies are detected within 1 year older boy had hypoglycemia (glucose 2.0 after onset in ϳ15% of cases of “classical” mmol/l) at 120 min of OGTT, suggesting From the 1National Health Service Trust, Epsom type 1 diabetes without islet-associated possible insulin secretion dysregulation. and St. Helier University Hospitals, Queen Mary’s autoantibodies at the onset of disease (3).

1836 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 Letters

The following case patient, who was would like to emphasize that it is essential from 13.6 to 33% (1,2) with a progressive confirmed as not having GADAs at 31 to measure islet-associated autoantibod- increase in risk that parallels the time after years after the onset of diabetes and was ies such as GADA periodically for the pre- transplant (3). Tacrolimus, a calcineurin followed as having “unclassified diabe- cise diagnosis of diabetes, especially in inhibitor, is a recent immunosuppressive tes,” is a rare case in whom GADA was patients given the diagnosis of “unclassified agent largely used to prevent and treat detected at 36 years. diabetes,” even if the patient has suffered transplant rejections often following The patient was diagnosed as having from diabetes for a long period of time. other immunosuppressive failures (4–5). type 2 diabetes at age 47 years, had an The incidence of post-transplant diabetes ϳ 1 HbA1c level of 7%, and was being TOSHIKATSU SHIGIHARA, MD mellitus (PTDM) in tacrolimus-treated 1 treated with a (gliben- AKIRA SHIMADA, MD, PHD patients was significantly higher than in 1 clamide). However, glycemic control sub- YOSHIHUMI SAISHO, MD those treated with cyclosporine (6,7) and 1 sequently worsened despite being treated TOSHIHIDE KAWAI, MD, PHD in pediatric-age patients (8). Usually 2 with 8.75 mg/day of , 150 HIROSHI MARUYAMA, MD, PHD PTDM refers to renal recipients, and only 1 mg/day of buformin, and 0.9 mg/day of TAKAO SARUTA, MD, PHD one pediatric case has been reported after , and she was admitted to the liver transplantation (9). PTDM in tacroli- 1 hospital at age 78. On admission, her From the Department of Internal Medicine, Keio mus-treated patients has been related to University School of Medicine, Tokyo, Japan; and height was 155 cm and her body weight 2 reduced pancreatic ␤-cell function and is 2 Sano-Kousei General Hospital, Tochigi, Japan. was 38.8 kg (BMI 16.1 kg/m ), with no Address correspondence to Akira Shimada, MD, generally reversed by dose reduction history of obesity. According to labora- PhD, Department of Internal Medicine, Keio Univer- (10–11). tory findings, her fasting plasma glucose sity School of Medicine, 35 Shinanomachi, Shin- Here we describe the ␤-cell function juku-ku, Tokyo 160-8582, Japan. E-mail: asmd@ level was 338 mg/dl and her HbA1c level sc.itc.keio.ac.jp. in a 15-year-old male liver transplant re- was 10.1%. Her insulin secretion was also © 2004 by the American Diabetes Association. cipient treated with tacrolimus at the on- low (serum C-peptide level 0.3 ng/ml on set of PTDM and 1 year after remission. fasting, 0.9 ng/ml at 2 h after breakfast, ●●●●●●●●●●●●●●●●●●●●●●● He underwent liver transplantation at age ␮ and 24-h urine C-peptide level 10.5 g/ References 7 years for Alagille Syndrome and was day), thus requiring insulin therapy (total 1. Zimmet PZ, Toumi T, Mackay R, Rowley subsequently treated with steroids and 16 units/day at discharge). Based on these MJ, Knowles W, Cohen M, Lang DA: La- cyclosporine. Because of acute rejection at findings, it was possible that she had tent autoimmune diabetes mellitus in age 15, treatment with cyclosporine was SPIDDM; however, GADA was negative adults (LADA): the role of antibodies to switched to tacrolimus and mycopheno- (detection limit Ͻ0.4 units/ml; 100% glutamic acid decarboxylase in diagnosis late mofetil. One month later, he pre- sensitivity and 100% specificity of the as- and prediction of insulin dependency. sented symptomatic hyperglycemia (42 say in the GADA proficiency test [Immu- Diabet Med 11:299–303, 1994 mmol/l) without ketoacidosis; his BMI 2. Kobayashi T, Itoh T, Kosaka K, Sato K, 2 nology of Diabetes Workshop], lab ID no. Tsuji K: Time course of islet cell antibod- was 21.3 kg/m , and his HbA1c was 9.4% 305), resulting in the diagnosis of “un- ies and ␤-cell function in non–insulin-de- (normal values 3.3–6.0). Initially, the pa- Ϫ1 Ϫ1 classified diabetes.” pendent stage of type 1 diabetes. Diabetes tient required 1.8 units kg day of At age 83, she was again admitted to 36:510–517, 1987 insulin. ␤-Cell function was investigated the hospital because of acute myocardial 3. Landin-Olsson M, Arnqvist H, Blohme G, by stimulation— basal C- infarction. On the second admission, her Littorin B, Lithner F, Nystrom L, Schersten peptide levels were 0.90 nmol/l (normal body weight was 39.4 kg (BMI 16.4 kg/ B, Sundkvist G, Wibell L, Ostman J, Lern- values 0.165–0.993) and 1.67 nmol/l af- m2). Laboratory results indicated that her mark A: Appearance of islet cell ter 6 min (relative increase 186%, normal fasting plasma glucose level was 198 mg/ autoantibodies after clinical diagnosis of values 130–377%). Tacrolimus was sub- dl, her HbA level 7.2%, and her 24-h diabetes mellitus. Autoimmunity 29:57– stituted by cyclosporine while continuing 1c 63, 1999 urine C-peptide level 12.5 ␮g/day. Sur- other immunosuppressive agents. This al- prisingly, GADA, which was negative at lowed a gradual decrease of insulin and its the time of her first admission, was now Normal ␤-Cell withdrawal within 5 weeks. One year positive (144 units/ml), although insuli- later, an oral glucose tolerance test noma-associated protein 2 antibody was Function in showed normal glucose tolerance (basal negative. Furthermore, HLA typing de- Post–Liver levels 4.5 mmol/l, peak 7.7). In addition, tected DR4, which is considered to be a Transplantation stimulated C-peptide response was nor- susceptible HLA type for type 1 diabetes mal (relative increase 231%), fasting in- (other HLA types: A24, A26, B35, B55, Diabetes Treated sulin level was 54.6 pmol/l, and HbA1c DR8). Based on these observations, she With Tacrolimus was 5.6%. was diagnosed as having SPIDDM. The absence of ketoacidosis and the The frequency of seroconversion of presence of normal C-peptide levels dur- GADA in diabetic patients who were orig- se of immunosuppressive agents is ing tacrolimus treatment indicate that inally diagnosed as having type 2 diabetes mandatory after organ transplanta- ␤-cell function was normal in our patient, is not known, and a more extensive large- U tions but may be complicated by not confirming the ␤-cell impairment as- scale study is needed to clarify the fre- the development of hyperglycemia or di- cribed to tacrolimus (9,10). The high in- quency of seroconversion in this type of abetes. The prevalence of diabetes after sulin dose required suggests that insulin diabetes. Based on this case, however, we liver transplantation in adulthood ranges resistance, which was not due to steroids

DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 1837 Letters since they were never withdrawn from 7. Cai TH, Esterl RM Jr, Nichols L, Cigarroa evaluating potential differences in ACR therapy, may have played a role. Further- F, Speeg KV, Halff GA: Improved immu- obtained from first-morning and random more, because proneness to diabetes de- nosuppression with combination tacroli- spot urines collected on the same day. pends on several genetic mechanisms, it is mus (FK506) and mycophenolic acid in A total of 717 adult diabetic patients possible that immunosuppressive agents orthotopic liver transplantation. Trans- with and without nephropathy were re- plant Proc 30:1413–1414, 1998 play only a triggering role in PTDM. In 8. Reisaeter AV, Hartmann A: Risk factors cruited from the outpatient clinic of the addition, since most PTDM cases were de- and incidence of posttransplant diabetes Diabetes Center, Tokyo Women’s Medi- scribed after renal transplantations, we mellitus. Transplant Proc 33:8S–18S, 2001 cal University Hospital, Tokyo, Japan. Pa- cannot exclude a putative role of the 9. Keshavarz R, Mousavi MA, Hassani C: Di- tients were instructed to bring a first- transplanted liver itself on the abnormal abetic ketoacidosis in a child on FK506 morning urine specimen to the clinic and peripheral insulin action. With the immunosuppression after a liver trans- then provide a random urine specimen spreading use of tacrolimus in liver trans- plant. Pediatr Emerg Care 18:22–24, 2002 immediately upon arriving at the clinic on plantation, pediatric diabetes practitio- 10. Al-Uzri A, Stablein DM, Cohn RA: Post- the same day. ACR was calculated from uri- ners will probably face many new cases of transplant diabetes mellitus in pediatric nary albumin and creatinine concentrations PTDM. renal transplant recipients: a report of the determined using radioimmunoassay and North American Pediatric Renal Trans- Jaffe’s method, respectively. Paired samples 1 plant Cooperative Study (NAPRTCS). NICOLINA DI COSMO, MD Transplantation 72:1020–1024, 2001 with a random urinary ACR of more than 1 PIETRO VAJRO, MD 11. Filler G, Neuschulz I, Vollmer I, Amendt 1,000 mg/g were excluded to provide a 2 DOMINIQUE DEBRAY, MD P, Hocher B: Tacrolimus reversibly re- more accurate range for estimating the rela- 3 GIULIANA VALERIO, MD, PHD duces insulin secretion in paediatric renal tionship between measurements. 1 MICHELA GIUGLIANO, MD transplant recipients. Nephrol Dial Trans- Paired samples were analyzed from 1 PIETRO BUONO, MD, PHD plant 15:867–871, 2000 668 patients (289 women and 379 men, 1 ADRIANA FRANZESE, MD mean age 58 Ϯ 12 years, 95% with type 2 diabetes). The majority (75%) of random From the 1Department of Pediatrics, Federico II Definition of spot urine was collected during a morning University, Naples, Italy; the 2Paediatric Hepatology visit (8:30 A.M. to 12:00 P.M.). There was a Unit, University Hospital of Bicentre, Le Kremlin Microalbuminuria in Bicetre, France; and the 3Faculty of Movement Sci- First-Morning and strong relationship between ACRs mea- ences, Parthenope University, Naples, Italy. sured from first-morning and spot urine Address correspondence to Adriana Franzese, Random Spot Urine samples, yielding a linear correlation on a MD, Department of Pediatrics, via S. Pansini 5, in Diabetic Patients logarithmic scale: log10 ACR (first- 80131 Naples, Italy. E-mail: [email protected]. ϭ © 2004 by the American Diabetes Association. morning sample) 0.8589 log10 ACR (random spot sample) Ϫ0.0604 (r ϭ ●●●●●●●●●●●●●●●●●●●●●●● easurement of albumin excretion 0.871). Applying this equation, ACR val- in a 24-h urine collection has long ues of 30–300 mg/g in a first-morning References been the “gold standard” for urine specimen would correspond to val- 1. Tabasco-Minguillan J, Mieles L, Carroll P, M Gavaler J, Van Thield DH, Starzl TE: Long- quantitative evaluation of albuminuria in ues of 51–391 mg/g in random spot col- term insulin requirement after liver trans- diabetic patients; however, collection er- lection. Using the ACR cutoff value of plantation with FK 506 in American vet- rors due to improper timing and missed 30–300 mg/g, 135 patients (20%) would erans. Transplant Proc 25:677–678, 1993 samples may lead to significant over- and receive a diagnosis of microalbuminuria 2. Margarit C, Rimola A, Gonzalez-Pinto I, underestimation of albuminuria. For con- based on first-morning urine, whereas 234 Cuervas-Mons V, Edo A, Andreu H: Effi- venience and consistency, the American patients (35%) would receive this diagno- cacy and safety of oral low-dose tacroli- Diabetes Association (1) and the National sis based on a random spot collection. mus treatment in liver transplantation. Kidney Foundation (2) have recently rec- This rather large discrepancy between Transplant Int 11:S260–S266, 1998 ommended measurement of albumin-to- ACR from first-morning and random spot 3. Greenspan LC, Gitelman SE, Leung MA, creatinine ratio (ACR) in a random spot urine may have important implications in Glidden DV, Mathias RS: Increased inci- dence in post-transplant diabetes mellitus urine collection for diagnosis of mi- the diagnosis of microalbuminuria in di- in children: a case-control analysis. Pedi- croalbuminuria. Microalbuminuria is di- abetes. We advocate strict adherence to atr Nephrol 17:1–5, 2002 agnosed if ACR ranges between 30 and the use of first-morning urine or possibly 4. Scott LJ, McKeage K, Keam SJ, Plosker 300 mg/g creatinine. The guidelines rec- an upward adjustment of the range for GL: Tacrolimus: a further update of its use ommended using a first-morning sample diagnosis of microalbuminuria using ACR in the management of organ transplanta- because of the potentially higher correla- from random spot urine. Further analysis tion. Drugs 63:1247–1297, 2003 tion with 24-h albumin excretion, but a of the relationship of ACR in first- 5. Debray D, Furlan V, Baudouin V, Houyel random sample is considered acceptable morning and random spot urines to 24-h L, Lacaille F, Chardot C: Therapy for acute if a first-morning specimen is not avail- urinary albumin excretion, as well as their rejection in pediatric organ transplant re- able. Measurement of ACR using a first- value in predicting future development of cipients. Paediatr Drugs 5:81–93, 2003 6. The US Multicenter FK 506 Liver Study morning or random urine sample may clinical proteinuria, is required. differ significantly, as exercise stress, di- Group: A comparison of tacrolimus (FK 1 506) and cyclosporine for immunosup- urnal variation, and other factors may af- TETSUYA BABAZONO, MD, PHD 1,2 pression in liver transplantation. N Engl fect urinary albumin excretion. We CHIEKO TAKAHASHI, MD, PHD 3 J Med 331:1110–1115, 1994 provide data from a cross-sectional study YASUHIKO IWAMOTO, MD, PHD

