410 Archives ofDisease in Childhood 1996;75:410-415

Ketoacidosis at the diagnosis of type 1 (insulin Arch Dis Child: first published as 10.1136/adc.75.5.410 on 1 November 1996. Downloaded from dependent) diabetes mellitus is related to poor residual cell function

Jorma Komulainen, Raisa Lounamaa, Mikael Knip, Eero A Kaprio, Hans K Akerblom, and the Childhood Diabetes in Finland Study Group

Abstract observed to be associated with age at diagno- The determinants of the degree of meta- sis,' degree of metabolic decompensation,9 bolic decompensation at the diagnosis of mild clinical symptoms at diagnosis,2910 and type 1 (insulin dependent) diabetes melli- strict initial blood glucose control.213 Diabetic tus (IDDM) and the possible role of ketoacidosis is a serious consequence of insuf- diabetic ketoacidosis in the preservation ficient insulin secretion.'4 In addition to possi- and recovery of residual P cell function ble acute complications, it may also influence were examined in 745 Finnish children the later outcome of diabetes. and adolescents. Children younger than 2 To study the effect of age, sex, and years or older than 10 years of age were socioeconomic factors on the clinical condition found to be more susceptible to diabetic ofthe patient at the diagnosis of IDDM, and to ketoacidosis than children between 2 and find out whether metabolic decompensation at 10 years of age (<2 years: 53.3%; 2-10 diagnosis is related to subsequent endogenous years: 16.9%; >10 years: 33.3%). Children insulin secretion and impaired metabolic con- from families with poor parental trol, 745 Finnish children and adolescents, educational level had ketoacidosis more aged 0.8-14.9 years, were evaluated at the time often than those from families with high of diagnosis of IDDM and then observed for parental educational level (24.4% v two years. 16.9%). A serum C peptide concentration of0.10 nmol/l or more was associated with Methods a favourable metabolic situation. Low PATIENTS serum C peptide concentrations, high As a part ofthe Finnish nationwide 'Childhood requirement of exogenous insulin, low diabetes in Finland' study,'5 801 probands Department of prevalence ofremission, and high glycated younger than 15 years, diagnosed as having Paediatrics, Kuopio haemoglobin concentrations were ob- IDDM during the recruitment period from 1 University Hospital, http://adc.bmj.com/ served during the follow up in the group of 1986 to 30 were offered Kuopio, Finland diabetic ketoacidosis at September April 1989, J Komulainen probands having the possibility of participating in the study. Of the diagnosis of IDDM. Thus diabetic these 745 had analyses of blood pH, serum C Department of ketoacidosis at diagnosis is related to a peptide concentrations, and blood glycated Epidemiology, the decreased capacity for P cell recovery National Public Health haemoglobin levels at the time of hospital after the clinical manifestation of IDDM admission. At the time of a clinical Institute, Helsinki, in children. admission, Finland examination including assessment of con-

(Arch Dis Child 1996;75:410-415) on September 28, 2021 by guest. Protected copyright. R Lounamaa sciousness and dehydration was performed, Keywords: ketoacidosis, serum C peptide, insulin dose, and the parents were asked to fill out a Department of questionnaire concerning the socioeconomic Paediatrics, University insulin dependent diabetes mellitus. of Oulu, Oulu, Finland status of the family. The subjects were then fol- M Knip lowed up in their own outpatient clinics (n = A chronic autoimmune destruction of the pan- 31) for two years. At six month intervals, the Department of creatic f cells results in decreasing endogenous recommended amount of insulin was re- Paediatrics, Peijas insulin secretion and the clinical manifestation corded, blood specimens werc taken for Hospital, Vantaa, haemoglobin and serum C peptide Finland of type 1 (insulin dependent) diabetes glycated E A Kaprio (IDDM). The clinical onset of the disease is concentrations, and a clinical examination often acute in children and adolescents, and including height and weight recording was per- The Children's diabetic ketoacidosis is present in 20-74% of formed. Hospital, II the patients.' Young age and female sex have The mean age of the probands was 8.4 years Department of been associated with an increased frequency of (range 0.8 to 14.9 years). The majority of them Paediatrics, University were males (n = 412; 55.3%). The subjects ofHelsinki, Helsinki, diabetic ketoacidosis.' However, there are only Finland limited data concerning the determinants of were divided into two groups: those with and H K Akerblom the degree of metabolic decompensation at the without diabetic ketoacidosis at diagnosis. In diagnosis of childhood IDDM. the longitudinal study the groups were com- Correspondence to: pared at the time of diagnosis and at six, 12, 18, Jorma Komulainen, It is well known that the capacity of residual Department of Paediatrics, 5 cells to secrete insulin is decreased at the and 24 months after diagnosis. Kuopio University Hospital, time of diagnosis of IDDM, often improving in PO Box 1777, FIN-7021 1 a few weeks after the initiation of exogenous LABORATORY MEASUREMENTS Kuopio, Finland. insulin treatment.8'-` The extent of improve- Capillary or venous blood pH was measured at Accepted 24 July 1996 ment in insulin secretory capacity has been the time of hospital admission. Diabetic Ketoacidosis affects residualf, cellffunction 411

