769 

Metabolic, immunological and clinical characterization of Type 1 diabetes diagnosed after the age of forty. 

M. Hernández, M. Rigla, A. Ortiz, J. M. Pou, A. de Leiva;
Endocrinology, Hospital de Sant Pau, Barcelona, Spain. 

Background and Aim: Most type 1 diabetic patients are diagnosed in the first decades of life. However, it is not unusual for the diagnosis to be made after age 40 (DM1Dx>40). The aim of our study is to review the clinical, biochemical and immunological features of DM1Dx>40 patients.
Materials and Methods: Medical records of DM1Dx>40 patients seen in our Department in the last 5 years were reviewed. Inclusion criteria were based on clinical manifestations at diagnosis (polyuria, polydipsia, weight loos, and ketosis), c-peptide levels (negativization in the first 2 years after diagnosis) and islet cell antibodies: ICA (indirect immunofluorecence assay); anti-GAD and IA2-protein (liquid-phase radiobinding assays). Immune markers of related autoimmune diseases were also determined. DM1Dx>40 patients were compared with a matched group of 34 DM1 patients with identical disease duration but diagnosed at younger age.
Results: 59 patients (67% women, 38.3% in control group, p<0.05), age at diagnosis 55.3 ± 10 years (23.0 ± 8 in controls), median diabetes duration 5.1 (0-29) years, BMI 24 ± 4.7 Kg/m2 (24.1 ±3 in controls, p=ns)) were studied. Ninety three percent of the patients showed polyuria, polydipsia and weight loss, and 62% ketosis or ketosis/acidosis at diagnosis. Despite intensive insulin treatment in most cases (80%), mean HbA1c in the last 5 years was 8.7% ± 1.3 (7.7% ± 1.3 in controls, p<0.05). A significantly higher proportion (34.5% vs 3.1% p<0.01) of DM1Dx>40 patients were receiving treatment for other autoimmune diseases (hypothyroidism: 16.4%, Grave´s disease: 7.1%, pernicious anaemia: 10.9%, vitiligo: 5.4% and positive thyroid antibodies: 36.2%). Information regarding all three islet antibodies (Ab) was available in 35 patients (mean time from diagnosis 23.7 months (0-257)), 80% of them being positive for at least 1 Ab (25.7%, 28.6% and 22.9% were positive for 3, 2 and 1 Ab respectively. In the subset of patients (N=19) with islet Ab determined at diagnosis the prevalence of positivity was similar to that found in their matched controls (80% vs 92% p=ns).
Conclusions: The investigated population of DM1Dx>40 patients shows predominance of females, increased prevalence of autoimmune diseases and similar profile of islet cell Ab at diagnosis than the reference group of DM1. Finally, glucose control was difficult under intensive insulin regimens.

770 

Islet mozaicism in a new form of persistent hyperinsulinaemic hypoglycaemia of infancy: correlation of morphology with clinical and physiological data. 

J. Rahier¹, Y. Guiot¹, K. Cosgrove², M. Nenquin¹, P. de Lonlay³, M. J. Dunne², J. Henquin¹, C. Sempoux¹;
¹University of Louvain, Brussels, Belgium, ²Sheffield University, Sheffield, United Kingdom, ³Hopital Necker-Enfants malades, Paris, France. 

Background and Aims: Most morphological studies of the pancreas of patients affected by persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) have focused on the differential diagnosis between focal and diffuse lesions since it has a major impact on the surgical management of the patient. However, certain cases are difficult to classify because of "atypical features". We aimed to understand the histopathophysiology of "atypical disease" and to evaluate its implications for treatment.
Materials and Methods: In a series of 200 PHHI cases reviewed at the microscope, 11 were considered "atypical" and studied by conventional microscopy, immunohistochemistry, patch-clamp electrophysiology (n=4) and radioimmunoassay for insulin secretion in vitro (n=3).
Results: Two types of islets were consistently identified in the pancreas: small islets with apparently "resting" B-cells exhibiting little cytoplasm and small nucleus, besides B-cells rich in cytoplasm with occasional enlarged nuclei. In "resting" islets, insulin was abundant and only limited amounts of proinsulin were found in the Golgi area. By contrast, in large islets, insulin storage was low and proinsulin production was high. These apparently hyperactive islets were either scattered throughout the pancreas or confined to a few lobules. Tissue obtained at surgery permitted comparison of B-cell KATP channels and insulin release in morphologically defined abnormal and healthy zones of the pancreas. No defects in the regulation of KATP channels by ATP, ADP and diazoxide were found, and insulin release was stimulated by glucose, tolbutamide or leucine + glutamine, and inhibited by diazoxide or calcium omission. Clinically, the patients had a normal birth weight; their hypoglycaemic episodes were of late onset (3-9 months) and treatable by diazoxide. No hyperinsulinism-hyperammonaemia syndrome was identified. In most cases preoperative catheterization was suggestive of a focal lesion. In 9/11 cases, PHHI was cured by a corporeo-caudal pancreatectomy, in the other 2 cases a caudal pancreatectomy was insufficient
Conclusion: We describe a new form of PHHI, characterized by a peculiar morphological mosaicism of the islets without detectable defects in stimulus-secretion coupling in B-cells, in particular without anomaly of KATP channels. This "atypical" form of PHHI is histologically and functionally distinct from those previously reported and is generally cured by partial pancreatic resection. The genetic background is still under investigation.