1838 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 Letters

From the 1Division of Nephrology and Hyperten- diabetes clinic at Johannesburg Hospital P Ͻ 0.05 after Bonferonni adjustment be- sion, Diabetes Center, Tokyo Women’s Medical and were mostly domestic workers, labor- ing significant. University School of Medicine, Tokyo, Japan; the 2Department of Food Science and Human Nutri- ers, and pensioners who were overweight Biochemical data (Table 1) showed tion, Tokyo Metropolitan College, Tokyo, Japan; and not undergoing lipid-lowering ther- unimpressive dyslipidemia in women and the 3Department of Medicine, Diabetes Center, apy. The higher socioeconomic cohort with no significant differences, although Tokyo Women’s Medical University School of Med- consisted of 82 patients (32 women and total and LDL cholesterol tended to be icine, Tokyo, Japan. 50 men), also with recently diagnosed lower and triglycerides higher in the Address correspondence to Tetsuya Babazono, MD, PhD, Division of Nephrology and Hyperten- type 2 diabetes studied during 2001– higher socioeconomic cohort. For men, sion, Diabetes Center, Tokyo Women’s Medical 2003. They attended a private diabetes similar trends emerged (P Ͻ 0.05 for trig- University School of Medicine, 8-1 Kawadacho, clinic in the same city and were mainly lycerides). In both sexes, diabetes control Shinjukuku, Tokyo 162-8666, Japan. E-mail: civil servants, clerks, and executives. was significantly worse in the Johannes- [email protected]. © 2004 by the American Diabetes Association. Again, the majority was overweight and burg Hospital setting. not receiving hypolipidemic drugs. Final- Comparing mean total cholesterol ly, we reevaluated lipid data from 47 Af- and triglyceride concentrations in African ●●●●●●●●●●●●●●●●●●●●●●● rican patients (mainly women, mean age diabetic patients (three-quarters of them References 55 years) with type 2 diabetes who at- women) from the 1976 survey with Afri- 1. American Diabetes Association: Nephro- tended Johannesburg Hospital complex can diabetic women attending the same pathy in diabetes (Position Statement). in 1976; they were predominantly do- clinic two decades later, serum choles- Diabetes Care 27 (Suppl. 1):S79–S83, 2004 Ϯ Ϯ 2. Keane WF, Eknoyan G: Proteinuria, al- mestic workers. terol had risen from 4.8 1.1 to 5.3 Venous blood was collected at 1.3 mmol/l (P Ͻ 0.01). Serum triglycer- buminuria, risk, assessment, detection, ϳ elimination (PARADE): a position paper 0800, and although not formally fast- ides, however, had not changed signifi- of the national kidney foundation. Am J ing, most subjects had not eaten over- cantly (1.2 Ϯ 0.5 to 1.5 Ϯ 1.1 mmol/l). Kidney Dis 33:1004–1010, 1999 night. Serum was analyzed for total Dyslipidemia in the higher socioeco- cholesterol, HDL cholesterol, and triglyc- nomic cohort of South African blacks with erides by automated enzymatic methods type 2 diabetes was unimpressive and not Lipid Levels in Black (4). LDL cholesterol was calculated using substantially greater than in their less so- South Africans With the Friedewald formula. (These differed phisticated counterparts, apart from mild from the 1976 automated techniques hypertriglyceridemia; importantly, total Type 2 Diabetes [5].) Long-term diabetes control was as- and LDL cholesterol tended to be lower. sessed by HbA1c concentrations. Statisti- This was our first misconception to be cor- Dispelling misconceptions cal analysis of data between patient rected and is explainable by two factors: groups utilized the unpaired t test, with tighter metabolic control and the likeli-

yslipidemia in type 2 diabetes typi- Table 1—Demographic, anthropometric, and biochemical characteristics of black South cally comprises hypertriglyceride- African patients with type 2 diabetes of differing socioeconomic status D mia and reduced HDL cholesterol, usually associated with hypercholesterol- Johannesburg hospital Private diabetes clinic emia (1). Relatively little is known about 1994–1996 2001–2003 its occurrence in developing African com- (Low socioeconomic (Higher socioeconomic munities, where the prevalence of type 2 community) cohort) diabetes may escalate dramatically (2). This is important because dyslipidemia Women constitutes a major risk factor for coro- n 241 32 nary artery disease (CAD) in type 2 diabe- Age (years) 53.6 Ϯ 5.4 53.9 Ϯ 10.8 tes (3). We therefore assessed serum BMI (kg/m2) 31.7 Ϯ 6.6 30.1 Ϯ 5.9 lipids of South African blacks with type 2 Total cholesterol (mmol/l) 5.3 Ϯ 1.3 4.9 Ϯ 1.0 diabetes of differing socioeconomic status LDL cholesterol (mmol/l) 3.3 Ϯ 1.4 3.1 Ϯ 1.0 and compared levels with those of pa- HDL cholesterol (mmol/l) 1.3 Ϯ 0.4 1.4 Ϯ 0.5 tients two decades earlier. Our initial ex- Triglycerides (mmol/l) 1.5 Ϯ 1.1 1.9 Ϯ 2.4 Ϯ Ϯ pectations were that dyslipidemia would HbA1c (%) 9.6 3.2* 7.9 1.5 be substantially greater in the higher so- Men cioeconomic group due to affluence and n 204 50 that lipids would have risen considerably Age (years) 52.6 Ϯ 4.9* 49.5 Ϯ 9.0 over time because of increasing urbaniza- BMI (kg/m2) 27.6 Ϯ 4.9 28.3 Ϯ 4.6 tion. Total cholesterol (mmol/l) 4.9 Ϯ 1.3 4.6 Ϯ 1.2 Our low socioeconomic community LDL cholesterol (mmol/l) 3.0 Ϯ 1.1 2.8 Ϯ 1.0 comprised 445 black African patients HDL cholesterol (mmol/l) 1.2 Ϯ 0.4 1.2 Ϯ 0.7 (241 women and 204 men) with recently Triglycerides (mmol/l) 1.6 Ϯ 1.2* 2.2 Ϯ 1.2 Ϯ Ϯ diagnosed type 2 diabetes studied be- HbA1c (%) 9.3 3.3* 8.5 2.1 tween 1994 and 1996. They attended the Data are means Ϯ SD. *P Ͻ 0.05 compared with private diabetes clinic.

DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 1839 Letters hood that they had more affordable access 3. Laakso M: Hyperglycaemia as a cardiovas- ing bare-metal stents (P Ͻ 0.00001). Un- to a prudent diet containing reduced sat- cular risk factor. International Diabetes fortunately, none of the studies gave urated fat and refined carbohydrates. Monitor 12:1–5, 2000 details about the respective ages of the di- Their higher triglyceride levels, sig- 4. Deeg R, Ziegenhorn J: Kinetic enzymatic abetic and nondiabetic patients, so cor- nificant in men despite better glycemia, method for automated determination of total cholesterol in men. Clin Chem 29: rections for possible differences in age could reflect greater insulin resistance in 1798–1802, 1983 were not feasible (1). A similar OR was these subjects who likely were less phys- 5. Anonymous: Simultaneous measure- found when DESs were considered (OR ically active than the less affluent subjects. ments of cholesterol and triglycerides: 2.24 [1.39–3.61], P ϭ 0.0009), suggest- By contrast total cholesterol levels may Auto Analyzer Manual AA11. Tarrytown, ing that the use of new DESs does not have risen significantly, if not dramati- NY, Technicon, 1970 allow to suppress differences between di- cally, over two decades, reflecting a rela- 6. Joubert J, McClean CA, Reid CM, Davel D, abetic and nondiabetic patients. In both tively small impact of westernization. Pilloy W, Delport R, Steyn L, Walker ARP: Ischaemic heart disease in black South Af- groups of patients, the rate of restenosis Our protocol revealed methodologi- was markedly and significantly (P Ͻ cal limitations: the automated techniques rican stroke patients. Stroke 31:1294– 0.00001) higher with bare-metal stents for lipid assays differed in the 1976 study, 1305, 2000 compared with DESs, with an OR of 6.33 the nonfasting collection of some serum (4.57–8.76) in the nondiabetic popula- samples may have influenced triglyceride concentrations, and the absence of formal tion and 5.27 (3.36–8.28) in the diabetic dietary histories limited our interpreta- Diabetes Is Still a population. tion of the lipid data. Nevertheless, these Risk Factor for These results demonstrated the po- findings have implications for evolving Restenosis After tential interest of DESs in patients at high CAD in Africans with type 2 diabetes. risk of restenosis. Nevertheless, even Their CAD prevalence remains low but Drug-Eluting Stent in when using DESs, the diabetes status re- may be increasing among urban dwellers Coronary Arteries mains a significant risk factor. This was (6). If subsequently confirmed, this sug- recently confirmed in a large cohort of gests that prolonged exposure to only patients who benefited from unrestricted modest dyslipidemia, particularly when e read with interest the meta- utilization of sirolimus-eluting stents combined with other risk factors such as analysis of the effect of diabetes compared with conventional bare-metal hypertension, smoking, and hypercoagu- W on restenosis rates among pa- stent implantation in the “real world” (7). lability, is the key atherogenic stimulus. tients receiving coronary angioplasty This research registry focused on a 1-year stenting (1). This meta-analysis of six cumulative rate of major adverse cardiac 1 clinical trials showed that the odds ratio BARRY I. JOFFE, DSC, FRCP events rather than on restenosis. It 1 (OR) of coronary artery restenosis associ- LARRY A. DISTILLER, BSC, FCP(SA), FACE showed that the benefit of DESs did not 2 ated with diabetes was 1.61 (95% CI reach statistical significance in diabetic W. JOHN KALK, MB, FRCP ϭ 1.21–2.14, P 0.004) in univariate logis- patients (OR 0.72 [95% CI 0.30–1.77], From the 1Centre for Diabetes and Endocrinology, tic regression models, but it decreased to P ϭ 0.50). Furthermore, diabetes was a 2 ϭ Johannesburg, South Africa; and the Derbyshire 1.30 (0.99–1.70, P 0.055) after age significant predictor of major adverse car- Royal Infirmary, Derbyshire, U.K. was controlled in multivariate models. All ϭ Address correspondence to Prof. Barry Joffe, Cen- diac events (OR 1.62 [1.09–2.43], P trials selected in this meta-analysis used 0.02) and of clinically driven target vessel tre for Diabetes and Endocrinology, 81 Central St., classical bare-metal stents. However, Houghton 2198, South Africa. E-mail: barry@ revascularization (OR 1.81 [1.10–2.99], cdecentr.co.za. drug-eluting stents (DESs) have been P ϭ 0.02) (Fig. 1). W.J.K. was formerly the head of the Diabetic shown to improve outcomes among pa- In conclusion, diabetes remains a ma- Clinic, Johannesburg Hospital, Johannesburg, tients undergoing percutaneous coronary jor risk factor for restenosis after both South Africa. intervention by significantly reducing re- © 2004 by the American Diabetes Association. bare-metal stents and DESs. Considering stenosis rates (2). We performed a meta-analysis of the the high prevalence and burden of coro- nary heart disease in diabetic patients, Acknowledgments— We thank Greg Dis- results from four recently published trials comparing bare-metal stents with DESs, specific studies should be performed in tiller for statistical help, Dr. Vanessa Panz for this population in order to test the possi- initial data processing, and Terry Newfield for two using sirolimus (RAVEL and SIRIUS) secretarial assistance. (3,4) and two using paclitaxel (TAXUS II bility of reducing the risk of restenosis and TAXUS IV) (5,6) (Fig. 1). These four and major cardiac events, including the trials comprised a significant proportion use of more effective DESs (2). ●●●●●●●●●●●●●●●●●●●●●●● of diabetic patients (ϳ20%) and provided References figures that allowed us to recalculate the ´ 1 1. Durrington P: Dyslipidaemia. Lancet 362: ANDRE J. SCHEEN, MD, PHD rate of restenosis after a follow-up of at 1 717–731, 2003 FABIAN WARZE´E 2. Amos AF, McCarty DJ, Zimmet P: The ris- least 6 months in both the diabetic and nondiabetic populations. The OR of in- ing global burden of diabetes and its com- From the 1Division of Diabetes, Nutrition and Met- plications: estimates and projections to stent restenosis in diabetic patients com- abolic Disorders, Department of Medicine, Centre the year 2010. Diabet Med 14 (Suppl. 5): pared with control subjects averaged 1.94 Hospitalier Universitaire, Sart Tilman, Lie`ge, Bel- 57–84, 1997 (95% CI 1.46–2.58) in the groups receiv- gium.

1840 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 Letters

Figure 1—Meta-analysis of four trials comparing the effects on restenosis of bare-metal stents and drug-eluting stents in diabetic and nondiabetic patients.

Address correspondence to Andre´ J. Scheen, Di- nosis in a native coronary artery. N Engl Major Diabetes vision of Diabetes, Nutrition and Metabolic Disor- J Med 349:1315–1323, 2003 ders, Department of Medicine, Centre Hospitalier 5. Colombo A, Drzewiecki J, Banning A, Complications Have Universitaire, Sart Tilman (B35), B-4000 Lie`ge, Bel- Grube E, Hauptmann K, Silber S, Dudek gium. E-mail: [email protected]. an Impact on Total © 2004 by the American Diabetes Association. D, Fort S, Schiele F, Zmudka K, Gua- gliumi G, Russell ME, for the TAXUS II Annual Medical Cost Study Group: Randomized study to of Type 2 Diabetes ●●●●●●●●●●●●●●●●●●●●●●● assess the effectiveness of slow- and moderate-release polymer-based pacli- References taxel-eluting stents for coronary ar- 1. Gilbert J, Raboud J, Zinman B: Meta-anal- randle et al. (1) found that the oc- tery lesions. Circulation 108:788–794, currence of diabetes-related comor- ysis of the effect of diabetes on restenosis 2003 rates among patients receiving coronary bidities in type 2 diabetic patients 6. Stone GW, Ellis SG, Cox DA, Hermiller B angioplasty stenting. Diabetes Care 27: are associated with an increase in average J, O’Shaughness C, Tift Mann J, Turco 990–994, 2004 M, Caputo R, Bergin P, Greenberg J, annual medical cost. 2. Sousa JE, Serruys PW, Costa MA: New Popma JJ, Russell ME, for the TAXUS-IV To investigate the medical cost attrib- frontiers in cardiology: drug-eluting stents Investigators: A polymer-based, pacli- utable to type 2 diabetes, we conducted a (part I & part II). Circulation 107:2274– retrospective longitudinal cost-of-care 2279, 2383–2389, 2003 taxel-eluting stent in patients with cor- 3. Morice M-C, Serruys PW, Sousa JE, Faja- onary artery disease. N Engl J Med 350: study in a diabetologic center in Italy. A det J, Ban Hayashi E, Perin M, Colombo A, 221–231, 2004 priori, we estimated to validly enroll 300 Schuler G, Barragan P, Guagliumi G, 7. Lemos PA, Serruys PW, van Domburg type 2 diabetic patients with at least 1 year Molnar F, Falotico R, for the RAVEL RT, Saia F, Arampatzis CA, Hoye A, of follow-up. To this aim, we randomly Study Group: A randomized comparison Degertekin M, Tanabe K, Daemen J, Liu selected 315 type 2 diabetic patients from of sirolimus-eluting stent with a stan- TKK, McFadden E, Sianos G, Hofma a base of ϳ2,000 diabetic patients attend- dard stent for coronary revascularization. SH, Smits PC, van der Giessen WJ, de ing the diabetologic center of Portogruaro Feyter PJ: Unrestricted utilization of N Engl J Med 346:1773–1780, 2002 during the period from January 2001 to sirolimus-eluting stents compared with 4. Moses J, Leon MB, Popma JJ, Fitzgerald August 2002. PJ, Holmes DR, O’Shaughnessy C, Caputo conventional bare stent implantation in RP, Kereiakes DJ, Williams DO, Teirstein the “Real World”: the Rapamycin Elut- Cost included hospitalizations, visits, PS, Jaeger JL, Kuntz RE, for the SIRIUS ing Stent Evaluated at Rotterdam Cardi- diagnostics, and pharmacological thera- Investigators: Sirolimus-eluting stents ology Hospital (RESEARCH) registry. pies and were quantified in the perspective versus standard stents in patients with ste- Circulation 109:190–195, 2004 of the National Health Service. We ex-

DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 1841 Letters tracted clinical and demographic informa- alysis on cost, since the care of type 2 di- (3). Patients with type 1 diabetes have tion from the electronic database and abetic patients developing end-stage renal major defects in insulin sensitivity at di- performed extensive chart review, includ- disease is not controlled by the diabeto- agnosis of overt diabetes (4–8). However, ing the comorbidities retinopathy, cardiop- logic center. the fact that pre-diabetic patients can athy (coronary heart disease), vasculopathy We did not consider the cost of sup- maintain normal blood glucose levels in (other than coronary heart disease), and plies for self-monitoring of blood glucose, spite of dramatically low insulin secretory nephropathy. which is, at any rate, minimal (ϳ€100 capacities suggests that their insulin sen- Ϫ Ϫ We analyzed the association between patient 1 year 1) and is not related to sitivity is normal. diabetes-related comorbidities and aver- the type of complication. Here we report that insulin sensitiv- age annual medical costs using univariate Our study confirms the findings of ity, measured by the glucose clamp and multiple linear regression analyses. In Brandle et al. regarding the annual medi- method in nine patients, remains normal the linear regression analysis, cost was cal cost and its determinants in type 2 even during the very late preclinical stage transformed using the square-root trans- diabetic patients. Strategies aimed at pre- of type 1 diabetes. None of these patients formation to better fit a Gaussian venting the onset of diabetes complica- had clinical symptoms of overt diabetes, distribution. tions are likely to reduce medical costs in spontaneous weight loss, or ketosis before Sixteen type 2 diabetic patients were the long term, while improving patients’ or at the time of the study. Mean age at excluded because it was found that their health. entry in the study was 27 years (range follow-up period was Ͻ1 year; the main 20–41). The mean BMI was 20.9 kg/m2 1 reasons were premature mortality and ANDREA MORSANUTTO, PHARMD (range 16.3–23.2). All patients were islet 2 loss to follow-up. A total of 299 type 2 PATRIZIA BERTO, PHARMD, MBA cell antibody positive, and seven of eight 2 diabetic patients were considered for this STEFANIA LOPATRIELLO, PHARMD tested had at least one susceptibility HLA 3 analysis and followed-up for an average of DARIO VOINOVICH, PHD haplotype. Mean fasting glucose level was 4 476 days, totaling 520 person-years of RENZO GELISIO, MD 7.2 Ϯ 1.3 mmol/l (range 5–9.6). Of the 1 observation. Their mean (ϮSD) age was LORENZO G. MANTOVANI, MSC, DSC eight patients who met the criteria for di- 68.6 Ϯ 8.8 years, and 201 (67.2%) were abetes, four had fasting blood glucose men. The mean systolic blood pressure, From the 1Center of Pharmacoeconomics, Depart- level Ͻ7 mmol/l; in the ninth patient, oral diastolic blood pressure, total cholesterol, ment of Pharmacological Sciences, University of Mi- glucose tolerance test disclosed impaired lan, Milan, Italy; 2PBE Consulting, Verona, Italy; the HDL cholesterol, HbA1c, and Hb levels 3 glucose tolerance. The mean HbA1c level Ϯ Ϯ Department of Pharmacological Sciences, Univer- Ϯ were 152.5 20.9 mmHg, 82.7 10.0 sity of Trieste, Trieste, Italy; and the 4Diabetologic was 6.4 0.8% (range 5.3–7.8; normal mmHg, 195.5 Ϯ 41.6 mg/dl, 50.2 Ϯ 20.3 Center, ULSS 10 Portogruarese, Portogruaro, Italy. values 5.0 Ϯ 0.5%). The sum of 1- and 3- mg/dl, 7.1 Ϯ 1.5%, and 13.9 Ϯ 1.5 g/dl, Address correspondence to Dr. Lorenzo G. Man- min plasma insulin levels after the intra- respectively. The average annual cost of tovani, Center of Pharmacoeconomics, Department venous glucose tolerance test was 15.3 Ϯ € of Pharmacological Sciences, University of Milan, care was 1,909.67 (i.e., $2,425 U.S.; ex- Via Balzaretti, 9 I-20133 Milan, Italy. E-mail: 5.8 mU/l (range 11–25). change rate, 1 Euro ϭ $1.27 U.S.); 52% of [email protected]. Four patients were treated with insu- costs were attributable to drugs, 28% to © 2004 by the American Diabetes Association. lin immediately after the metabolic explo- hospitalizations, 11% to diagnostics, and rations reported here. Four others have 9% to visits. ●●●●●●●●●●●●●●●●●●●●●●● initiated permanent insulin therapy A total of 101 (33.8%) type 2 diabetic References within 24 months of follow-up. The last patients were free of diabetes-related co- 1. Brandle M, Zhou H, Smith BR, Marriott D, patient was still non–insulin dependent morbidities, 117 (39.1%) had one com- Burke R, Tabaei BP, Brown MB, Herman when last seen 1 year after the study. plication, and 81 (27.1%) had two or WH: The direct medical cost of type 2 During clamp studies, the insulin more complications. The more frequent diabetes. Diabetes Care 26:2300–2304, dose-response curve of preclinical type 1 complication was vasculopathy, which af- 2003 diabetic subjects was superimposable to fected 89 (29.8%) type 2 diabetic pa- that of 20 healthy control subjects. Maxi- tients, followed by cardiopathy (79 mal glucose infusion rate, at a plasma in- [26.4%]), retinopathy (66 [22.1%]), and Normal Insulin sulin level of 1,400 Ϯ 120 mU/l, was Ϫ Ϫ nephropathy (65 [21.7%]). 17.2 Ϯ 1.6 mg kg 1 min 1 (Fig. 1). It Sensitivity During Ϫ Ϫ The annual medical costs increased the Late Preclinical was 16.4 Ϯ 0.6 mg kg 1 min 1 in 20 with the number of complications from control subjects at a similar plasma insu- €1,039.59 ($1,320 U.S.) to 1,808.17 Stage of Type 1 lin level: 1,500 Ϯ 100 mU/l. By contrast, ($2,296 U.S.) and to 3,141.21 ($3,989 Diabetes the maximal glucose infusion rate was sig- U.S.) in type 2 diabetic patients with nificantly lower in 15 patients with symp- none, one, and two and more complica- tomatic diabetes of recent onset (11 Ϯ 1.4 Ϫ Ϫ tions, respectively, with the association n most cases, type 1 diabetes is the late mg kg 1 min 1, P ϭ 0.003 by Mann- being statistically significant in both uni- consequence of a ␤-cell autoimmune Whitney U test). These results confirm, at variate (Kruskall-Wallis test, 73,035; P Ͻ I destruction leading to absolute insulin an even later stage of the natural history of 0.0001) and multiple linear regression deficiency (1). At onset of clinical diabe- the disease, those observed in a substudy analyses (R2 ϭ 0.21; F test 82.5, P Ͻ tes, ␤-cell mass is thought to be reduced of the Diabetes Prevention Trial-1 (9). 0.0001). by 80–90% (2), and 73% of adult patients Thus, the onset of overt clinical diabetes We could not assess the impact of di- have ketosis or ketoacidosis at diagnosis may be triggered by the addition of insu-

