LETTERS

than the healthy group. When patients monocytes stimulated with IL-1-␤, tumor OBSERVATIONS were divided into the three groups ac- factor, or IFN-␥. J Immunolgy 141:3945–3950, 1988 cording to duration of , the high- ␤ est levels were observed in patients with 3. Bach LW: Interleukin-1 -mediated beta- newly diagnosed diabetes. These results cell inhibition in vivo: a role of circulating The Role of Platelet- interleukin-1␤ in the pathogenesis of in- Activating Factor in may indicate that PAF plays a role in the sulin dependent diabetes mellitus. Danish development of . There are Med Bull 43:39–57, 1996 Pathogenesis of Type few reports on this issue. In an experi- 4. Campbell L, Kay TWH, Oxbrow L, Har- 1 Diabetes mental study about the role of PAF in the rison LC: Essential role for interferon-␥ development of type 1 diabetes, it was de- and interleukin-6 in autoimmune - tected that administration of recombinant dependent diabetes in NOD/Wehi mice. PAF-acetyl hydrolase, which inactivates J Clin Invest 87:739–742, 1991 latelet-activating factor (PAF) is a PAF to rats, caused a decrease in insulitis 5. Signore A, Pozilli P, Gale EA, Andreani D, phospholipid mediator that exhibits (6). Another experimental study reported Beverly PC: The natural history of lym- phocyte subsets infiltrating the pancreas diverse and potent effects on many that the PAF synthesis capacity of poly- P of NOD mice. Diabetologia 32:282–289, cell types (1). PAF is a potent mediator of morphonuclear leukocytes was increased 1989 hypersensitivity and inflammatory reac- in diabetic rats (7). 6. Lee ES, Jiang J, Sund GC, Simonson WT: tions (2). Type 1 diabetes is caused by There is also clinical research that re- Recombinant human platelet-activating autoimmune destruction of the ␤-cells in ports an increased serum level of PAF in factor acetylhydrolase reduces the fre- the pancreas, which is initiated years be- type 1 diabetes. However, in these stud- quency of diabetes in the diabetes-prone fore the clinical presentation of disease ies, increased levels of PAF were attrib- BB rat. Diabetes 48:43–49, 1999 (3). In recent-onset type 1 diabetes and in uted to the ongoing and 7. Akiba S, Naka M, Hashizume T, Sugatani animal models of autoimmune diabetes, a were thought to accentuate the develop- J, Fujii T, Sato T: Stimulation of platelet- characteristic pathological finding in the ment of micro- and macrovascular com- activating factor synthesis in polimorpho- nuclear leukocytes from streptozocin islets of Langerhans is the accumulation of plications (8,9). In our study, high levels ␤ induced diabetic rats. J Biochem (Tokyo) mononuclear cells and -cell death (insuli- of PAF detected in patients who had dia- 117:425–433, 1995 tis) (4,5). In this study, we investigated the betes for a long duration when compared 8. Nathan N, Denizot Y, Huc MC, Claverie role of PAF as an inflammatory mediator in with the healthy group might be associ- C, Laubie B, Benveniste J, Arnaux B: Ele- pathogenesis of type 1 diabetes, which is a ated with vascular complications. vated levels of paf-acether in blood of chronic inflammatory process. In conclusion, PAF levels are in- patients with type 1 diabetes mellitus. Di- Serum PAF levels of 38 type 1 dia- creased in children with type 1 diabetes. abetes Metab 18:59–62, 1995 betic patients and 22 healthy children This increment was higher in children 9. Spangenberg P, Schymik C, Hoffmann B, with an age range of 5–15 years were eval- with new-onset diabetes and may be im- Ostermann G, Ruhling K, Till U: Blood uated by a high-performance liquid chro- portant in the etiopathogenesis of type 1 platelet behaviour in patients with a type matography method. Statistical analysis diabetes. Further research supporting the 1 diabetes mellitus. Exp Clin Endocrinol 94:329–337, 1989 was performed by the nonparametric use of PAF antagonists in patients with Kruskall-Wallis and Mann-Whitney U new-onset diabetes is required. tests. Average serum PAF levels of pa- 1 tients and healthy children were mea- BETU¨ L ERSOY, MD Spontaneous 2 sured to be 445.11 Ϯ 55.79 and 198.0 Ϯ AFIG HU¨ SEYINOV 2 Diabetic Myonecrosis 80.0 pg/ml, respectively. Serum PAF lev- S¸ U¨ KRAN DARCAN

els of the patient group were significantly 1 higher than those of the healthy children From the Department of Pediatrics, Division of Pe- Ͻ diatric Endocrinology and Metabolism, Celal Bayar (P 0.01). The patients were divided University School of Medicine, Manisa, Turkey; and iabetic muscle infarction is an un- into three groups according to the dura- the 2Department of Pediatrics, Division of Pediatric usual complication of late-stage di- tion of diabetes as newly diagnosed, 3 Endocrinology and Metabolism, Ege University abetes. The first case was reported School of Medicine, Izmir, Turkey. D months to 5 years, and Ͼ5 years. Average in 1965 by Angervall and Stener (1). Address correspondence to Dr. Betul Ersoy, MD, Ͻ serum PAF levels in these groups were Department of Pediatrics, Division of Pediatric En- There have been 100 cases reported 757.8 Ϯ 82.2, 307.3 Ϯ 27.1, and docrinology and Metabolism, Celal Bayar University since then (4). Clinical presentation is an 387.0 Ϯ 57.9 pg/ml, respectively. In the School of Medicine, Manisa, Turkey. E-mail: betul. acute atraumatic painful swelling of the newly diagnosed patient group, serum [email protected]. affected muscle and a palpable mass. Di- PAF levels were found to be significantly © 2005 by the American Diabetes Association. abetic muscle infarction has predilection Ͻ higher than those of the other groups (P ●●●●●●●●●●●●●●●●●●●●●●● for the quadriceps and thigh muscles and 0.01). There was no significant difference is found in diabetic subjects with estab- in serum PAF levels between the group References lished nephropathy and retinopathy (2). 1. Bonavida B, Mencia-Huerta JM: Platelet- with diabetes duration of 3 months to 5 We report a case of spontaneous Ͼ activating factor and cytokine network in years and that with diabetes duration 5 inflammatory processes. Clin Review Al- quadriceps necrosis in a type 2 diabetic years (P Ͼ 0.01). lergy 12:381–395, 1994 patient on hemodialysis. A 59-year-old Serum PAF levels of patients with 2. Valone FH, Epstein LB: Biphasic platelet- woman had a history of type 1 diabetes were significantly higher activating factor synthesis by human Ͼ20 years and unsatisfactory glycemic