771 

Comparison of rapidly and slowly progressive forms of autoimmune Type 1 diabetes mellitus in adults: similarities and differences. 

N. Hosszúfalusi¹, Á. Vatay¹, K. Rajczy², É. Pozsonyi², L. Horváth¹, A. Grosz³, L. Romics¹, I. Karádi¹, G. Füst¹, P. Pánczél¹;
¹3rd Dept. Int. Med., Semmelweis Univ., Budapest, ²Natl. Inst. Hematol. Immunol., Budapest, ³Polyclinic Hosp. Broth. Saint John's of God, Budapest, Hungary. 

Background and Aims:The autoimmune type 1 diabetes mellitus is divided into a rapidly and a slowly progressive form. The latter subgroup is mainly manifested in the adulthood and called as the latent autoimmune diabetes in adults (LADA). Our aims were to compare the clinical parameters, the pattern of islet-cell specific autoantibodies and the prevalence of predisposing genotypes in LADA to adult-onset type 1 diabetes with rapid progression. The clinical feature and the presence of islet-cell autoantibodies of LADA were further compared with type 2 diabetes.
Materials and Methods:The clinical parameters (BMI, WHR, serum lipid levels and presence of hypertension) and the islet-cell specific autoantibodies (ICA, GADA and IA-2A) were measured in 38 patients with LADA, 48 subjects with adult-onset (age at onset >25 years) type 1 diabetes, and 190 with type 2 diabetes. The genetic study was performed in patients with LADA and type 1 diabetes with onset >30 years of age. Logistic regression analyses were used to evaluate potential confounding by covariables.
Results:There were no differences in the clinical parameters between LADA and adult-onset type 1 diabetes. Patients with LADA had lower BMI (p<0.0001), WHR (p=0.003), total cholesterol (p=0.005), triglyceride (p=0.002), higher HDL-cholesterol levels (p=0.047) and lower prevalence of hypertension (p=0.025) compared to patients with type 2 diabetes. Single autoantibody positivity was seen more often in LADA than in type 1 diabetes (52.6% vs 22.9% respectively; p=0.0082, Fisher’s exact test). Prevalence of predisposing genotypes were increased both in LADA and adult-onset type 1 diabetes compared to the control population: HLA-DQB1*0302 (37% and 43% vs 15%; p<0.0001, p<0.0001), DR4 (43% and 55% vs 18%; p<0.001, p<0.0001) and DR3/DR4 (11% and 12% vs 3%; p<0.05, p<0.01; respectively). The presence of high-risk DR4-DQB1*0302 haplotype was more common in LADA (40%) and in adult-onset type 1 diabetes (52%) than in the controls (14%; p<0.01, p<0.0001; respectively). There were no differences in the frequencies of these alleles and haplotype between the two patient groups.
Conclusions:1) LADA has similar clinical characteristics as adult-onset type 1 diabetes. 2) Patients with LADA rather have single islet-cell specific autoantibody positivity compared to adult-onset type 1 diabetes. 3) The prevalence of HLA-DQB1*0302, DR4, DR3/DR4 risk alleles and DR4-DQB1*0302 high-risk haplotype did not differ in the two forms of autoimmune diabetes.

772 

Point of care blood ketone testing of diabetic patients in the emergency department. 

O. Eray¹, F. Bektas¹, S. Akbas²;
¹Emergency Department, Akdeniz University School of Medicine, Antalya, ²Biochemistry Department, Akdeniz University School of Medicine, Antalya, Turkey. 