ketoacidosis was defined as a blood pH of less Table 1 Data on ketoacidosis, degree ofconsciousness, and than 7.30. dehydration in study population at the diagnosis ofIDDM Arch Dis Child: first published as 10.1136/adc.75.5.410 on 1 November 1996. Downloaded from Serum C peptide concentrations were ana- No (%/) lysed in one central laboratory with a radioim- pH 7.30 or more 584 (78.4) munoassay, as described earlier,"6 by using 7.20-7.29 87 (11.7) antiserum K6 (Novo Research Institute, Bags- 7.10-7.19 40 (5.4) vaerd, Denmark). The detection limit of the 7.00-7.09 18 (2.4) <7.00 16(2.1) assay was 0.03 nmolIl. Consciousness Normal 655 (87.9) Standard methods for blood glycated hae- Impaired 90 (12.1) moglobin (HbA1) and HbA1C analysis were Dehydration No 274 (36.8) Mild 354 (47.5) used in the various hospitals (n = 31) Severe 98 (13.1) participating in the study. To make the results Unknown 19 (2.6) comparable, they were expressed as a SD score above the mean for non-diabetic subjects. impaired consciousness, while 21 (23.3%) of ASSESSMENT OF CONSCIOUSNESS AND the probands with impaired consciousness had DEHYDRATION a blood pH value of 7.30 or more. Twenty one Degree of consciousness and dehydration was (21.4%) of the children who were rated to be assessed by the clinician examining the patient severely dehydrated had a blood pH value of at the time of hospital admission. Conscious- 7.30 or more. Sixteen (2.1%) children had a ness was estimated to be either normal or blood pH value of less than 7.00. One of them impaired. Dehydration was rated to be absent, (6.2%) was considered to have normal con- mild (<8% in children younger than 12 years sciousness, and four (25.0%) were considered of age, <7% in older children), or severe (8% to be only mildly dehydrated. or more, 7% or more, respectively). Serum C peptide concentrations were ana- lysed in 697 probands (93.6%). Fourteen of them (2.0%) had an undetectable serum C DAILY INSULIN DOSE AND REMISSION peptide concentration at diagnosis, and 141 The recommended amount of insulin and the (20.2%) had a concentration of less than 0.10 weight of the proband were recorded at each nmolIl. They were considered 'low' secretors. six monthly visit, and the daily insulin dose The clinical and laboratory data of 'low' and (IU/kg/day) was calculated. Partial remission 'high' secretors are presented in table 3. was defined as an insulin dose less than 0.5 The mean age of the study population was IU/kg/day in combination with a glycated hae- 8.4 years (range 0.8 to 14.9 years). Thirty of moglobin (HbA1 or HbA1) not exceeding the the subjects (4.0%) were younger than 2.0 mean laboratory specific reference level by 4 years of age (group A), 432 of them (58.0%) SD score or more. were 2.0-10.0 years old (group B), and 283 (38.0%) were older than 10.0 years (group C).

SOCIOECONOMIC FACTORS More than half (58.4%) of the subjects in the http://adc.bmj.com/ Families were divided into groups according to oldest age group were pubertal at the diagnosis parental education, taxable income, and place of IDDM. Ketoacidosis was more common in of residence. Families in which at least one of age group A (n = 16; 53.3%, p<0.001) and in the parents had an academic degree were clas- age group C (n = 72; 25.4%, p<0.01) than in sified as ones with high parental education, age group B (n = 73; 16.9%). Impaired whereas other families were classified as ones consciousness was found more often in age with low parental education. Low income was = group A (n 10; 33.3%) than in age group B on September 28, 2021 by guest. Protected copyright. considered as a reported annual income of less than FIM 90 000 ($US 18 000), medium Table 2 Laboratory data ofstudy population at time of income that of FIM 90-150 000 ($US 18- hospital admission 30 000), and high income that of more than FIM 150 000 ($US 30 000). Urban families No Mean Median SD Range had their homes in a city, town or suburb, while pH 745 7.34 7.37 0.11 6.83-7.58 rural families lived in a village or outside a B glucose (mmol/l) 739 21.6 20.2 9.6 3.2-107.0 population centre. C peptide (nmol/l) 697 0.19 0.15 0.14 0-1.29 GHb (SD score) 565 12.9 12.2 6.0 0.2-38.8