980 DIABETES CARE, VOLUME 28, NUMBER 4, APRIL 2005 Letters control despite insulin therapy. This con- volving the thigh, can extend to the calf Potentially dition was complicated by proliferative (5). Curiously, muscle enzymes could be retinopathy, neuropathy, and nephropa- normal or marginally elevated. Important thy. In 2003, the patient progressed to The pathogenesis of this disease is un- Contribution of end-stage renal disease and required he- clear. Several hypotheses have been sug- Dextrose Used as modialysis. Her serum creatinine level gested. Muscle infarction could be caused was 5.7 mEq/l (normal value 0.5–1.3). by atherosclerosis and diabetic microan- Diluent to Other medical problems included hyper- giopathy. Other hypotheses discuss an al- Hyperglycemia in tension, heart failure with pulmonary hy- teration in the -fibrinolisis Hospitalized Patients pertension, and moderate myocardial system as the cause of diabetic muscle depression. Coronary vessels were nor- infarction, as described by Palmer and mal by catheterism. Greco (6) in two patients with this dis- everal recent studies have shown in- The patient was admitted for a painful ease and antiphospholipid syndrome. creased morbidity and mortality as- swelling of her left anterior thigh for 7 Gargiulo et al. (7) indicated the role of S sociated with hyperglycemia in days. There was no history of recent antiphospholipid antibodies in the pro- patients hospitalized for cardiovascular trauma or muscular injection. On physi- gession of diabetes complications. illnesses and acute illness requiring inten- cal examination, she showed a localized In summary, diabetic myonecrosis sive care (1). While many of these studies swelling and heating of the left thigh. Her should be suspected in diabetic patients have utilized intensive insulin therapy body temperature was 37.3°C. Labora- who develop a painful swollen muscle. (IIT) as a means of controlling hypergly- tory findings included a normal leukocyte 1 cemia, to our knowledge the possible iat- count at 10,000 cells/mcl (normal value JAVIER REYES-BALAGUER, MD 2 rogenic contribution of intravenous 5,000–10,000), with 84.6% (55–65) neu- ELENA SOLAZ-MORENO, MD 2 medications has been overlooked. trophils; at 313.5 IU/l (32– CARMEN MORATA-ALDEA, PHD 2 A 78-year-old man with type 2 diabe- 162); alkaline phosphatase at 424 IU/l (40– PATRICIA ELORZA-MONTESINOS, MD tes was hospitalized for respiratory fail- 190); fibrinogen at 468 mg/dl (150–350); 1 ure. Glycemic control was suboptimal lactate dehydrogenase at 327 IU/l (150– From the Allergy Division, Hospital Universitario ϩ La Fe, Valencia, Spain; and 2Internal Medicine, Hos- despite continuous insulin infusion. The 450); Na at 126.5 mEq/l (135–145); and ϩ pital Universitario La Fe, Valencia, Spain. diabetes service observed infusion of Van- K at 5.7 mEq/l (3.5–5.0). Address correspondence to Javier Reyes- comycin mixed in 250 ml of 5% dextrose A Doppler ultrasound of her left infe- Balaguer, MD, Hospital Universitario La Fe, Servicio rior limb excluded a deep venous thrombo- de Alergia, Avenida Campanar 21, 46009 Valencia (D5W) while examining the patient. Med- sis and revealed minimal atheromatosis. Espan˜ a. E-mail: [email protected]. ication review revealed four different in- © 2005 by the American Diabetes Association. Magnetic resonance imaging demonstrated travenous medications in D5W amounting to Ͼ1 l daily. This prompted edema and pronounced swelling of the left ●●●●●●●●●●●●●●●●●●●●●●● rectus femoris in T2-weighted sequences review of medication profiles for all pa- that suggested a muscular necrosis. The References tients followed by the diabetes service. Of 1. Angervall L, Stener B: Tumoriform focal 10 patients, 7 were receiving intravenous contralateral thigh was normal. muscular degeneration in two diabetic pa- The differential diagnoses, i.e., deep medications mixed in D5W (median 1 tients. Diabetologia 1:39–42, 1965 [range 1–4]). All of these patients re- venous thrombosis, thromboflebitis, frac- 2. Chow KM, Szeto CC, Wong TY, Leung ture, pyomiositis, necrotizant fascitis, my- FK, Cheuk A, Li PK: Diabetic muscle in- quired insulin therapy, and three (43%) ositis or dermatomyositis, and connective farction (Letter). Diabetes Care 25:1895, required an insulin drip to achieve mean tissue tumor, were excluded by the clini- 2002 glucose values ranging from 129 to 223 cal presentation, together with the ultra- 3. Trujillo-Santos AJ: Diabetic muscle in- mg/dl. Several of the intravenous medica- sound and magnetic resonance imaging. farction. Diabetes Care 26:211–215, 2003 tions could be given in normal saline A diagnosis of diabetic muscle necrosis 4. Maclsaac RJ, Jerums G, Scurrah L: Dia- rather than D5W (2) (Table 1). Five of was made. Symptomatic treatment, bed betic muscle infarction. Med J Aust 177: these patients were hospitalized long 323–324, 2002 rest, and analgesia were continued, and enough for an intervention. After remov- 5. Bunch TJ, Birskovich LM, Eiken PW: Di- ing dextrose diluent from their intrave- the pain improved in a period of 3–4 abetic myonecrosis in a previously weeks. healthy woman and review of a 25-year nous medications, four of the five patients According to the literature, diabetic Mayo Clinic experience. Endocr Pract showed improved glycemic control with muscle infarction is more frequent in 8:343–346, 2002 mean glucose values decreasing by 17–51 long-standing diabetic women (ϳ15 6. Palmer GW, Greco TP: Diabetic thigh mg/dl (mean 39 mg/dl). We attempted years), with an average age at presentation muscle infarction in association with an- to reduce subsequent iatrogenic hyper- of 43 years and multiple end-organ dia- tiphospholipid antibodies. Semin Arthritis glycemia by communicating with the betes complications, retinopathy, neu- Rheum 60:272–280, 2001 pharmacist to “provide all intravenous ropathy, nephropathy in peritonal 7. Gargiulo P, Schiaffini R, Bosco D, Ciam- medications mixed in normal saline” for palini P, Pantaleo A, Romani B, Arcieri P, dialysis or hemodialysis, and gastroenter- Andreani D: Diabetic microangiopathy: each diabetic patient we managed. opathy (3). It has predilection for the lupus anticoagulant dependent thrombo- Hyperglycemia is common in hospi- quadriceps (62%), hip adductors (13%), sis tendency in type 1 (insulin-depen- talized patients and has been shown to be hamstrings (8%), and hip flexors (2%) dent) diabetes mellitus. Diabet Med 14: an important marker of increased mortal- (4). Myonecrosis, although typically in- 132–137, 1997 ity and poor clinical outcome (1). A recent