Background and Aims: Reliable and rapid measurement of blood or urine ketones is an important tool in determining the diagnosis and emergency treatment of diabetic patients, who may have diabetic ketosis or diabetic ketoacidosis. The reliability and performance of a bedside capillary blood ketone test in emergency department patients was compared with reference testing in our university medical center laboratory.
Materials and Methods: Known diabetic patients presenting to our tertiary care university ED between April and October of 2001 with any medical complaint and a high fingerstick glucose (>200mg/dl) were included, after obtaining informed consent to participate. All subjects were then tested for blood b-hydroxybutyrate with a bedside capillary blood test (MediSense^™ Optium^™), and any positive test was confirmed by reference testing in the central laboratory. b-hydroxybutyrate dehydrogenase catalyzes the oxidation of b-hydroxybutyrate to acetoacetate. During this oxidation, an equimolar amount of nicotinamide adenine dinucleotide (NAD) is reduced to NADH. NADH absorbs light at 340 nm and, therefore, the increase in absorbance at 340 nm is directly proportional to the b-hydroxybutyrate concentration in the sample. Blood b-hydroxybutyrate level was measured by BM 4010 spectrophotometer based on the described method above (Sigma Diagnostic^®). Diabetic patients presenting with only minor or major trauma were not enrolled.
Results: Of 479 diabetic patients included in the study, 139 had a positive capillary blood b-hydroxybutyrate level (> 0.1 mmol/L). Upon reference testing in these patients, hyperkenotemia (>0.42 mmol/L) was found in 48 patients (ketosis in 35%). The calculated blood pH was less than 7.3 in 18 of these 48 patients (ketoacidosis in 38%). Paired capillary and venous b-hydroxybutyrate levels were not statistically different from each other (t testing, p=0.704, correlation coefficient r=0,716). The sensitivity and specificity of blood ketone testing, urine testing, anion gap and serum bicarbonate levels in determining hyperketonemia were 91% and 56%, 82% and 54%, 63% and 43%, 93% and 22% respectively.
Conclusion: A rapid bedside capillary test for b-hydroxybutyrate can accurately measure blood concentrations of b-hydroxybutyrate in diabetic patients in an emergency department setting. This device can be used as a reliable diagnostic test to detect emergency metabolic problems in diabetic patients, such as DK or DKA. Further studies should be designed to determine the cost-effectiveness and clinical usefulness of such a device in decision making in emergency department diabetic patients

773 

A mortality prediction model in diabetic ketoacidosis. 

T. N. Panagiotou, S. P. Efstathiou, A. G. Tsiakou, D. I. Tsioulos, I. D. Zacharos, A. G. Mitromaras, S. E. Mastorantonakis, T. D. Mountokalakis;
Third Department of Medicine, Sotiria General Hospital, Athens, Greece. 

Background and Aims: To assess the value of clinical and laboratory parameters in predicting mortality in patients presenting with diabetic ketoacidosis (DKA).
Materials and Methods: The records of all DKA admissions within 10 years were reviewed. Eighteen variables were evaluated at initial presentation and twenty at 12 and 24 hours from admission. A scoring system derived from these variables was compared to the APACHE III scoring system.
Results: Among 154 patients (52 males, mean age 58 ±12 years), 20 (13%) died in hospital. Multivariate analysis yielded 6 variables as significant independent predictors of mortality: severe coexistent diseases (SCD) (p < 0.001, OR 16.3, 95% CI 4.2, 69.7) and pH < 7.0 (p < 0.001, OR 8.7, 95% CI 2.7, 56.8), at presentation; units of regular insulin required in the first 12 hours > 50 (p < 0.001, OR 7.9, 95% 2.1, 55.2) and serum glucose > 300 mg/dl (p < 0.001, OR 8.3, 95% CI 2.4, 40.2), after 12 hours; depressed mental state (p < 0.001, OR 8.6, 95% CI 3.3, 59.7) and fever > 38°C (p < 0.004, OR 5.8, 95% CI 2.1, 38.2), after 24 hours. An integer-based scoring system was derived, as follows: Number of points = 6 (SCD at presentation) + 4 (pH < 7.0 at presentation) + 4 (regular insulin required > 50 IU after 12 hours) + 4 (serum glucose > 300 mg/dl after 12 hours) + 4 (depressed mental state after 24 hours) + 3 (fever after 24 hours). Patients with 0-14 points had 0.86% risk of death, whereas for those with 19-25 points the risk was 93.3%. Median APACHE III scores differed significantly (p < 0.001) among groups of patients stratified according to the above scoring system.
Conclusion: Risk stratification of patients with DKA is possible from simple clinical and laboratory variables available during the first day of hospitalization.

774 

Identification and classification of symptoms of hyperglycaemia in people with insulin-treated diabetes mellitus. 

R. E. Warren¹, I. J. Deary², B. M. Frier¹;
¹Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, ²Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom. 