= STATISTICAL ANALYSIS GHb glycated haemoglobin. Statistical analyses were performed by using Table 3 Clinical and laboratory data in diabetic children contingency table analysis with X2 statistics, the with serum C peptide concentrations < 0. 10 nmolll ('low' unpaired t test, Mann-Whitney U test, multiple secretors) and in those with > 0.10 nmolll ('high' linear regression analysis, correlation analysis, secretors). SD values are given in parentheses and one way analysis of variances (ANOVA) 'High' with covariance analysis or loglinear analysis. 'Low'secretors secretors (n=141) (n=556) p Age (years) 6.7 (3.8) 8.9 (3.6) < 0.001 Results B pH 7.29 (0.13) 7.36 (0.10) < 0.001 B glucose (mmol/l) 26.5 (11.1) 20.4 (8.6) < 0.001 The clinical data of the study population at GHb (SD score) 13.6 (5.1) 12.8 (6.1) NS hospital admission are summarised in table 1, Impaired 23.4% 9.2% < 0.001 and the laboratory data in table 2. Sixty nine consciousness Dehydration 79.4% 59.5% < 0.001 (42.9%) of the 161 subjects with a blood pH value of less than 7.30 were estimated to have GHb = glycated haemoglobin. 412 Komulainen, Lounamaa, Knip, Kaprio, i4kerblom, et al

(1) (n = 48; 11.1%, p<0.001) or in age group C (n = 32: 11.3%, p<0.00 1). Younger children had lower serum C peptide Arch Dis Child: first published as 10.1136/adc.75.5.410 on 1 November 1996. Downloaded from concentrations than older children. The mean - (SD) serum C peptide concentration in age 6 (1) group A was 0. 1 1 (0. 10) nmol/l, in age group B Ef 0.2 0.18 (0.13) nmol/l, and in age group C 0.22 E (0.15) nmol/l (AvB:p

-__ cr ] higher at the time of diagnosis and during the http://adc.bmj.com/ 0~ whole follow up period (fig 1) than in the o_ 6 12 18 24 Time (months) ketoacidosis group. This held true even after adjustment for age and sex. Partial remission 557 602 284 633 n was less common in the ketoacidosis than in Figure 2 Frequency ofclinical remission in the diabetic ketoacidosis group (shadowed the non-ketoacidosis group (fig 2). The recom- columns) and non-diabetic ketoacidosis group (empty columns) during thefollow up period. mended amount of insulin was higher in the (1) p<0. 0001, (2) p = 0.009, X2 test. ketoacidosis than in the non-ketoacidosis group after adjustment for age (fig 3). Multiple on September 28, 2021 by guest. Protected copyright. insulin injection regimens were used more (3) often in the ketoacidosis than in the non- (3) ketoacidosis group (six months: 28% v 12%; 12 months: 38% v 24%; 18 months: 47% v 33%; 24 months: 56% v 49%). The ketoacido- m sis group had worse glucose control when assessed by glycated haemoglobin concentrations (table 5). 0 CAuz0 Table 4 Clinical condition at diagnosis ofIDDM in the children fromfamilies with high or low parental education, r.a mean (SD) .5,c High parental Low parental 0c9 education education (n=254) (n=431) p Age (years) 8.4 (3.8) 8.5 (3.8) NS pH 7.36 (0.10) 7.33 (0.12) < 0.01 DKA 16.9% 24.4% < 0.05 0 6 12 18 24 Time (months) Dehydration 63.3% 63.3% NS Impaired 8.7% 14.4% < 0.05 718 630 671 294 653 nl consciousness C peptide (nmol/l) 0.20 (0.15) 0.18 (0.13) 0.06 Figure 3 Mean (SD) daily insulin dose (IUlkglday) in the diabetic ketoacidosis group B glucose (mmol/l) 21.1 (9.0) 21.7 (9.0) NS (shadowed columns) and non-diabetic ketoacidosis group (empty columns) three weeks GHb (SD score) 12.7 (6.1) 13.1 (6.0) NS after diagnosis (time point 0) and during the follow up period. (1) p<0. 0001, (2) p = 0. 001, (3) p = 0. 002 (multiple linear regression analysis). GHb = glycated haemoglobin; DKA - diabetic ketoacidosis. Ketoacidosis affects residual ,8 cellfunction 413