DIABETES CARE, VOLUME 28, NUMBER 4, APRIL 2005 981 Letters

Table 1—Drugs compatible in normal saline automatically made in D5W* sulin glargine in two type 1 diabetic wom- Acetazolamide Cimetidine Doxycycline Norepinephrine en; both cases were free of any pregnancy Alprostadil Ciprofloxacin† Esmolol† Octreotide complications and with no direct effect on Aminophylline† Clindamycin† Heparin† Penicillins*† embryogenesis. Argatroban Cyclosporine Ibutilide Steroids‡ We report on five case subjects who Azithromycin Dobutamine† Lidocaine† Valproate sodium used glargine during unplanned preg- Cephalosporins†§ Dopamine† Nesiritide Vancomycin nancy (Table 1). All five diabetic women attended their first diabetes evaluation at *Includes nafcillin, penicillin G potassium, and piperacillin/tazobactam. †Manufacturer premade item(s). ‡Includes dexamethasone, hydrocortisone, and methylprednisolone. §Includes cefazolin, cefepime, cefo- our Outpatient Clinic between November taxime, cefoxitin, ceftazidime, ceftriaxone, and cefuroxime. 2002 and February 2004. None had evi- dence of retinopathy or autonomic neu- ropathy and they had normal urinary ●●●●●●●●●●●●●●●●●●●●●●● albumin excretion. They initiated study found that a modest increase in glargine 5–12 months before conception mean glucose from 80–99 to 100–119 References because of frequent nocturnal hypoglyce- mg/dl in an intensive care unit (ICU) set- 1. American College of Endocrinology: mia and suboptimal glycemic control. In- ting led to a 27% relative increase in mor- American College of Endocrinology Con- sensus Development Conference on Inpa- sulin glargine was started as part of a tality (3). A prospective, randomized, tient Diabetes and Metabolic Control: basal-bolus regimen with an average dose controlled trial found that the use of IIT to position statement [article online], 2003. of 25 Ϯ 17 IU/day (range 14–56) given as maintain blood glucose Յ110 mg/dl led Availablefromhttp://www.aace.com/pub/ a single predinner subcutaneous injec- to relative risk reduction of death in the ICC/inpatientStatement.php tion. The first diabetes assessment after ICU by 42% (4). The American Associa- 2. Trissel L: Handbook of Injectable Drugs. commencement of pregnancy occurred at tion of Clinical Endocrinologists (AACE) 12th ed. Bethesda, MD, American Society the 6th gestational week in three cases, has recently published guidelines on the of Heath-Systems Pharmacists, 2003 while the remaining women were seen at management of inpatient hyperglycemia 3. Krinsley J: Association between hypergly- the 8th and 12th week of gestation, re- (1). Protocols to prevent iatrogenic hy- cemia and increased hospital mortality in spectively. Their HbA at that time was perglycemia induced by use of dextrose as a heterogeneous population of critically ill 1c patients. Mayo Clin Proc 78:1471–1478, 7.3 Ϯ 0.8%. Due to the lack of controlled a diluent would also decrease resource 2003 data on the safety and efficacy of glargine utilization by decreasing the frequency of 4. Van den Berghe G, Wouters P, Weekers F, in pregnant women, all patients were blood glucose measurement and insulin Verwaest C, Bruyninckx F, Schetz M, switched to NPH in the morning and bed- administration. Vlasselaers D, Ferdinande P, Lauwers P, time, along with the usual premeal insulin Our preliminary observations suggest Bouillon R: Intensive insulin therapy in therapy. After 2 weeks of the new insulin that inpatients with diabetes frequently critically ill patients. N Engl J Med 345: regimen, three women were started on receive intravenous medications mixed in 1359–1367, 2001 continuous subcutaneous insulin infu- dextrose. Review of medications used in sion because optimal control could not be intravenous lines while examining the pa- attained. In all five patients, strict glyce- tient and careful review of medications Use of Insulin mic control was achieved, with an average and diluents can improve glycemic status Glargine During the HbA of 6.0 Ϯ 0.2% at the end of preg- and clinical outcomes. Creating a system 1c nancy. Pre-eclampsia developed in one to correct and prevent this occurrence can First Weeks of patient at the 32nd week of gestation, and improve patient care and decrease re- Pregnancy in Five neither progression in retinopathy nor source utilization. Future guidelines for Type 1 Diabetic other microangiopatic complications inpatient would be were detected. Previous observations improved by including this recommenda- Women have reported that the use of glargine is tion. associated with worsening eye disease in he long-acting analog glargine is a type 2 diabetic women (2). Babies (two 1 BRYAN J.KRAJICEK, MD new insulin with 24-h persistence. males and three females) were delivered 2 YOGISH C.KUDVA, MBBS This peculiar peakless action profile at a mean gestational age of 36.6 Ϯ 1.1 3 T HEATHER A.HURLEY, PHARMD accounts for significant risk reduction for weeks by cesarean section in all but one nocturnal and a more sta- woman. Mean birth weight was 3,066 Ϯ From the 1St. Marys Hospital, Critical Care Unit, ble daily plasma glucose profile (1,2). 898 g, with one baby Ͼ4 kg, whereas the Rochester, Minnesota; the 2Division of Endocrinol- Only a few reports have described the use other four babies’ weights were adequate ogy, Diabetes, Nutrition & Metabolism, Mayo Clinic of insulin glargine during human preg- for gestational age. There was neither ma- College of Medicine, Rochester, Minnesota; and the 3Department of Pharmacy Services, Mayo Clinic nancy, so its use is not recommended at jor nor minor congenital malformation, College of Medicine, Rochester, Minnesota. present. Animal studies have addressed and none of the babies had any complica- Address correspondence to Yogish C. Kudva, the safety and efficacy of glargine during tions during the postpartum period. MD, MBBS, W18A, Division of Endocrinology, Di- pregnancy, showing no direct effect on Our experience is limited to a few abetes, Nutrition & Metabolism, Mayo Clinic, 200 First St., SW, Rochester, MN 55905. E-mail: kudva. reproduction and embryo-fetal develop- subjects; nevertheless, all the observed [email protected]. ment (3). Recently, Devlin et al. (4) and women used insulin glargine from the © 2005 by the American Diabetes Association. Holstein et al. (5) reported the use of in- preconception period to 6–12 weeks’