Background and Aims: Many people with insulin-treated diabetes report symptoms which they recognise to be associated with hyperglycaemia, but these have seldom been studied in the diabetic population. The self-reported symptoms of hyperglycaemia were examined to determine whether these co-segregate in a similar manner to the symptoms of hypoglycaemia. The intensity of hyperglycaemic symptoms was examined in relation to other factors, including quality of glycaemic control, duration of insulin therapy and symptomatic awareness of hypoglycaemia.
Materials and Methods: In a pilot study, 70 people with insulin-treated diabetes reported, in an open-ended fashion, symptoms which were associated with hyperglycaemia. Eighteen symptoms were reported by more than one person, and these were used to construct a questionnaire. 400 consecutive people with insulin-treated diabetes were interviewed using this questionnaire during their routine outpatient attendance. Subjects reported whether they associated each of the 18 symptoms with hyperglycaemia, and the subjective intensity of each symptom. Demographic details, duration of diabetes, other drugs and HbA1c measurements were recorded, and subjects rated their awareness of hypoglycaemia on a validated scale. The statistical technique of principal components analysis (PCA) was used to examine the structure of associations among the symptoms of hyperglycaemia.
Results: 90% of subjects reported experiencing symptoms of hyperglycaemia. The commonest were dry mouth, thirst, not feeling right, needing to urinate and drowsiness. PCA suggested two correlated components (using the scree slope criterion): behavioural (irritable, restless, tense, poor concentration) and osmotic (thirst, not feeling right, needing to urinate, unusual taste in the mouth). With regression analysis, mean symptom intensity was positively associated with younger age and higher HbA1c. The mean (+/- SD) blood glucose threshold for the onset of symptoms was 15.2 (+/-3.9) mmol/l, and the threshold was elevated with higher HbA1c, older age, male sex and impaired awareness of hypoglycaemia (p<0.01 for all analyses). The symptoms associated with the behavioural and osmotic components were not differentially affected by other variables.
Conclusions: People with insulin-treated diabetes commonly report symptoms associated with hyperglycaemia. Principal components analysis can separate these into two groups characterized by osmotic and behavioural symptoms. Symptoms are more intense in younger people and those with a high prevailing blood glucose. Symptoms are reported at lower levels of blood glucose in those with strict glycaemic control, younger age, female sex and normal awareness of hypoglycaemia.

775 

Prevalence of auto immune diseases in type 1 diabetic patients treated either with intraperitoneal insulin infusion with implantable pumps or subcutaneous insulin infusion with external pumps. 

N. M. Jeandidier¹, V. Lassmann-Vague², L. Dufaitre-Patouraux², S. Boivin¹, EVADIAC Study Group;
¹Endocrinology and Diabetology, University Hospital, Strasbourg, ²University Hospital, Marseille, France. 

Background and Aims: Increased frequency of auto immune diseases in type 1 diabetic patients, treated by intraperitoneal insulin (IP) infusion using implantable devices has been suggested in a previous small population study though not confirmed in a second study. The aim of this study was to assess the prevalence of clinical and/or biological auto immunity markers in a large population of type 1 diabetic patients recruited in 15 EVADIAC centers.
Materials and Methods: Prevalence of auto-immunity was assessed in a cross-sectional study. Two groups of type 1 diabetic patients (Group 1 treated with an implantable pump and IP insulin infusion, Group 2 treated with an external pump and subcutaneous insulin infusion (CSII)) were matched for age, gender and duration of disease: 154 (75 men) vs 121 patients (58 men) with a mean +/- SD age of 47 +/- 10.2 vs 46.3 +/- 11.2 years and diabetes duration of 24.8 +/-10.2 vs 23.6 +/- 9.1 years respectively. The duration of insulin infusion was of 6.1 +/- 3.4 vs 6.1 +/- 4.6 years respectively. All patients characteristics were comparable in the 2 groups. Existing clinical organ specific auto immune diseases were recorded. In patients free of clinical diseases, TSH, anti TPO, anti Intrinsic Factor (IF), and Anti Insulin Antibody (AIA) levels were measured.
Results:Total clinical auto immune disease prevalence, 13.0 vs 14.9 %, as well as the prevalence of Hashimoto thyroiditis, 8.4 vs 7.4 %, hyperthyroidism, 1.3 vs 2.4 %, pernicious anemia, 1.9 vs 0.8 %, and vitiligo, 1.3 vs 4.1 % were comparable in Group 1 and 2 respectively. No Addison disease was reported in our population.
The percentage of patients found to have TSH > 4 or < 0.4 mU/l, 8 vs 12%, positive anti TPO antibody, 25.9 vs 30.6%, or positive anti FI levels 3.9 vs 4.1 %, was comparable in groups 1 and 2 respectively. As previously reported, AIA levels were significantly higher in group 2 after 6 years of IP infusion (Student test with inequality of variance, p< 0.001). Interestingly, the percentage of patients suffering from clinical or biological auto immune diseases was not correlated with the mean AIA levels.
Conclusion: The prevalence of clinical or subclinical auto immune diseases studied is comparable in type 1 diabetic patients treated either with subcutaneous or intraperitoneal insulin infusion suggesting no activation of autoimmunity by IP route of insulin infusion.