Table 5 Mean glycated haemoglobin values expressed as of IDDM. These findings support the idea SD score above the mean levelfor non-diabetic subjects in that, by effective diabetes education among the diabetic ketoacidosis (DKA) and non-DKA groups (t test) general population, it may be possible to Arch Dis Child: first published as 10.1136/adc.75.5.410 on 1 November 1996. Downloaded from DKA No Mean (SD) p further decrease the proportion of those with ketoacidosis at diagnosis. At diagnosis - 442 12.2 (5.9) < 0.001 + 123 15.5 (5.7) Children under 2 years of age were more 6 months - 401 3.9 (3.4) < 0.001 prone to diabetic ketoacidosis. This is probably + 118 4.9 (4.3) because of the rapid progression of their 12 months - 392 5.3 (3.7) = 0.001 + 111 6.7 (4.2) disease, in combination with difficulties in rec- 18 months - 167 5.4 (3.7) < 0.01 ognising diabetic symptoms in this age group. + 49 7.1 (3.8) The majority (62.5%) of patients with diabetic 24 months - 369 6.4 (4.0) < 0.01 + 107 7.7 (4.7) ketoacidosis were, however, older than 10 years. This disposition to diabetic ketoacidosis among subjects in the oldest age group is somewhat more surprising. It may be that they Serum C peptide concentrations at the time pay less attention to their symptoms, and are of diagnosis correlated strongly with later admitted to the hospital at a later stage. This is serum C peptide levels (six months: r = 0.40, supported by the finding of a higher glycated p<0.001; 12 months: r = 0.42, p<0.001; 18 haemoglobin in that age group, indicating a months: r = 0.33, p<0.001; 24 months: r = longer period of glucose intolerance before the 0.33, p<0.001). There was also a significant diagnosis of their disease. correlation between initial glycated haemo- There were no differences in blood pH and globin and subsequent glycated haemoglobin frequency of diabetic ketoacidosis or impaired values (six months: r = 0.20, p<0.001; 12 consciousness between sexes. However, fe- months: r = 0.26, p<0.001; 18 months: r = males had significantly higher serum C peptide 0.12, NS; 24 months: r = 0.23, p<0.001). concentrations but they also tended to have higher glycated haemoglobin levels than males. Discussion These findings, which are in accordance with At diagnosis, over one fifth (21.6%) of our dia- the observations of Drash,' are somewhat puz- betic children and adolescents had diabetic zling since in general there is an inverse corre- ketoacidosis, defined as a blood pH value of lation between serum C peptide and glycated less than 7.30. This is quite a low proportion, haemoglobin levels during a follow up of since in a previous survey' more than one third diabetic patients. They may be explained by (35.3%) of Finnish children and adolescents possible differences in insulin sensitivity had diabetic ketoacidosis at the diagnosis of between sexes, since an increased insulin IDDM. The definition of diabetic ketoacidosis requirement in adolescent females with was the same as that in our study. Our observa- IDDM, as well as an impaired insulin sensitiv- tions indicate that the prevalence of diabetic ity in healthy adolescent girls, has been