982 DIABETES CARE, VOLUME 28, NUMBER 4, APRIL 2005 Letters

Table 1—Clinical characteristics of five type 1 diabetic pregnancies ject is the youngest child reported with systemic insulin allergy and the only pa- Perinatal tient who was treated without any adverse Age HbA1c Use of mortality event by glargine insulin in infancy. (years)/ preconception/ glargine in Glargine dose Time of Newborn and/or A neonate girl, the first child of con- white end of pregnancy in pregnancy delivery weight congenital Patient class* pregnancy (%) (weeks) (IU/day) (weeks) (g) malformation sanguineous parents, was born at full term after uneventful pregnancy. She was 1 32/B 7.0/6.7 6 18 35 2,220 No small for gestational age with a birth 2 26/C 6.4/6.4 12 56 37 3,500 No weight of 1,430 g. Although the infant 3 41/C 7.0/6.2 8 18 38 4,400 No had been fed properly from birth, she was 4 32/D 7.6/5.8 6 14 37 2,850 No presented with complaint of poor weight 5 27/B 8.7/5.8 6 20 36 2,360 No gain at 2 months of age. On admission, *White Classification of Diabetes in Pregnancy (7). Class A: Diet alone, any duration or onset age. Class B: she weighted 1,700 g (below the third Onset at age Ն20 years, duration Ͻ10 years. Class C: Onset between the ages of 10 and 19 years, duration 10–19 years. Class D: Onset before the age of 10 years, duration Ͻ20 years, background retinopathy or percentile) and appeared malnourished (not pre-eclampsia). Class R: Proliferative retinopathy or vitreous hemorrhage. Class F: Ne- and dehydrated. The blood glucose con- phropathy with Ͼ500 mg/day proteinuria. Class RF: Criteria for both classes R and F coexist. Class H: centration was 33.2 mmol, and there was Arteriosclerotic hearth disease clinically evident. Class T: Prior renal transplantation. All classes below A no acidosis or ketonuria. HbA1c and C- require insulin therapy. peptide levels were 9.7% and Ͻ0.5 ng/ ml, respectively. Anti-GAD and anti–islet cell antibodies were negative. The diagno- postconception. Hyperglycemia during 3. Hofmann T, Horstmann G, Stammberger sis of was established. I: Evaluation of the reproductive toxicity the first 8 weeks of gestation, as clearly The treatment with human NPH insulin reported by Mills et al. (6), increases the and embryotoxicity of insulin glargine (LANTUS) in rats and rabbits. Int J Toxicol (Humulin N; Lilly) was initiated. During risk of congenital anomalies. In our re- subsequent 10-month follow-up, the pa- port, insulin glargine does not seem to 21:181–189, 2002 4. Devlin JT, Hothersall L, Wilkis JL: Use of tient demonstrated normal growth and affect embryo-fetal development in this insulin glargine during pregnancy in a development and HbA1c level decreased critical period of embryogenesis. How- type 1 diabetic woman (Letter). Diabetes to 5.7%. ever, the small number of women and the Care 25:1095–1096, 2002 At 1 year of age, immediately after early discontinuation of therapy with in- 5. Holstein A, Plaschke A, Egberts EH: Use each insulin injection, she developed al- sulin glargine do not allow us to draw any of insulin glargine during embryogenesis lergic reactions, including macular skin final conclusion. Nevertheless, this observa- in a pregnant woman with type 1 diabe- rush, pruritus, and dermographism, on tion, as well as other anecdotic observa- tes. Diabet Med 20:779–780, 2003 her trunk and all injection sites. Although 6. Mills JL, Baker L, Goldman AS: Malforma- tions, emphasizes the need for properly she had been treated with antiallergic planned investigations. tions in infants of diabetic mothers occur before the seventh gestational week: im- drugs along with NPH insulin, the allergic reactions continued. Eosinophilia on pe- GRAZIANO DI CIANNI, MD plications for treatment. Diabetes 28:292– 293, 1979 ripheral blood smear was not detected, LAURA VOLPE, MD 7. Hare JW, White P: and the serum level of total IgE was 18 CRISTINA LENCIONI, MD and the White classification. Diabetes Care IU/ml (normal range Ͻ150 IU/ml). Un- KYRIAZOULA CHATZIANAGNOSTOU, MD 3:394–396, 1980 fortunately, tests for insulin-specific IgE ILARIA CUCCURU, MD and IgG were not performed. However, ALESSANDRA GHIO, MD the patient demonstrated allergic reac- LUCA BENZI, MD tions to different kinds of human insulin, STEFANO DEL PRATO, MD Successful Treatment of Insulin Allergy in including human regular insulin (Humu- From the Department of Endocrinology and Metab- lin R; Actrapid) and NPH insulin (Humu- olism, Section of Diabetes, University of Pisa, Pisa, a 1-Year-Old Infant lin N; Insulatard), not only following Italy. With Neonatal subcutaneous injection but also after in- Address correspondence to Dr. Graziano Di tradermal test. Intradermal tests con- Cianni, Department of Endocrinology and Metabo- Diabetes by Lispro lism, Section of Diabetes and Metabolic Diseases, firmed the insulin allergy. Ospedale di Cisanello, Via Paradisa, 2, I-56126 Pisa, and Glargine Insulin Gradual insulin desensitization with Italy. E-mail: [email protected]. low doses of regular insulin was not suc- © 2005 by the American Diabetes Association. cessful. We considered treating the pa- ystemic insulin allergy is a rare con- ●●●●●●●●●●●●●●●●●●●●●●● tient with rapid-acting insulin analogs dition and has usually been reported and examined skin reactions to lispro References in adults. Human insulin analogs (Humalog; Lilly) and aspart (Novorapid; 1. Ratner RE, Hirsch IB, Neifing JL, Garg SK, S have been proposed for the treatment of Novo Nordisk). Intradermal tests were Mecca TE, Wilson CA: Less hypoglycemia with insulin glargine in intensive insulin insulin allergy (1,2). Here we report a negative for both. Lispro treatment was therapy for type 1 diabetes. Diabetes Care 1-year-old infant with generalized allergy initiated, and no allergic reaction was ob- 23:639–643, 2000 to insulin who has been successfully served. However, prolonged treatment of 2. Bolli G, Owens DR: Insulin glargine. Lan- treated with the insulin analogs lispro and a 1-year-old infant with repeated injec- cet 356:443–445, 2000 glargine. To our knowledge, this case sub- tions of lispro four to five times a day was