1842 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 Letters

missions in cyclosporin-treated IDDM patients. Diabetes Care 16:880– 895, 1993 8. DeFronzo RA, Matsuda M, Barrett E: Di- abetic ketoacidosis: a combined meta- bolic-nephrologic approach. Diabetes Rev 2:209–238, 1994 9. Greenbaum CJ, Prigeon RL, D’Alessio DA: Impaired ␤-cell function, incretin effect, and glucagon suppression in patients with type 1 diabetes who have normal fasting glucose. Diabetes 51:951–957, 2002 10. Le´vy-Marchal C, Patterson C, Green A: Variation by age group and seasonality at diagnosis of chilhood IDDM in Europe. Diabetologia 38:823–830, 1995

COMMENTS AND RESPONSES

Figure 1—Glucose clamp study. Dose-response curves obtained during the euglycemic- hyperinsulinemic clamps in patients with preclinical diabetes (E). For the purpose of comparison, Comparative Study results obtained in control subjects (■) and in patients with symptomatic diabetes studied within 1–3 week after diagnosis (‚) are shown. The latter two are from ref. 7. of Prognostic Value for Coronary Disease lin resistance to insulin deficiency; the affiliated with the Service d’immunologie-diabe´tologie, Risk Between the triggers may be external or internal fac- hoˆpital Cochin, Assistance Publique-Hoˆpitaux de U.K. Prospective tors. In this respect, the seasonal peaks of Paris, Paris, France; R.B. is currently affiliated with UMR 5018 CHU Rangueil, Toulouse, France. Diabetes Study and the incidence of diabetes (10) suggest that †Deceased in August 2003. viral infections may play a role in the very © 2004 by the American Diabetes Association. Framingham Models final act of the preclinical phase by trig- gering insulin resistance and metabolic ●●●●●●●●●●●●●●●●●●●●●●● Response to Protopsaltis et al. storm. The respective parts of insulin de- References ficiency and insulin resistance may be de- 1. The Expert Committee on the Diagnosis terminants for the onset and duration of and Classification of Diabetes Mellitus: he comparison by Protopsaltis et al. the honeymoon period. Report of the Expert Committee on the Di- (1) of the Framingham risk equations agnosis and Classification of Diabetes Mel- and the U.K. Prospective Diabetes 1 T ETIENNE LARGER, MD, PHD litus. Diabetes Care 20:1183–1197, 1997 Study (UKPDS) risk engine as predictors of 2 BENJAMIN RAKOTOAMININA, MD 2. Pipeleers D, Ling Z: Pancreatic Beta cells coronary risk in diabetes is of interest, as 1 MOHAMMED EDDOUKS, PHD in insulin-dependent diabetes. Diabetes previous analyses have shown that the Fra- 3 JOSE´ TIMSIT, MD Metab Rev 8:209–227, 1992 mingham equations can underestimate ab- 3 CHRISTIAN BOITARD, MD 3. Karjalainen J, Salmela P, Ilonen J, Surcel solute coronary heart disease (CHD) risk in 1 H-M, Knip M: A comparison of childhood ROGER ASSAN, MD † diabetic subjects by a factor of 2 or more 1 and adult type 1 diabetes mellitus. N Engl RE´ MY BURCELIN, PHD (2,3). The sensitivity and specificity analy- 2 J Med 320:881–886, 1989 JEAN-JACQUES ROBERT, MD, PHD 4. Yki-Jarvinen H, Koivisto V: Natural ses presented by the authors, however, are difficult to interpret because of method- From the 1Service d’endocrinologie-diabe´tologie, course of insulin resistance in type 1 dia- Hoˆpital Bichat, Assistance Publique-Hoˆpitaux de betes. N Engl J Med 315:224–230, 1986 ological concerns. They examined the inci- Paris, Paris, France; the 2Unite´ Diabe`tedel’Enfant et 5. Gray R, Cowan P, Duncan L, Clarke B: dence of coronary angiographically de l’Adolescent, Hoˆpital Necker-Enfants Malades, Reversal of insulin resistance in type 1 di- determined CHD but not “hard” CHD (de- Assistance Publique-Hoˆ pitaux de Paris, Paris, abetes following initiation of insulin treat- 3 fined as fatal or nonfatal myocardial infarc- France; and the Service d’immunologie clinique, ment. Diabet Med 3:18–23, 1986 tion) as estimated by the UKPDS risk engine Hoˆpital Necker-Enfants Malades, Assistance Pub- 6. Nijs H, Radder J, Fro¨lich M, Krans H: The lique-Hoˆpitaux de Paris, Paris, France (4). Their use of a retrospective survivor co- course and determinants of insulin action hort introduces bias, as patients with fatal Address correspondence to Dr. Etienne Larger, in type 1 (insulin-dependent) diabetes Service d’endocrinologie-diabe´tologie, Hoˆpital Bi- mellitus. Diabetologia 32:20–27, 1989 CHD will have been excluded. This may ex- chat, 46 rue H. Huchard, 75877 Paris cedex 18, plain the apparent poor performance of France. E-mail: [email protected]. 7. Burcelin R, Eddouks M, Beylot M, Nor- M.E. is currently affiliated with the UFR de Physi- mand S, Boitard C, Feutren G, Landais HbA1c as a risk predictor, since myocardial ologie, Faculte´ des sciences, nutrition et endocrinolo- P, Riou JP, Girard JR, Bach JF, Assan RI: infarction is more often fatal in those with gie, Errachidia, Morocco; J.T. and C.B. are currently Hypersensitivity to insulin during re- higher HbA1c (5). The use of a mixed cohort

DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 1843 LETTERS

of type 1 and type 2 diabetic subjects is 5. Stevens RJ, Coleman RL, Adler AI, Strat- myocardial infarction incidence, the ton IM, Matthews DR, Holman RR: Risk problematic because the UKPDS risk en- range of HbA1c was from 5.5 to 11%, so gine, a type 2 diabetes–specific risk calcula- factors for myocardial infarction case fa- we can say that 11% (upper limit) is two tor, has not been evaluated in subjects with tality and stroke case fatality in type 2 di- times 5.5% or 1 more time 5.5% (lower type 1 diabetes. The UKPDS analysis (6) abetes (UKPDS 66). Diabetes Care 27:201–207, 2004 limit). Therefore 1 refers to one time and cited by the authors shows that a 1% decre- 6. UKPDS Group: Association of glycaemia not 1%. The percent symbol was added ment in HbA1c was associated with a 37% with macrovascular and microvascular by mistake. risk reduction in microvascular disease, not complications of type 2 diabetes (UKPDS Moreover, as the UKPDS study a 10-fold reduction (90%). 35). BMJ 321:405–412, 2000 showed, improved glycemic control had A full validation of a risk model re- no significant impact in cardiovascular quires a prospective study of a cohort to outcomes in patients with type 2 diabetes. which the model is applicable. In the case Comparative Study The Veterans Affairs Cooperative Study of the risk engine, a cohort with type 2 of Prognostic Value (4) also showed a nonstatistical signifi- diabetes and suitable demographic char- cant deterioration of CVD events in inten- acteristics (3) is needed. Covariates for Coronary Disease sively treated patients compared with should be measured at the beginning of those receiving standard treatment. follow-up, and the cohort should be mon- Risk Between the The exception for reducing mortality itored for the end points addressed by the U.K. Prospective model. In the case of the risk engine, these Diabetes Study and from myocardial infarction was in the end points would be fatal and nonfatal overweight UKPDS cohort patients myocardial infarction and sudden cardiac Framingham Models treated with metformin (5). However, death. Publication of the observed rate of metformin use was not associated with CHD in the cohort and of the mean pre- Response to Stevens and Holman lower blood glucose levels compared with dicted rate according to the model would insulin or , so it can be as- then allow an evaluation of risk tools sumed that the cardioprotective effects of against true rates of heart disease. An ideal e appreciate the comments of metformin could be interpreted by its study would also adjust for assay differ- Stevens and Holman (1) regard- well-known actions in the atherothrom- ences, if appropriate, and for regression W ing our analysis comparing the botic risk profile (6) and blood pressure dilution and competing risks if necessary. accuracy of the U.K. Prospective Diabetes levels through nonglycemic pathways. Study (UKPDS) (2) and Framingham Summarizing the previously epide- 1 RICHARD J. STEVENS, PHD, models in the prediction of 10-year risk miologic data, since coronary heart dis- 1 RURY HOLMAN, FRCP for coronary artery disearse (CAD) in di- ease is a multifactorial disease and abetic patients. In our letter, we men- glycemic control is not significantly asso- From the 1Diabetes Trials Unit, Oxford Centre for tioned that the diagnosis of CAD was ciated (7,8) with reduced CVD risk in di- Diabetes, Endocrinology and Metabolism, Univer- established by coronary angiography. In abetic patients, it can be assumed that the sity of Oxford, Oxford, U.K. Address correspondence to Dr. Richard Stevens, addition, this study was performed in a small contribution of chronic hyperglyce- cohort of patients with type 2 diabetes Diabetes Trials Unit, Oxford Centre for Diabetes, mia (HbA1c) at the incidence of macrovas- Endocrinology and Metabolism, Churchill Hospital, and included a 10-year follow-up. In the cular complications has a respectively Old Road, Oxford, OX3 7LJ U.K. E-mail: sample of cases with myocardial infarc- weak contribution on the calculation of [email protected]. tion who were examined during this anal- © 2004 by the American Diabetes Association. coronary heart disease risk by the UKPDS ysis, fatal and nonfatal cases were mathematical model. included. ●●●●●●●●●●●●●●●●●●●●●●● Finally, we absolutely agree with We agree that this analysis was retro- References Stevens and Holman that prospective spective with its disadvantages, and it is studies will be needed to determine the 1. Protopsaltis ID, Konstantinopoulos PA, absolutely equitable that the variables Kamaratos AV, Melidonis AI: Compara- validity of the predictive value for both of used by both of these models should have tive study of prognostic value for coronary these models. disease risk between the U. K. Prospective been determined at the beginning of fol- low-up. However, it is obvious that this Diabetes Study and Framingham models 1 (Letter). Diabetes Care 27:277–278, 2004 study was designed as a retrospective, IOANNIS D. PROTOPSALTIS, PHD 2 2. Yeo WW, Rowland Yeo K: Predicting since the UKPDS prediction model has GEORGE NIKOLOPOULOS, MD 1 CHD risk in patients with diabetes melli- recently constituted a useful cardiovascu- ANDREAS MELIDONIS, PHD tus. Diabet Med 18:341–344, 2001 lar disease (CVD) risk prognostic model. 3. Stevens RJ, Adler AI, Stratton IM, Manley In the epidemiologic analysis of the UK- From the 1Diabetes Center, General Hospital Tza- SE, Holman RR: The UKPDS in Wiscon- PDS, Stratton et al. (3) showed that the ef- neio of Piraeus, Piraeus, Greece; and the 2Hellenic sin: comparing cardiovascular models fect of HbA1c values on microvascular Center for Infection Disease Control, Athens, from the UK to data from the US (Ab- Greece. stract). Diabetes 50 (Suppl. 1):A204, 2001 complications over a range of 5.5–11% was nearly 10-fold, whereas the effect of HbA Address correspndence to Dr. Andreas Melido- 4. UKPDS Group: The UKPDS Risk Engine: 1c nis, General Hospital Tzaneio of Piraeus, Zanni & a model for the risk of coronary heart dis- on myocardial infarction incidence, over Afentouli 1, 18536 Piraeus, Greece. E-mail: ease in type 2 diabetes (UKPDS 56). Clin the same range of HbA1c, was 2-fold. [email protected]. Sci 101:671–679, 2001 Regarding the effect of HbA1c on © 2004 by the American Diabetes Association.

1844 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 Letters

●●●●●●●●●●●●●●●●●●●●●●● number of subjects are considerable, the Hierro, Unidad de Vitaminas, 28035 Madrid, Spain. References nutritional and public health relevance on E-mail: [email protected]. 1. Stevens RJ, Holman R: Comparative study a population basis is uncertain, at least © 2004 by the American Diabetes Association. of prognostic value for coronary disease concerning ␤-cryptoxanthin. The authors ●●●●●●●●●●●●●●●●●●●●●●● risk between the U.K. prospective diabe- report that dietary intake is on average Ͻ4 tes study and Framingham models (Let- ␮g ␤-cryptoxanthin/day in both groups, References ter). Diabetes Care 27:1843–1844, 2004 1. Montonen J, Ja¨rvinen R, Knekt P, Reun- 2. Protopsaltis ID, Konstantinopoulos PA, with the lowest and highest quartiles Ͻ Ͼ ␮ anen A: Dietary antioxidant intake and Kamaratos AV, Melidonis AI: Compara- 0.3 to 4.2 g/day. However, regard- risk of type 2 diabetes. Diabetes Care 27: tive study of prognostic value for coronary less of the value obtained for the risk ratio 362–366, 2004 disease risk between the U. K. Prospective (0.58 [95% CI 0.44–0.78]), these data 2. Granado F, Olmedilla B, Blanco I, Rojas- Diabetes Study and Framingham models should be interpreted in practical terms. Hidalgo E: Major fruits and vegetables (Letter). Diabetes Care 27:277–278, 2004 In developed countries, ␤-cryptoxan- contributors to the main serum carote- 3. Stratton IM, Adler AI, Neil HA, Mathews thin is mostly provided by citrus fruits, noids in the Spanish diet. Eur J Clin Nutr DR, Manley SE, Cull CA, Hadden D, (2,3) and, after these major contributors 50:246–250, 1996 Turner RC, Holman RR: Association of are considered, dietary ␤-cryptoxanthin 3. O’Neill ME, Carroll Y, Corridan B, glycaemia with macrovascular and micro- Olmedilla B, Granado F, Blanco I, Van vascular complications of type 2 diabetes intake may be easily assessed, making misclassification of individuals unlikely, den Berg H, Hininger I, Rousell AM, Cho- (UKPDS 35): prospective observational pra M, Southon S, Thurnham DI: A Euro- study. BMJ 321:405–412, 2000 especially when considering extreme cen- ␤ pean Carotenoid Database to assess 4. Abraira C, Colwell JA, Nuttall F, Sawin tiles. Also, -cryptoxanthin content in carotenoid intakes and its use in a five- CT, Henderson W, Comstock JP, Eman- fresh orange and mandarin is 120–1,300 country comparative study. Brit J Nutr 85: uele NV, Levin SR, Pacold I, Lee HS: Car- ␮g/100 g (3,4). Thus, assuming the low- 499–507, 2001 diovascular events and correlates in the est end of this range, intake of ␤-crypto- 4. Poorvliet EJ, West CE: The carotenoid Veterans’ Affairs Diabetes Feasibility trial. xanthin in the highest quartile in content of foods with special reference to Arch Intern Med 157:181–188, 1997 Montonen et al.’s study (ϳ5 ␮g/day) developing countries. Vitamin A Field 5. UK Prospective Diabetes Study (UKPDS) would be equivalent to the consumption Support Project (VITAL). Arlington, VA, Group: Effect of intensive blood –glucose Ͻ International Science and Technology In- control with metformin on complications in of 5 g fresh orange or mandarin per day, which is less than one-twentieth of a stan- stitute, 1993 overweight patients with type 2 diabetes 5. Olmedilla B, Granado F, Southon S, Wright (UKPDS 34). Lancet 352:854–865, 1998 dard portion. AJA, Blanco I, Gil-Martinez E, Berg HVD, 6. Mamputu JC, Wiernsperger NF, Renier G: In other European countries, median ␤ Corridan B, Roussel AM, Chopra I, Thurn- Antiatherogenic properties of metformin: -cryptoxanthin intake is 0.45–1.36 mg/ ham DI: Serum concentrations of carote- the experimental evidence (Review). Dia- day (2,3); the southern countries have noids and vitamins A, E, and C in control betes Metab 29:6S71–6S76, 2003 higher intakes than those in the north, a subjects from five European countries. Brit J 7. Wild SH, Dunn CJ, McKeigue PM, Comte difference that is also observed in their se- Nutr 85:227–238, 2001 S: Glycemic control and cardiovascular rum levels (5). Because there is a biologi- disease in type 2 diabetes: a review. Dia- cal correlation between ␤-cryptoxanthin betes Metab Res Rev 15:197–204, 1999 8. Huang ES, Meigs JB, Singer DE: The effect intake and serum concentrations, it is rea- Dietary Antioxidant of interventions to prevent cardiovascular sonable to assume that the lower the in- Intake and Risk of disease in patients with type 2 diabetes take the lower the serum concentrations. mellitus. Am J Med 111:633–642, 2001 Considering these facts, in our opin- Type 2 Diabetes ion, it is very difficult to imagine any po- tential beneficial effects associated with Response to Granado-Lorencio and Dietary Antioxidant the intake of such low amounts of ␤-cryp- Olmedilla-Alonso Intake and Risk of toxanthin as those reported by Montonen et al. (1), even when the statistical evi- Type 2 Diabetes dence is strong. Where nutritionally rele- e would like to express our warm vant population-based recommendations thanks to Granado-Lorencio and Response to Montonen et al. are concerned, we should not forget the W Olmedilla-Alonso for carefully multifactorial nature of the disease and reading our article (1) and for their com- that people, in the real world, consume ments regarding the inverse association he results by Montonen et al. (1) re- foods and diets. between ␤-cryptoxanthin intake and dia- garding the potential role of dietary betes risk (2). Granado-Lorencio and T antioxidants in the prevention of type FERNANDO GRANADO-LORENCIO, PHD Olmedilla-Alonso pointed out that the ␤ 2 diabetes are of considerable interest. The BEGONA OLMEDILLA-ALONSO, PHARMD, PHD -cryptoxanthin intake in our study pop- authors identify ␤-cryptoxanthin as a pre- ulation was exceptionally low; therefore, ventive factor, regardless of adjustment for From the Unidad de Vitaminas, Hospital Universi- any potential beneficial effect associated other potential confounding factors, and tario Puerta de Hierro, Madrid, Spain; and the with such low amounts of ␤-cryptoxan- point out that data support the hypothesis Redes Tema´ticas de Investigacio´n del Instituto de thin is difficult to imagine. Salud Carlos III, Madrid, Spain. RCMN C03/08 and that “a sufficient intake of antioxidants plays RGMBE G03/090 (B.O.-A). In epidemiologic studies, it is difficult a role in type 2 diabetes prevention.” Address correspondence to Fernando Granado- to draw conclusions about the absolute Although the follow-up time and Lorencio, PhD, Hospital Universitario Puerta de amount of a specific nutritional com-

DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 1845 Letters pound necessary for a beneficial health risk of type 2 diabetes. Diabetes Care 27: are a poor insulin regimen to achieve near effect. One of the main reasons for this is the 362–366, 2004 euglycemia because there is no short- or fact that nutrient composition tables are un- 2. Granado-Lorencio F, Olmedilla-Alonso B: rapid-acting insulin to blunt postprandial der continuing development. A common al- Dietary antioxidant intake and risk of type 2 hyperglycemia. (The authors acknowl- ternative technique, which we used in the diabetes (Letter). Diabetes Care 27:1845, edge this in their discussion.) How many 2004 present study, is to rank the study popula- 3. O’Neill ME, Carroll Y, Corridan B, Olm- of the eight patients in the control group tion according to the intakes. In such an edilla B, Granando F, Blanco I, Van den Berg were on twice-daily NPH insulin? Even approach, the validity of the results depends H, Hininger I, Rousell AM, Chopra M, Sou- the ones on MIX insulin (I assume this is a on the accuracy of the ranking, so absolute thon S, Thurman DI: A European carot- premixed insulin) are not on an optimal in- intake levels are less important. enoid database to assess carotenoid intakes sulin regimen for achieving near euglyce- In our analyses, the assessment of and its use in a five-country comparative mia. One example illustrates this point. ␤-cryptoxanthin intake was based on an- study. Br J Nutr 85:499–507, 2001 How does one adjust the MIX insulin dose alyzed values of Finnish foods available in 4. Brugård Konde Å, Staffas A, Dahl P, in a patient whose preprandial glucose con- the late 1980s. However, more recent es- Becker W: Carotenoids in Foodstuff in Swe- centrations before supper are in the lower timates of the ␤-cryptoxanthin content of den (in Swedish with an English sum- part of the goal range but whose preprandial oranges have been shown to be much mary). Uppsala, Sweden, National Food lunch values exceed the goal range? Administration, 1996 (Reports of the Na- higher than those used in the present tional Food Administration 12) For both of these reasons one would study (average orange intake 29 g/day). expect higher postprandial glucose con- To ensure the accuracy of our analyses, centrations in the control group receiving we recalculated the ␤-cryptoxanthin in- Twice-Daily NPH or only insulin (which is borne out in Fig. take using more recent published values 2A) and consequently higher HbA1c lev- (3,4). We calculated the ␬ coefficient be- Mixture els. Hopefully these issues will not be ig- tween quartiles of the recalculated and the Versus Triple nored in subsequent long-term studies. original variables and noted a high level of agreement between these two variables Therapy: Apples MAYER B. DAVIDSON, MD ␬ϭ ( 0.9), suggesting that the study par- Versus Oranges From the Clinical Trials Unit, Charles R. Drew Uni- ticipants are very similarly ranked using versity, Los Angeles, California. either the original or the recalculated Response to Poulsen et al. Address correspondence to Dr. Mayer B. David- ␤-cryptoxanthin intake values. Thus, the son, MD, Director, Clinical Trials Unit, Charles R. ␤ Drew University, 1731 East 120th St., Los Angeles, inverse association between -cryptoxan- CA 90059. E-mail: [email protected]. thin intake and diabetes risk presented in oulsen et al. (1) recently demon- © 2004 by the American Diabetes Association. our article is justified. strated that triple therapy In conclusion, we suggest that the sig- P (metformin, , and ●●●●●●●●●●●●●●●●●●●●●●● nificant inverse association between the preprandial ) lowered References ␤ intake of -cryptoxanthin and the risk of HbA1c levels much better than twice- 1. Poulsen MK, Henriksen JE, Hother- type 2 diabetes observed in our study is a daily NPH or MIX insulin in type 2 di- Nielsen O, Beck-Nielsen H: The com- valid finding. The importance of this find- abetic patients. They then claim that the bined effect of triple therapy with ing in the prevention of type 2 diabetes, reason for this improvement, compared rosiglitazone, metformin, and insulin as- however, remains to be established. with the patients treated with insulin part in type 2 diabetic patients. Diabetes alone, is the superiority of specifically Care 26:3273–3279, 2003 1 JUKKA MONTONEN, MSC treating the three pathophysiological 1,2 PAUL KNEKT, PHD components of type 2 diabetes (periph- 3 The Combined Effect RITVA JARVINEN¨ , PHD eral insulin resistance, hepatic insulin 1 ANTTI REUNANEN, MD, PHD resistance, and impaired glucose- of Triple Therapy stimulated insulin secretion). Given the with Rosiglitazone, From the 1Department of Health and Functional Ca- design of the study, this conclusion is pacity, National Public Health Institute, Helsinki, Metformin, and 2 suspect for two reasons. Finland; the Social Insurance Institution, Helsinki First, the glycemic goals for the two and Turku, Finland; and the 3Department of Clini- Insulin Aspart in cal Nutrition, University of Kuopio, Kuopio, Fin- groups were different. The goals for pa- Type 2 Diabetic land. tients receiving only insulin were a pre- Address correspondence to Jukka Montonen, Na- prandial value of 5–7 mmo1/l. The goal Patients tional Public Health Institute, Department of Health for patients receiving triple therapy was a and Functional Capacity, Mannerheimintie 166, 00300 Helsinki, Finland. E-mail: jukka. postprandial value of 5–7 mmol/l. Response to Poulsen et al. montonen@ktl.fi. Achieving a postprandial goal of 5–7 © 2004 by the American Diabetes Association. mmol/l will necessarily lead to better con- trol than achieving the same goal prepran- have some concerns regarding the re- ●●●●●●●●●●●●●●●●●●●●●●● dially (since in the latter situation the sults of Poulsen et al.’s (1) study, which References postprandial glucose concentrations will I suggested that triple therapy with insu- 1. Montonen J, Ja¨rvinen R, Knekt P, Reun- obviously be higher). lin aspart, metformin, and rosiglitazone anen A: Dietary antioxidant intake and Second, twice-daily NPH injections was superior to continuing treatment

1846 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 Letters with NPH insulin alone or NPH plus reg- tic doses resulted in only partial amelio- 2-year follow-up study that includes ular insulin (referred to as the control ration of insulin sensitivity after 6 months 400 subjects, will hopefully answer this group). These results should be inter- (1). It would be interesting to evaluate the question. preted with caution because of several long-term effects and cost-effectiveness of Davidson (1) and Mikhail (2) focus limitations in the study’s design. First, I this form of triple therapy in type 2 dia- on the different ways of monitoring blood disagree with the authors for applying betes in well-designed trials. glucose values when using the two ap- “identical” goals for metabolic control in proaches. They claim that a focus on the both study groups. Although the glycemic NASSER MIKHAIL, MD, MSC postprandial values in the triple therapy target was similar in both arms, the timing group compared with preprandrial values of self-monitored blood glucose was dif- From the Olive View-UCLA Medical Center, UCLA in the control group favors the triple ther- School of Medicine, Sylmar, California. ferent. Thus, the adjustment of the insulin Address correspondence to Dr. Nasser Mikhail, apy group. However, self-monitored glu- dosage in the control group aimed at Olive View-UCLA Medical Center, Department of cose values showed that the preprandial blood glucose levels between 5 and 7 Medicine, 14445 Olive View Dr., Sylmar, CA values were identical in the triple therapy mmol/l in the preprandial period, 91342. E-mail: [email protected]. group and the control group. Hence, the © 2004 by the American Diabetes Association. whereas in the triple therapy group, insu- adjustment of the insulin dosage would lin adjustment targeted the same range of ●●●●●●●●●●●●●●●●●●●●●●● have been identical only if the prepran- blood glucose but in the postprandial pe- drial blood glucose values were also used riod. Clearly, setting a glycemic goal of References in the triple therapy group (as in the con- 1. Poulsen MK, Henriksen JE, Hother- 5–7 mmol/l for postprandial blood glu- trol group). The curve for self-monitored cose was quite aggressive and substan- Nielsen O, Beck-Nielsen H: The com- bined effect of triple therapy with glucose in the triple therapy group is flat tially lower than the recommendations of rosiglitazone, metformin, and insulin as- (no postprandial rise in blood glucose val- the American Diabetes Association part in type 2 diabetic patients. Diabetes ues), with a geometric mean of ϳ7 Ͻ ( 10.0 mmol/l) (2). This more stringent Care 26:3273–3279, 2003 mmol/l, which is close to the findings in glycemic target in the triple therapy group 2. American Diabetes Association: Stan- nondiabetic subjects. However, monitor- compared with the control group may ex- dards of medical care for patients with di- ing higher postprandial blood glucose plain, at least in part, the superior meta- abetes mellitus (Position Statement). values in the control group (NPH insulin bolic control observed with the triple Diabetes Care 26 (Suppl. 1):S33–S50, alone) may have resulted in a further rise 2003 therapy regimen. In addition, the bias that of the insulin dose, as proposed by favored the triple therapy group (e.g., Mikhail. We do not expect, however, to providing closer follow-up and care) The Combined Effect see a further effect of this on blood glu- could not be excluded since the study was cose values, since the 50% increase we not blinded. Moreover, the investigators of Triple Therapy already performed did not influence may have been reluctant to further in- with Rosiglitazone, HbA1c values (3), but this postulate is still crease insulin doses in the control group Metformin, and not tested. The last argument against the to achieve the study’s preprandial glyce- criticism raised is that we aimed for the mic goal because of the concern over hy- Insulin Aspart in same HbA1c values in both groups, which poglycemia. Second, some patients in the Type 2 Diabetic means that we did not rely on blood glu- control group received NPH twice daily Patients cose values only. Thus, we cannot prove and others received a mixture of NPH that monitoring the postprandial values plus . These two treatment in the control group also would have im- regimens are different and should not be Response to Davidson and Mikhail proved the glucose control in that group, included in a single group because dia- but we showed that triple therapy was betic subjects receiving NPH alone may able to nearly normalize HbA1c values in have inadequate plasma levels of post- e were not able to normalize type 2 diabetic patients, which has never prandial insulin. Third, one limitation of HbA1c values completely during been the case when using NPH insulin triple therapy is the high cost of treatment W triple therapy probably due to treatment alone. and related laboratory tests, a factor that the fact that insulin action was not com- We conclude that this trial confirms was not clarified in the study presumably pletely normalized by rosiglitazone and our hypothesis that the key to the treat- because the three drugs were provided at metformin, as stated by Davidson (1). ment of type 2 diabetic patients is to con- no cost by the respective companies. Still, insulin-mediated glucose uptake trol postprandial blood glucose values by Despite these limitations, this pilot was only 60% normal during triple ther- reconstructing the insulin peaks after investigation addressed an attractive ther- apy; however, a longer treatment period meals and by improving insulin action in apeutic approach that targeted the three or a more potent insulin synthesizer may skeletal muscle, fat, and liver cells. Triple main defects in the pathophysiology of help in that respect. Another way to fur- therapy seems to be a safe and effective type 2 diabetes. In this respect, the study’s ther reduce HbA values is to use a more 1c treatment of hyperglycemia in type 2 dia- findings suggested that insulin resistance aggressive algorithm, increasing the No- betic patients, but further studies, espe- was probably the hardest abnormality to vorapid dose further before meals. How- cially of a longer duration, are needed. correct. Indeed, the combination of the ever, this may induce more hypoglycemic two insulin-sensitizing agents, metformin attacks during the day time. The South and rosiglitazone, in maximum therapeu- Danish Diabetes Study, a newly initiated HENNING BECK-NIELSEN, MD, MSCI

DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 1847 Letters

From the Department of Endocrinology, Odense mal population (10%). These women MD, FRCP, King’s College, Denmark Hill Campus, University Hospital, University of Southern Den- may not have been equally represented in New Medical School Building, Bessemer Road, Lon- mark, Odense C, Denmark. don SE5 9PJ, U.K. E-mail: stephanie.amiel@kcl. Address correspondence to Dr. Henning Beck- the two groups, as 30% more women in ac.uk. Nielsen, Odense University Hospital, Department of the ultrasound-defined group met their © 2004 by the American Diabetes Association. Endocrinology, Kloevervaenget 6,4, 5000 Odense criteria for insulin therapy. C, Denmark. E-mail: henning.beck-nielsen@ouh. More importantly, the women with ●●●●●●●●●●●●●●●●●●●●●●● fyns-amt.dk. larger babies were treated more aggres- © 2004 by the American Diabetes Association. References sively. Because their outcome was not dif- 1. Schaefer-Graf UM, Kjos SL, Fauzan OH, ●●●●●●●●●●●●●●●●●●●●●●● ferent from less aggressively treated Buhling KJ, Siebert G, Buhrer C, Laden- women without initially large babies, dorf B, Dudenhausen JW, Vetter K: A ran- References there is the possibility that the latter might domized trial evaluating a predominantly 1. Davidson MB: Twice-daily NPH or mix- have done better if they had been using fetal growth–based strategy to guide ture insulins versus triple therapy: apples the same glycemic targets as the women management of gestational diabetes in versus oranges (Letter). Diabetes Care 27: Caucasian women. Diabetes Care 27:297– 1846, 2004 with large babies. They certainly had higher fasting glucose concentrations, 302, 2004 2. Mikhail N: The combined effect of triple 2. Jovanovic L: Never say never in medicine: therapy with rosiglitazone, metformin, and more of the LGA babies were born to confessions of an old dog (Editorial). Di- and insulin aspart in type 2 diabetic pa- women who did not receive insulin in ei- abetes Care 27:610–612, 2001 tients (Letter). Diabetes Care 26:1846– ther group. At the very least, the protocol 1847, 2003 favors the authors’ hypothesis that insulin 3. Poulsen MK, Henriksen JE, Hother- intervention before the onset of fetal over- A Randomized Trial Nielsen O, Beck-Nielsen H: The com- growth is not helpful. bined effect of triple therapy with Jovanovic (2) draws attention to the Evaluating a rosiglitazone, metformin, and insulin as- part in type 2 diabetic patients. Diabetes discrepancy in glucose targets but worries Predominantly Fetal Care 26:3273–3279, 2003 that her own policies, based on strict gly- Growth–Based cemic control and resulting in a lower macrosomia rate in her GDM population Strategy to Guide A Randomized Trial than in the local background population, Management of may have achieved this at the cost of an Gestational Diabetes Evaluating a increase in small-for-gestational-age Predominantly Fetal (SGA) babies. For us, in a clinic of pre- in Caucasian Women Growth–Based dominantly African and Carribean back- ground, SGA is not an issue. Using Response to Amiel and Blott Strategy to Guide Jovanovic’s protocols in women diag- Management of nosed by World Health Organization cri- Gestational Diabetes teria, our SGA rate is Ͻ5%. Because SGA e appreciate Amiel and Blott’s (1) is defined as babies in the lowest 10th interest in our study (2) and in Caucasian Women percentile, our current rate is lower than W thank them for their helpful dis- that of the background population. cussion. They rightly pointed out that the Response to Schaefer-Graf et al. Schaefer-Graf et al.’s study supports diagnostic criteria used in Germany at the the use of strict glycemic control in time of our study had been lower than women with demonstrably large babies. those of the American Diabetes Associa- chaefer-Graf et al. (1) rightly suggest This is valuable evidence that such prob- tion. We were also aware that we treated that the management of women lems may respond to intervention with some women who would have been con- S with gestational diabetes mellitus insulin even after the onset of fetal over- sidered healthy in other countries. To (GDM) should be based on more than gly- growth. Reassuringly, none of the differ- demonstrate that the fetal growth–based cemic factors alone. However, the study ences in the rates of SGA in the study approach is also safe for women with a in which they conclude that strict glyce- approached significance. We would not, more severe glucose intolerance, we re- mic control is not useful in the absence of therefore, support the authors’ suggestion peated the analysis for a subgroup of the measurements of fetal overgrowth has that we abandon glycemic indications for women who fulfilled the diagnostic crite- two unusual features. insulin therapy in our population until a ria of Carpenter and Coustan (3) (80% of The authors’ criteria for diagnosing randomized prospective trial using simi- our population). Again, there was no ad- GDM are lower than those of the World larly strict glucose targets in all groups verse outcome in the ultrasound group. Health Organization or the American Di- shows that it does more harm than good. The limitation to women who qualified abetes Association, and they may be in- for gestational diabetes mellitus (GDM) 1 cluding women who could be considered STEPHANIE A. AMIEL, BSC, MD, FRCP based on Carpenter and Coustan criteria 2 normal. This is supported by the fact that MAGGIE BLOTT, FRCOG diminished the difference in the rate of there is little difference between the rate insulin therapy. Because of the higher de- From the 1Department of Diabetes, King’s College of large-for-gestional-age (LGA) babies in Hospital, London, U.K.; and the 2Royal Victoria In- gree of glucose intolerance in these both their groups (12.1% above the 90th firmary, Newcastle upon Tyne, U.K. women, more women qualified for insu- percentile) and that of the defining nor- Address correspondence to Prof. S.A. Amiel, BSc, lin therapy in the standard group. We also

1848 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 Letters realized that in the whole population, the Address correspondence to Dr. Ute M. Schaefer- with MSL with the euglycemic- rate of women who met the criteria for Graf, Department of Obstetrics, Vivantes Medical hyperinsulinemic clamp and found the Center, Mariendorfer Weg 28, 12051 Berlin, Ger- insulin was higher in the ultrasound than many. E-mail: [email protected]. ISI to be higher in one and lower in two in the standard group. However, this was © 2004 by the American Diabetes Association. male subjects in comparison with sex- not because of an unequal representation and BMI-matched control subjects (2). of fetal macrosomia, as suggested by the ●●●●●●●●●●●●●●●●●●●●●●● The good insulin sensitivity in patient 1 in authors. The rate of an abdominal cir- the study of Haap et al. may indeed be Ͼ References cumference of 75th percentile at entry 1. Amiel S, Blott M: A randomized trial eval- related to the low visceral fat mass in this was not different between both groups. It uating a predominantly fetal growth– very patient, but it is rather questionable was more likely due to our low diagnostic based strategy to guide management of whether this finding is typical in MSL. gestational diabetes in Caucasian women criteria, which included women with a From five patients with MSL identified in low degree of glucose intolerance and, (Letter). Diabetes Care 27:1848, 2004 our clinic, computed tomographies of the therefore, less frequent need of insulin. 2. Schaefer-Graf UM, Kjos SL, Fauzan OH, abdomen had been performed in two case The low rate of large-for-gestational-age Buhling KJ, Siebert G, Buhrer C, Laden- (LGA) babies was an effect of intensive dorf B, Dudenhausen JW, Vetter K: A ran- subjects, and the degree of visceral fat was domized trial evaluating a predominantly described as comparable with that of treatment. The studies of Langer et al. (4) fetal growth–based strategy to guide and Buchanan et al. (5) demonstrate that a healthy subjects. In a systematic evalua- management of gestational diabetes in tion of the fat mass and deposition in 18 normal LGA rate can be achieved in GDM Caucasian women. Diabetes Care 27:297– when we aim for a very tight control. 302, 2004 patients with MSL by computed tomogra- We were very grateful that Lois Jo- 3. Carpenter MW, Coustan DR: Criteria for phy, Enzi et al. (3) also did not describe a vanovic’s comment (6) emphasized the screening tests for gestational diabetes. distinct reduction of visceral fat in these aspect of an increased risk for intrauterine Am J Obstet Gynecol 144:768–773, 1982 patients. Given this and the considerable growth retardation in some women with 4. Langer O, Levy J, Brustman L, Anyaegbu- phenotypical and clinical variability in GDM. When we discuss treatment strate- nam A, Merkatz R, Divon M: Glycemic patients with MSL (4), the conclusion of a gies for GDM, we always focus on how to control in gestational diabetes mellitus: good insulin sensitivity in MSL patients how tight is tight enough: small for gesta- reduce neonatal macrosomia. When we tional age versus large for gestational age? should not be generalized. Studies in did a subanalysis comparing the outcome Am J Obstet Gynecol 161:646–653, 1989 larger populations are mandatory, al- of women with hyperglycemia but nor- 5. Buchanan TA, Kjos SL, Montoro MN, Wu though not easily performed due to the mal fetal growth treated with (standard PY, Madrilejo NG, Gonzalez M, Nunez V, rareness of the disease. In a literature group) or without (ultrasound group) in- Pantoja PM, Xiang A: Use of fetal ultra- search of our own, we identified about sulin, we also attempted to determine sound to select metabolic therapy for 400 cases published since the first de- pregnancies complicated by mild gesta- whether withholding insulin would in- scription by Brodie in 1846 (5). crease the LGA and cesaerean section tional diabetes. Diabetes Care 17:275– 283, 1994 One further aspect on MSL seems rates. We were surprised when we real- worth mentioning: three of the five pa- ized the high rate of SGA in the standard 6. Jovanovic L: Never say never in medicine: confessions of an old dog (Editorial). Di- tients with MSL in our clinic had obstruc- group. The overall rate of SGA was similar abetes Care 27:610–612, 2001 tive sleep apnea syndrome (OSAS). We in both study groups. We did not con- clude that the policy of strict glycemic recently identified (5) the presence of control is harmful for the general popula- Multiple Symmetric OSAS as an independent risk factor con- tion with GDM. We suggested the use of tributing to insulin resistance. Thus, the an additional test, the measurement of the Lipomatosis: A investigation for OSAS in MSL patients fetal abdominal circumference, to decide Paradigm of might also be useful in the discussion of who will benefit and for whom a tight Metabolically insulin sensitivity and of other metabolic glucose control might be harmful due to a aspects of MSL. reduction of the maternal fuel supply to Innocent Obesity? the fetus. Although the differences be- 1 tween the groups were obvious, when we Response to Haap et al. IGOR A. HARSCH, MD 1 looked at the outcome of the women who SIMIN POUR SCHAHIN, MD 2 were treated differently according to the RODERICH WIEDMANN, MD study protocol, the small sample sizes re- he study of Haap et al. (1) on two sulting from the subanalysis impaired our patients with multiple symmetric li- From the 1Department of Medicine I, Friedrich- possibilities of an adequate statistical T pomatosis (MSL), also known as the Alexander University Erlangen-Nuremberg, Erlan- analysis. In the future, we hope to initiate Launois-Bensaude Syndrome, adds inter- gen, Germany; and the 2Department of Surgery, and cooperate in multicenter studies to esting new insights into a condition still Friedrich-Alexander University Erlangen-Nuremberg, gather more evidence to prove our results. poorly understood. Erlangen, Germany. As for the conclusions drawn con- Address correspondence to Igor Alexander Harsch, 1 MD, Department of Medicine I, Friedrich-Alexander UTE M. SCHAEFER-GRAF, MD, PHD cerning insulin sensitivity in patient 1, we University, Division of Endocrinology and Metabo- would like to suggest some caution. Our lism, Ulmenweg 18, 91054 Erlangen, Germany. E- From the1 Department of Obstetrics, Vivantes Med- study group has also measured the insulin mail: [email protected]. ical Center, Berlin, Germany. sensitivity index (ISI) in three subjects © 2004 by the American Diabetes Association.

DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 1849 Letters

●●●●●●●●●●●●●●●●●●●●●●● The original idea was to present a sit- tive and otherwise healthy, but due to his References uation where a substantial increase in extreme obesity (BMI 64 kg/m2) would 1. Haap M, Siewecke C, Thamer C, body fat mass was not accompanied by not fit into the magnetom, and we were Machann J, Schick F, Ha¨ring H-U, Szei- decreased insulin sensitivity, which is in unable to assess his visceral fat mass. This mies RM, Stumvoll M: Multiple symmet- much contrast to common belief. And in aspect is not necessarily in conflict with ric lipomatosis: a paradigm of metabolically innocent obesity? (Brief Report). Diabetes fact, fat accumulation, if confined to the our original hypothesis but just another Care 27:794–795, 2004 subcutaneous compartment, was not as- mechanism to render someone insulin re- 2. Harsch IA, Pour Schahin S, Fuchs FS, sociated with much insulin resistance. By sistant. Probably, among two equally Hahn EG, Lohmann T, Konturek PC, selecting these two specific patients for obese subjects with OSAS, the one with Ficker JH: Insulin resistance, hyperlep- argument’s sake, we may have introduced only subcutaneous fat accumulation is tinemia, and obstructive sleep apnea in a bias. But this is beside the point because more insulin sensitive. Launois-Bensaude syndrome. Obes Res even if everything we said held true for In conclusion, at some point the rea- 10:625–632, 2002 only these two subjects and no other pa- soning becomes circular and our way of 3. Enzi G, Biondetti PR, Fiore D, Mazzoleni tient with MSL, our findings would be no presenting these selected patients with F: Computed tomography of deep fat less interesting. And this is the reason why MSL may be just another way of demon- masses in multiple symmetrical lipomato- sis. Radiology 144:121–124, 1982 we specifically put “paradigm” in the title strating that subcutaneous fat is metabol- 4. Enzi G, Busetto I, Ceschin E, Coin A, rather than the syndrome alone. Never- ically more innocent than visceral fat (5). Digito M, Pigozzo S: Multiple symmetrical theless, Harsch et al. (2) appropriately 1 lipomatosis: clinical aspects and outcome pointed out that fat accumulation in MSL MICHAEL HAAP, MD 1 in a long-term longitudinal study. Int J need not necessarily be confined to the CLAUS THAMER, MD 1 Obes 26:253–261, 2002 subcutaneous compartment and that, HANS-ULRICH HARING¨ , MD 2 5. Brodie BC: Lectures Illustrative of Various without doubt, if it included the visceral ROLF MARKUS SZEIMIES, MD Subjects in Pathology and Surgery. London, 1,3 compartment, insulin resistance would MICHAEL STUMVOLL, MD Longman, Brown, Green, and Longman, be present. 1846, p. 275–282 Since our observation was accepted From the 1Department of Endocrinology, Metabo- 6. Harsch IA, Pour Schahin S, Radespiel- for publication, we were able to recruit lism and Pathobiochemistry, University of Tu¨ - Tro¨ger M, Weintz O, Jahreiss H, Fuchs FS, bingen, Tu¨ bingen, Germany; the 2Department of Wiest GH, Hahn EG, Lohmann T, Kon- two more patients with the clinical ap- Dermatology, University of Regensburg, Regens- turek PC, Ficker JH: Continuous positive pearance of MSL and very little visceral burg, Germany; and the 3Third Medical Depart- airway pressure treatment rapidly improves fat. The whole-body fat volume of the two ment, University of Leipzig, Leipzig, Germany. insulin sensitivity in patients with obstruc- subjects was ϳ14 and 20 l, respectively. Address correspondence to Michael Stumvoll, tive sleep apnea syndrome. Am J Respir Crit The subcutaneous-to-visceral abdominal MD, Third Medical Department, University of Care Med 169:156–162, 2004 Leipzig, Philipp-Rosenthal-Str. 27, 04301 Leipzig, fat ratio as measured by magnetic reso- Germany. E-mail: [email protected] nance imaging was 3.3 and 5.9, respec- leipzig.de. tively, compared with BMI-, age-, and © 2004 by the American Diabetes Association. Multiple Symmetric sex-matched control groups (1.6 and 1.4, Lipomatosis: A respectively). Consistent with the small ●●●●●●●●●●●●●●●●●●●●●●● visceral fat mass, liver fat was much lower References Paradigm of in both patients. Intramyocellular lipids 1. Haap M, Siewecke C, Thamer C, Metabolically in soleus and tibialis anterior muscles Machann J, Schick F, Haring HU, Szeim- were also lower than those in the control ies RM, Stumvoll M: Multiple symmetric Innocent Obesity? groups. And again, both MSL patients lipomatosis: a paradigm of metabolically were substantially more insulin sensitive innocent obesity? (Brief Report). Diabetes Response to Harsch, Schahin, and than their respective control groups. For Care 27:794–795, 2004 2. Harsch IA, Michaeli P, Hahn EG, Ficker Wiedmann the sake of completeness we also came across a subject with clinical MSL and JH, Konturek PC: Launois-Bensaude syn- drome in a female with type 2 diabetes. type 2 diabetes. But there are a number of Med Sci Monit 9:CS5–CS8, 2003 e have recently suggested (1) that reasons, which have little to do with our 3. Harsch IA, Schahin SP, Wiedman R: Mul- patients with multiple symmet- line of argument, for such a patient to ac- tiple symmetric lipomatosis: a paradigm W ric lipomatosis (MSL) may repre- quire secondary types of diabetes, for ex- of metabolically innocent obesity? (Let- sent a paradigm for metabolically ample, via alcohol-induced pancreatitis. ter). Diabetes Care 27:1849–1850, 2004 innocent fat accumulation. Harsch and Finally, the comment of Harsch et al. 4. Harsch IA, Schahin SP, Radespiel-Troger colleagues (2,3) raise some justified regarding a higher prevalence of obstruc- M, Weintz O, Jahreiss H, Fuchs FS, Wiest words of caution with respect to the gen- tive sleep apnea syndrome (OSAS) among GH, Hahn EG, Lohmann T, Konturek PC, eralization of this statement. It is probably patients with MSL is interesting and valu- Ficker JH: Continuous positive airway true that we cannot make general meta- able. OSAS seems to be an independent pressure treatment rapidly improves insu- lin sensitivity in patients with obstructive bolic inferences on the syndrome of MSL risk factor for insulin resistance (4). Upon sleep apnea syndrome. Am J Respir Crit as such based on our rather limited sam- reexamination of our small cohort, we in- Care Med 169:156–162, 2004 ple size. But this was not our intention, deed identified a man with documented 5. Montague CT, O’Rahilly S: The perils of and we welcome the opportunity to clar- OSAS (not among the ones reported). portliness: causes and consequences of vis- ify our line of argument. This patient appeared to be insulin sensi- ceral adiposity. Diabetes 49:883–888, 2000

1850 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 Letters

Has RoboCop Got Hence, Becton Dickinson has im- Dr. Jacques Garden, Chairman of the De- proved the quality of their insulin sy- partment of Metallurgy at the University Diabetes? ringes dramatically since the pictures of Grenoble, France (unpublished obser- were published, the syringes have been vation). e received a picture series from manipulated to produce false evidence of In Garden’s study, 80 diabetic pa- Becton Dickinson (Fig. 1A, here syringe defects, or Robocop was used as a tients from the Diabetes Service of Dr. Die- W transformed to black and white test subject. ter Look returned their used pen needles and translated from Swedish) showing and indicated the number of times each how syringes look after one, three, and BO BERGER, MD specific needle had been used. All needles five injections. We were astonished at PAVEL BURIAN, MD were used in a customary fashion and how deformed the syringes were after a KRISTINA NILSSON spanned the range of manufacturer types, few injections. MONA KARLEN gauges, and needle lengths. Needles were To test the reproducibility of the sy- ELISABETH RYLANDER used from 2 to 38 times. Needle tips were ringe deformation, one physician and two then resterilized for safety reasons and ex- From the Department of Medicine, Skovde Central amined by electron microscopy (2). nurses, all with ordinary builds and with- Hospital, Skovde, Sweden. out scars or metal implants, tested Becton Address correspondence to Dr. Bo Berger, Med. The tip damage found by Garden Dickinson’s insulin pen syringes Micro- klin, KSS, S-54185 Sko¨ vde, Sweden. E-mail: ranged from mild bending of the extreme Fineϩ 31 gauge ϫ 8 mm. We used the [email protected]. tip to a hook-like distortion of the entire syringes 1, 3, 5, and 10 times for injec- © 2004 by the American Diabetes Association. distal shaft of the needle. Loss of the tip tions in the abdominal fat. One syringe was seen on one occasion. Some needles was thereafter used to penetrate an ordi- Has RoboCop Got appeared undamaged, even after many re- nary rubber mousepad 100 times, then to uses. (In this regard Garden’s findings cut into a wooden computer table, and, Diabetes? agree with those of Berger et al.) However, finally, to cut a metal lamp foot. Pictures a clear association was seen between the were taken of the syringes with a Zeiss Response to Berger et al. severity of tip damage and the number of Axioscope 2.5ϫ lens with a lateral light needle reuses. source and a Canon 10D camera with 6.2 Among the needles, some looked just mpx resolution. The only syringe that e thank Berger et al. (1) for rais- like the ones provided by Berger et al. looked similar to the used syringes in Bec- ing questions about the serious Some were much worse than the ones we ton Dickinson’s picture series was the one W issue of reusing insulin syringes have chosen to show the public. We are that cut into a metal lamp foot. The sy- and pen needles. The source of the pho- unsure why the results of Berger et al. dif- ringes used 0, 1, 3, 5, 10, and 100 times tographs used by Becton Dickinson is an fer from our own. Among the possible are without distortion of the tip (Fig. 1B). independent study conducted in 1997 by causes are 1) the magnification used was

Figure 1—The picture series distributed by Becton Dickinson (A), and our own pictures of used syringes (B).

DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 1851 Letters at least an order of magnitude less than syringes (4). Finally, reusing syringes can betes Care, 1 Becton Dr., Franklin Lakes, NJ 07481. that of Garden (Ͼ300ϫ), 2) the health lead to suboptimal therapy. With sy- E-mail: [email protected]. care professionals in their study may be ringes, the patient can bring significant © 2004 by the American Diabetes Association. more careful than patients when perform- amounts of NPH into the regular or lispro ●●●●●●●●●●●●●●●●●●●●●●● ing injections or may use different tech- vial. With pens, leaving the needle on be- niques, or 3) they viewed fewer samples, tween uses can lead to incomplete injec- References and sampling error may have resulted. tions, which may cause the patient to 1. Berger B, Burian P, Nilsson K, Karlen M, We would welcome a full discussion of underdose themselves and receive as little Rylander E: Has RoboCop got diabetes? (Letter). Diabetes Care 27:1851, 2004 this study with Berger et al. as 35% of the expected dose (5). 2. Look D, Strauss K: [Nadeln mehrfach ver- We advise against pen needle and in- We believe the issue of insulin syringe wenden?] Diabetes Journal 10:S31–S34, sulin syringe reuse for a number of rea- and pen needle reuse to be serious, with 1998 sons. First, the syringes may become real safety concerns that have not been 3. Strauss K, De Gols H, Hannet I, Partanen hooked, as we have previously described. fully explored in the past. We welcome a TM, Frid A: A pan-European epidemio- The “hook” at the tip of the syringe may more complete scientific discussion of logic study of insulin injection technique break off and become lodged in the skin, this issue. in patients with diabetes. Pract Diab Int and the pain of injection with a syringe 19:71–76, 2002 increases with each reuse. 4. Paily R: Perinephric abscess from insulin BARRY H. GINSBERG, MD, PHD Second, studies conducted by a series syringe reuse. Am J Med Sci 327:47–48, KENNETH STRAUSS, MD 2004 of nurses in Europe have shown signifi- 5. Parkes JL, Slatin SL, Pardo S, Ginsberg cant increases in lipodystrophy in pa- From Becton Dickinson Medical Systems, Diabetes BH: A new consensus error grid to evalu- tients who reuse insulin syringes and pen Care, Franklin Lakes, New Jersey. ate the clinical significance of inaccuracies needles (3). Third, there are reports of in- Address correspondence to Dr. Barry H. Gins- in the measurement of blood glucose. Di- creased infections from reuse of insulin berg, BD Medical Systems, VP Medical Affairs, Dia- abetes Care 23:1143–1148, 2000

1852 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004