ketoacidosis at the diagnosis of childhood reported."'7-19 Our observation of higher en- http://adc.bmj.com/ IDDM has decreased over the last decade in dogenous insulin secretion probably reflects our country. earlier clinical manifestation of IDDM in Among other populations, a higher preva- females than in males. lence of diabetic ketoacidosis has been re- The discrepancy between the clinical and ported in children and adolescents at the pres- laboratory findings of the patients at the entation of IDDM. In the study of Elamin et al diagnosis of IDDM was remarkable. Nearly ketoacidosis was present at diagnosis in 73.9% one fourth of the probands who were diag- on September 28, 2021 by guest. Protected copyright. of Sudanese children.6 Drash reported at diag- nosed as having impaired consciousness still nosis a blood pH of 7.2 or less in 20%, and a had a blood pH value of 7.30 or more. The bicarbonate concentration of 15 mmol/l or less same was found in more than one fifth of the in 42% of diabetic children and adolescents in severely dehydrated patients. On the other Pittsburgh, USA,3 and Couper et al observed a hand, one of the 16 patients with a blood pH plasma pH of less than 7.30 in six of 25 value of less than 7.00 was considered to have Australian children (24%) with newly diag- normal consciousness, and four of them were nosed IDDM.5 In a recent study from southern considered to be only mildly dehydrated. England,7 a blood pH value of less than 7.35 or These observations are probably at least partly a bicarbonate value of less than 21.0 mmol/l due to interobserver variation in the definition was observed in 29.7% of children younger of consciousness and dehydration. They also than 15 years of age at the diagnosis ofIDDM. clearly show the value of blood pH analysis in The low proportion of children presented the evaluation of the child at the diagnosis of with ketoacidosis at the diagnosis of IDDM is IDDM. Comparisons of the frequency of remarkable. Because of the high incidence of diabetic ketoacidosis between different popula- IDDM in Finland, its symptoms and signs are tions should be based on blood pH measure- fairly well known, and the diagnosis is most ments. often made before ketoacidosis occurs. Reports on the residual f cell function at Socioeconomic factors had only a minor effect diagnosis of IDDM in children have been on the clinical condition of the diabetic somewhat conflicting. Ludvigsson and Heding children at the diagnosis of the disease. found detectable serum C peptide concentra- However, children from families with high tions in all 12 newly diagnosed diabetic parental education were less prone to ketoaci- children,9 while Sochett et al reported a median dosis, reflecting earlier suspicion and diagnosis serum C peptide concentration of 0.03 nmol/l 414 Komulainen, Lounamaa, Knip, Kaprio, Akerblom, et al

before insulin treatment, undetectable low lev- up) may have been too small to discern a pos- els (less than 0.025 nmol/l) in 29% of their sible correlation between initial pH and C pep- subjects, and concentrations below 0.10 nmol/l tide concentrations during the follow up. Arch Dis Child: first published as 10.1136/adc.75.5.410 on 1 November 1996. Downloaded from in 85% of the children.20 In the present study, Partial remission was less common in the 98% of the subjects had measurable endog- ketoacidosis group than in the non- enous insulin secretion at diagnosis, identified ketoacidosis group. The remission is consid- by serum C peptide concentrations of 0.03 ered to be a result of the functional recovery of nmol/l or more. The median serum C peptide existing [ cells and increasing peripheral insu- concentration was 0.15 nmol/l, which is in lin sensitivity after the initiation of insulin good accordance with an earlier report from treatment. Accordingly, clinical remission re- Finland."2 Four fifths (79.8%) of the children flects a better preserved [ cell mass, which pro- in the present study had serum C peptide con- tects the child from developing diabetic centrations of 0.10 nmol/l or more. These dif- ketoacidosis at diagnosis. ferences between different populations seem to In spite of a larger dose ofexogenous insulin, be real, since Daneman et al reported the mean the ketoacidosis group had poorer metabolic (SD) serum C peptide levels to be 0.15 (0.12) control in the present study. This may be of nmol/I in northern Finland,4 and 0.05 (0.07) importance, since poor metabolic control is nmol/l in southern Ontario at clinical presenta- related to higher risk of future diabetic tion. They may be explained by possible differ- retinopathy and nephropathy, at least in adult ences in the speed of P cell destruction, reflect- patients,22 and possibly in paediatric patients as ing variations in the aetiology of IDDM. The well.2' 24 other possible explanation would be different In conclusion, ketoacidosis at the diagnosis timing in diagnosis. This is, however, unlikely ofIDDM is related to poorer subsequent [B cell to be the only explanation, since we observed a function and impaired metabolic control dur- mean (SD) serum C peptide of 0.12 (0.12) ing at least the first two years of clinical disease. nmol/l even in the probands with diabetic Both the metabolic decompensation assessed ketoacidosis. by the blood pH value at diagnosis and the ini- Young age was associated with lower serum tial serum C peptide concentrations predict the C peptide concentrations. In particular, chil- later [ cell recovery. Together these observa- dren younger than 2.0 years of age were low tions indicate that diabetic ketoacidosis at insulin secretors. This is in good agreement diagnosis reflects a more advanced [ cell with earlier observations,"20 and reflects a destruction leading to reduced [ cell recovery smaller absolute [B cell mass and a more and poorer metabolic control after the institu- aggressive P cell destruction in infants and tion of exogenous insulin treatment. Accord- young children. ingly, avoidance of initial diabetic ketoacidosis Earlier data on the possible relationship may facilitate good metabolic control over the between endogenous insulin secretion and first years of manifest IDDM. metabolic decompensation at diagnosis are