DIABETES CARE, VOLUME 28, NUMBER 4, APRIL 2005 983 Letters very difficult. We therefore decided to test 3. Chase HP, Dixon B, Pearson J, Fiallo- clinic, the clinical appearances (Fig. 1B) the long-acting analog insulin glargine Scharer R, Walravens P, Klingensmith G, and sequence of events suggested a prob- that would meet daily requirement of Rewers M, Garg SK: Reduced hypoglycemic able diagnosis of wrist neuroarthropathy. basal insulin. Skin tests were also negative episodes and improved glycemic control in In addition, there were also signs of a with glargine insulin. Thus, the treatment children with type 1 diabetes using insulin marked peripheral sensorimotor neurop- glargine and neutral protamine Hagedorn with glargine insulin (Lantus; Aventis) insulin. J Pediatr 143:737–740, 2003 athy affecting the lower limbs and a typi- was commenced with the permission of cal Charcot pattern of deformity affecting parents. The patient received bedtime the left foot (although it had not previ- Ϫ Ϫ glargine insulin (0.7 units kg 1 day 1) ously been recognized as such). This had and, as needed, mealtime lispro insulin Charcot started with a spiral fracture of the left Ϫ Ϫ (0.1 units kg 1 day 1). This insulin Neuroarthropathy of fibula following minor trauma, with later regimen provided less hypoglycemic epi- development of spontaneous fractures of sodes than NPH insulin twice daily and the Wrist in Type 1 the proximal phalanx of the second toe Ͻ achieved HbA1c values 7%. During the Diabetes and the base of the fifth metatarsal, even- 6-month follow-up, we did not observe tually leading to typical clinical and radio- any allergic reaction or adverse event due logical appearances of midfoot to insulin glargine. harcot neuroarthropathy typically neuroarthropathy. Insulin glargine has been used in the affects the joints of the foot and an- Charcot neuroarthropathy rarely af- treatment of toddlers and children with C kle in diabetes (1); neuroarthropa- fects joints other than the foot and ankle type 1 diabetes (3). Because the systemic thy of the wrist is extremely rare (2,3). in diabetes (1). Joint involvement in the insulin allergy did not respond to the anti- A 53-year-old right-handed white Cau- upper limb is extremely unusual; only histaminic drug and desensitization ther- casian woman, who was a rose grower, pre- two reports of neuroarthropathy affecting apies, we have inevitably used insulin sented to rheumatology with an the wrist have been described before glargine to treat the 1-year-old infant with uncomfortable, swollen right wrist. She had (2,3). The likely explanation for the rarity neonatal diabetes. Once-daily dose of in- type 1 diabetes of 23 years’ duration and of wrist neuroarthropathy probably re- sulin glargine provided effective glycemic had undergone right ulnar nerve decom- flects the lesser degrees of peripheral sen- control and less hypoglycemic event and pression at the elbow for focal entrapment sorimotor and autonomic neuropathy was well tolerated in our infant patient. neuropathy 3 years previously. She had re- affecting the upper compared with the This case indicates that the insulin analog sidual wasting of the small muscles of the lower limbs and the fact that the latter glargine can be considered as a safe alter- right hand with mild weakness of the ab- possess major weight-bearing joints native treatment in very young children ductor digiti minimi and sensory signs con- (especially foot and ankle), which are with allergic reactions to human recom- sistent with bilateral ulnar neuropathy subjected to continual trauma. Neuroar- binant insulin. (more marked on the right). At the right thropathy likely results from the combi- o wrist, there was loss of 50 of both dorsiflex- nation of loss of protective sensation, a CENGIZ KARA, MD ion and palmar flexion. direct result of sensorimotor neuropathy, ALEV OGUZ KUTLU, MD Plain X-ray showed cystic changes in and hemodynamic changes (hyperemia) OLCAY EVLIYAOGLU, MD the distal radius and carpus with joint due to autonomic neuropathy, which HATICE BILGILI, CDE space narrowing, which had not been eventually lead to osteolysis and deminer- NURDAN YILDIRIM, CDE present 3 years earlier at the time of ulnar alization of bone (4), in the presence of nerve decompression. Laboratory investi- recurrent minor joint trauma (5). We be- From the Department of Pediatric Endocrinology, gation revealed a markedly elevated alka- lieve that within a susceptible milieu Dr. Sami Ulus Children’s Hospital, Ankara, Turkey. line phosphatase (250 units/l [normal (later development of foot neuroar- Address correspondence to Cengiz Kara, MD, range 25–110]) and a normal C-reactive thropathy), the impact of ulnar entrap- Konrad Adenauer Cad, no. 19/7 Sancak Mah, Ͻ 06550, Ankara, Turkey. E-mail: cengizkara68 protein ( 2 mg/l [normal range 0–10]). ment neuropathy (6) and the patient’s @yahoo.com. No sedimentation rate was recorded. Ra- vocation (rose pruning, which generated © 2005 by the American Diabetes Association. dioisotope bone scan demonstrated in- recurrent wrist trauma) contributed to creased uptake in the right radiocarpal the development of wrist neuroarthropa- ●●●●●●●●●●●●●●●●●●●●●●● joint. A diagnosis of osteoarthritis was thy in this particular case. When neuro- References made, and she was treated with a splint arthropathy affects the lower limb, 1. Abraham MR, Al-Sharafi BA, Saavedra and nonsteroidal anti-inflammatory treatment is focused on weight-sparing GA, Khardori R: Lispro in the treatment of drugs with some initial symptomatic ben- maneuvers and off-loading of the joint insulin allergy (Letter). Diabetes Care 22: efit. However, she experienced continual (5). However, this case suggests that the 1916–1917, 1999 wrist swelling, and repeat plain X-ray 2 benefits of using casts in neuroarthropa- 2. Moriyama H, Nagata M, Fujihira K, Yamada years later showed further loss of joint thy may not lie solely in weight redistri- K, Chowdhury SA, Chakrabarty S, Jin Z, space and more subchondral sclerosis but bution/off-loading, but also in reducing Yasuda H, Ueda H, Yokono K: Treatment with human analog (GlyA21, ArgB31, no periarticular osteoporosis (Fig. 1A). the attendant hyperemia by enforced un- ArgB32) insulin glargine (HOE901) resolves This was accompanied by progressive de- deruse of the limb. a generalized allergy to human insulin in formity of the right wrist, eventually lead- Charcot neuroarthropathy can, albeit type 1 diabetes (Letter). Diabetes Care 24: ing to marked limitation of movement rarely, affect joints other than those of the 411–412, 2001 and loss of function. At referral to our foot (2,3,7). Early recognition is crucially

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A: Multiple neuropathic joints, including the wrist, in a patient with diabetes mel- litus: JAMA 209:1690–1692, 1969 3. Bayne O, Lu EJ: Diabetic Charcot’s ar- thropathy of the wrist. Clin Orthopedics 357:122–126, 1998 4. Young MJ, Marshall A, Adams JE, Selby PL, Boulton AJ: Osteopenia, neurological dysfunction, and the development of Charcot neuroarthropathy. Diabetes Care 18:34–38, 1995 5. Rajbhandari SM, Jenkins RC, Davies C, Tesfaye S: Charcot neuroarthropathy in diabetes mellitus. Diabetologia 45:1085– 1096, 2002 6. Vinik A, Mehrabyan A, Colen L, Boulton A: Focal entrapment neuropathies in dia- betes. Diabetes Care 27:1783–1788, 2004 7. Lambert AP, Close CF: Charcot neuroar- thropathy of the knee in type 1 diabetes; treatment with total knee arthroplasty. Diabet Med 19:338–341, 2002 8. Jude EB, Selby PL, Burgess J, Lilleystone P, Mawer EB, Page SR, Donohoe M, Foster AV, Edmonds ME, Boulton AJ: Bisphos- phonates in the treatment of Charcot neuroarthropathy: a double-blind ran- domised controlled trial. Diabetologia 44: 2032–2037, 2001

COMMENTS AND RESPONSES

Lipids and Glucose in Type 2 Diabetes: What About the ␤-Cell and the Mitochondria?