partly controversial. Kaar' and Couper et al 5 We are grateful to all participants and their families as well as to http://adc.bmj.com/ the hospitals and their staff. We thank Ms Liisa Toivanen, Mr reported an inverse relation between HbAlc at Janne Pitkiniemi, and Mr Esa Virtala for their skilful assistance diagnosis and both contemporaneous serum C in the collection and sorting of the data. This work was supported by the Orion Corporation Research Foundation, peptide levels and those observed 7-14 days Helsinki, Finland, the Kyllikki and Uolevi Lehikoinen Founda- later. On the other hand, Sochett et al found no tion, Helsinki, the Finnish Cultural Foundation, North-Savo Foundation, Kuopio, Finland, and the Aima and K A Snellman difference in mean C peptide concentration Foundation, Oulu, Finland. The Childhood Diabetes in between children with diabetic ketoacidosis Finland project has been supported by the Association of Finn- and those with normal acid-base status ish Life Insurance Companies, the Sigrid Juselius Foundation, (pH the National Institute of Health, USA (NIH grant DK-37957), on September 28, 2021 by guest. Protected copyright. B7.35).2o In the present study, we observed a the University of Helsinki, the Juvenile Diabetes Foundation, USA (grant 188517), the Nordisk Insulin Foundation and the milder metabolic deterioration in children who Novo-Nordisk A/S, Denmark. had a serum C peptide concentration of 0.10 nmol/l or more than in children with a lower The Childhood Diabetes in Finland (DiMe) Study Group is composed ofthe following members: Principal investigators: HK serum C peptide concentration. Our data indi- Akerblom, J Tuomilehto; Coordinators: R Lounamaa, L cate that even a relatively small amount of Toivanen; Data management: E Virtala, J Pitkaniemi. Local inves- tigators: A Fagerlund, M Flittner, B Gustafsson, C Haggquist, A endogenous insulin secretory capacity prevents Hakulinen, L Herva, P Hiltunen, T Huhtamiki, N-P Huttunen, the child from serious metabolic decompensa- T Huupponen, M Hyttinen, T Joki, R Jokisalo, M-L Kiar, S Kallio, E A Kaprio, U Kaski, M Knip, L Laine,J Lappalainen, J tion at the diagnosis of IDDM. Maenpia, A-L Makela, K Niemi, A Niiranen, A Nuuja, P Our data clearly show worse residual [3 cell Ojajirvi, T Otonkoski, K Pihlajamaki, S Pontynen, J Rajantie, J Sankala, J Schumacher, M Sillanpaa, M-R Stihlberg, CH function in children with diabetic ketoacidosis Strfihlmann, T Uotila, M Vare, P Varimo, G Wetterstrand. Spe- at the diagnosis of the disease. The serum C cial investigators: A Aro (National Public Health Institute, Helsinki), M Hiltunen (Institute of Biomedical Sciences, peptide concentrations were lower and insulin University of Tampere), H Hurme (Abo Akademi, Pedagogic doses higher in the ketoacidosis group. Inter- Faculty in Vaasa), H Hy6ty (Institute of Biomedical Sciences, University ofTampere), J Ilonen (Department ofVirology, Uni- estingly, most of the observed differences versity of Turku), J Karijalainen (Department of Paediatrics, between the ketoacidosis and the non- University of Oulu), M Knip (Department of Paediatrics, Uni- versity of Oulu), P Leinikki (National Public Health Institute, ketoacidosis groups were preserved for the Helsinki), A Miettinen (Department of Bacteriology and whole two year observation period. This is in Immunology, University ofHelsinki), T Petiiys (Department of Bacteriology and Immunology, University of Helsinki), L contrast with the findings of Sochett et al,20 Rasianen (Department of Nutrition, University of Helsinki), H who reported no relation between initial pH Reijonen (Department of Virology, University of Turku), A Reunanen (Social Insurance Institute, Helsinki), T Saukkonen and basal or stimulated serum C peptide con- (Children's Hospital, University of Helsinki), E Savilahti (Chil- centrations at diagnosis or during the first year dren's Hospital, University of Helsinki), E Tuomilehto-Wolf (National Public Health Institute, Helsinki), P Vahasalo of clinical disease. However, the number of (Department of Paediatrics, University of Oulu), S M Virtanen probands in the Sochett's study (33 for follow (Departmnent ofNutrition, University of Helsinki). Ketoacidosis affects residualf cellffunction 415

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