Response to Boden and Laakso

Figure 1—A: Plain X-ray of the right wrist showing loss of joint space with increasing subchon- n the September issue of Diabetes Care, dral sclerosis. B: Right wrist deformity. Boden and Laakso (1) review various I methods by which fatty acids and fat important because joint immobilization Department of Diabetes, Division of Medicine, tissue promote the pathogenic process combined with the use of bisphospho- Taunton and Somerset Hospital, Musgrove Park, deteriorating to type 2 diabetes. They em- Taunton TA1 5DA, U.K. E-mail: paul.lambert@ nates may halt the process of joint disin- tst.nhs.uk. phasize the effect of peripheral fat storage tegration and prevent ensuing joint © 2005 by the American Diabetes Association. in muscle and liver on the development of deformity and loss of function (5,8). and diabetes but ne- ●●●●●●●●●●●●●●●●●●●●●●● glect, however, to discuss the effect of fat A. PAUL LAMBERT, PHD deposition in and around the ␤-cell on References COLIN F. CLOSE, MD ␤ 1. Sinha S, Munichodappa CS, and Kozak -cell function and apoptosis as a patho- physiologic event in the development of From the Department of Diabetes, Division of Med- GP: Neuroarthropathy (Charcot joints) in icine, Taunton and Somerset Hospital, Taunton, diabetes mellitus. Medicine 51:191–210, the disease. U.K. 1972 In their review, Boden and Laakso Address correspondence to Dr. Paul Lambert, 2. Feldman MJ, Becker KL, Reefe WE, Longo mention only the increase in insulin se-

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cretion and glucose-stimulated insulin se- was found in diabetic patients (8), thus damage in type 2 diabetes. Diabetes 53: cretion (GSIS) in response to exposure to rendering them more susceptible to FFA- 1412–1417, 2004 free fatty acids (FFAs). This response is induced mitochondrial damage and the 8. Schrauwen P, Hesselink MK, Blaak EE, said to be attenuated in diabetic patients slippery slope that follows. Another un- Borghouts LB, Schaart G, Saris WH, and their relatives, thus demonstrating a coupling protein, UCP2, is suspected of Keizer HA: Uncoupling protein 3 content is decreased in of patients tendency toward ␤-cell failure during the playing a role in glucose sensitivity and ␤ with type 2 diabetes. Diabetes 50:2870– disease. This effect is a short-term effect. insulin secretion in -cells and is upregu- 2873, 2001 When obese individuals were exposed to lated by chronically elevated FFAs (9). 9. Chan CB, Saleh MC, Koshkin V, Wheeler high levels of FFAs for prolonged periods Genetic polymorphism in this protein MB: Uncoupling protein 2 and islet func- of time, a decline in GSIS was observed was found to be associated with insulin tion. Diabetes 53:S136–S142, 2004 (2). The effect of chronically elevated resistance and increased risk of type 2 di- 10. D’Adamo M, Perego L, Cardellini M, FFAs highlights a major contribution of abetes (10). Marini MA, Frontoni S, Andreozzi F, ␤-cell lipotoxicity to the pathogenic pro- Sciacqua A, Lauro D, Sbraccia P, Federici M, Paganelli M, Pontiroli AE, Lauro R, cess deteriorating to type 2 diabetes . This ROY ELDOR, MD Perticone F, Folli F, Sesti G: The ␤-cell lipotoxicity has been studied thor- ITAMAR RAZ, MD Ϫ866A/A genotype in the promoter of the oughly. It has been shown that high levels human uncoupling protein 2 gene is as- of FFAs have a detrimental effect on ␤-cell From the Department of Medicine, Diabetes Research Center, Hadassah-Hebrew University, sociated with insulin resistance and in- survival and insulin secretion (3). In ZDF Jerusalem, Israel. creased risk of type 2 diabetes. Diabetes rats, these effects were related to en- Address correspondence to Roy Eldor, Depart- 53:1905–1910, 2004 hanced accumulation of triglycerides in ment of Medicine, Hadassah-Hebrew University the islets and ␤-cells (4). A high FFA and Hospital, Jerusalem 91120, Israel. E-mail: royeldor triglyceride load in human islets induced @bezeqint.net. © 2005 by the American Diabetes Association. Lipids and Glucose in caspase-mediated apoptosis, probably Type 2 Diabetes: through the ceramide pathway (5). Fur- ●●●●●●●●●●●●●●●●●●●●●●● thermore, thiazoldinediones, which are References What About the known to improve insulin resistance 1. Boden G, Laakso M: Lipids and glucose in ␤-Cell and the through a reduction in fat content of mus- type 2 diabetes: what is the cause and ef- cle and liver, cause a dramatic improve- fect? Diabetes Care 27:2253–2259, 2004 Mitochondria? ment in insulin secretion in diabetic 2. Carpentier A, Mittelman SD, Bergman patients (6). Based on these effects, it RN, Giacca A, Lewis GF: Prolonged ele- Response to Eldor and Raz would seem nearsighted to emphasize the vation of plasma free fatty acids impairs role of FFAs in diabetes as mainly a pe- pancreatic ␤-cell function in obese non- ripheral one on muscle and liver tissue. diabetic humans but not in individuals rs. Eldor and Raz (1) assert that Although type 2 diabetes is characterized with type 2 diabetes. Diabetes 49:399– “high levels of FFAs [free fatty ac- by peripheral insulin resistance that 408, 2000 ids] have a detrimental effect on 3. Shimabukuro M, Zhou YT, Levi M, Unger D ␤ might be related to deranged fat metabo- RH: Fatty acid-induced cell apoptosis: a -cell survival and insulin secretion.” We lism, it is becoming clear that it is not link between obesity and diabetes. Proc agree, but only in relation to patients who solely a disease of glucose-utilizing tissue Natl Acad Sci USA 95:2498–2502, 1998 have dysfunctional ␤-cells, i.e., patients but might also be a result of a lipotoxic 4. Lee Y, Hirose H, Zhou YT, Esser V, Mc- with pre-diabetes, impaired glucose toler- effect on the ␤-cell. Garry JD, Unger RH: Increased lipogenic ance, or type 2 diabetes (2–5). On the Other areas that should be high- capacity of the islets of obese rats: a role in other hand, in people with normally func- lighted include the role of lipotoxic mito- the pathogenesis of NIDDM. Diabetes 46: tioning ␤-cells, there is much evidence chondrial damage as a core process in the 408–413, 1997 that FFAs, rather than impairing, actually pathogenesis of type 2 diabetes and the 5. Lupi R, Dotta F, Marselli L, Del Guerra S, augment insulin secretion. For instance, role of mitochondrial uncoupling pro- Masini M, Santangelo C, Patane G, Boggi several groups have recently shown that U, Piro S, Anello M, Bergamini E, Mosca teins (UCPs) as culprit proteins and a pos- F, Di Mario U, Del Prato S, Marchetti P: in healthy individuals, elevation of sible defense mechanism in diabetes. Prolonged exposure to free fatty acids has plasma FFAs, for as long as 96 h, poten- Mitochondrial dysfunction has been cytostatic and pro-apoptotic effects on tiated glucose-stimulated insulin secre- noted in diabetes and may result from an human pancreatic islets: evidence that tion (2,6–8). Moreover, lowering plasma enhanced effect of lipid peroxides formed ␤-cell death is caspase mediated, partially FFA levels, rather than improving insulin in the mitochondria as a result of FFA dependent on ceramide pathway, and secretion, has been shown to actually de- excess. This damage can then lead to fur- Bcl-2 regulated. Diabetes 51:1437–1442, crease insulin secretion (9,10). Thus, ther FFA accumulation through dimin- 2002 there is currently little evidence to sup- ished oxidative capacity (7). The 6. Cavaghan MK, Ehrmann DA, Byrne MM, port the concept of FFA-induced ␤-cell mitochondrial UCPs seem to play a role in Polonsky KS: Treatment with the oral an- lipotoxicity in normal human subjects. tidiabetic agent troglitazone improves ␤ the protection of the mitochondria from beta cell responses to glucose in subjects Moreover, the concept of -cell lipotox- these harmful effects by preventing the with impaired glucose tolerance. J Clin In- icity would be difficult to reconcile with formation of lipid peroxides (7). They vest 100:530–537, 1997 the observation that Ͼ50% of obese peo- were implied as culprit proteins in diabe- 7. Schrauwen P, Hesselink MK: Oxidative ple with chronically elevated FFA levels tes when a 50% reduction in UCP3 levels capacity, lipotoxicity, and mitochondrial never develop type 2 diabetes during their

986 DIABETES CARE, VOLUME 28, NUMBER 4, APRIL 2005 Letters lifetime, despite the fact that most of them © 2005 by the American Diabetes Association. and ketone bodies on basal insulin secre- are insulin resistant. tion in type 2 diabetes. Diabetes 48:577– Drs. Eldor and Raz also state that li- ●●●●●●●●●●●●●●●●●●●●●●● 583, 1999 potoxicity-induced mitochondrial dam- 6. Boden G, Chen X, Rosner J, Barton M: References Effects of a 48-h fat infusion on insulin age is a “core process in the pathogenesis 1. Eldor R, Raz I: Lipids and glucose in type of type 2 diabetes.” We agree that there is ␤ secretion and glucose utilization. Diabetes 2 diabetes: what about the -cell and the 44:1239–1242, 1995 mitochondrial dysfunction in patients mitochondria? (Letter). Diabetes Care 28: 7. Jensen CB, Storgarrd H, Holst JJ, Dela F, with pre-diabetes as well as in patients 985-986, 2005 Madsbad S, Vaag AA: Insulin secretion 2. Kashyap S, Belfort R, Gastaldelli A, with diabetes. It is not known, however, and cellular glucose metabolism after pro- Pratipanawatr T, Berria R, Pratipanawatr whether this is a primary or secondary longed low-grade intralipid infusion in W, Bajaj M, Mandarino L, DeFronzo R, defect. Moreover, whereas it is possible, young men. J Clin Endocrinol Metab 88: Cusi K: A sustained increase in plasma perhaps even likely, that high fatty acid 2775–2783, 2003 levels contribute to mitochondrial dys- free fatty acids impairs insulin secretion in nondiabetic subjects genetically predis- 8. Carpentier A, Giacca A, Lewis GF: Effect function, to our knowledge, there are posed to develop type 2 diabetes. Diabetes of increased plasma non-esterified fatty presently no human data to support this 52:2461–2474, 2003 acids (NEFAs) on arginine-stimulated in- assertion. 3. Storgaard H, Jensen CB, Vaag AA, Volund sulin secretion in obese humans. Diabeto- A, Madsbad S: Insulin secretion after logia 44:1989–1997, 2001 1 GUENTHER BODEN, MD short- and long-term low grade free fatty 9. Dobbins RL, Chester MW, Daniels MB, 2 MARKKU LAAKSO, MD acid infusion in men with increased risk McGarry JD, Stein DT: Circulating fatty of developing type 2 diabetes. Metabolism acids are essential for efficient glucose- From the 1Temple University Health Science Cen- 52:885–894, 2003 stimulated insulin secretion after pro- ter, General Clinical Research Center, Philadelphia, longed fasting in humans. Diabetes 47: 2 4. Stefan N, Stumvoll M, Bogardus C, Pennsylvania; and the Kuopio University Hospital, Tataranni PA: Elevated plasma nonesteri- 1613–1618, 1998 Kuopio, Finland. 10. Boden G, Chen X, Iqbal N: Acute lower- Address correspondence to Dr. Guenther Boden, fied fatty acids are associated with deteri- MD, Temple University Health Science Center, Gen- oration of acute insulin response in IGT ing of plasma fatty acids lowers basal eral Clinical Research Center, North Broad St., 4W, but not NGT. Am J Physiol Endocrinol insulin secretion in diabetic and nondia- Philadelphia, PA 19140. E-mail: guenther.boden@ Metab 284:E1156–E1161, 2003 betic subjects. Diabetes 47:1609–1612, tuhs.temple.edu. 5. Boden G, Chen X: Effects of fatty acids 1998

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