Diagnosis of a patient with oncogenic osteomalacia using a phosphate uptake bioassay of serum and magnetic resonance imaging.

A previously healthy man with no family history of fractures presented with muscle pain, back pain and height loss. Investigations revealed hypophosphataemia, phosphaturia, undetectable serum 1,25-dihydroxyvitamin D and severe osteomalacia on bone biopsy, suggestive of a diagnosis of oncogenic osteomalacia. Thorough physical examination did not locate a tumour. Support for the diagnosis was obtained by detection of phosphate uptake inhibitory activity in a blinded sample of the patient's serum using a renal cell bioassay. On the basis of detection of this bioactivity, a total body magnetic resonance (MR) examination was performed. A small tumour was located in the right leg. Removal of the tumour resulted in the rapid reversal of symptoms and the abnormal biochemistry typical of oncogenic osteomalacia. Inhibitory activity was also demonstrated using the bioassay in serum from two other patients with confirmed or presumptive oncogenic osteomalacia, but not in serum from two patients with hypophosphataemia of other origin. This is the first case to be reported in which the diagnosis of oncogenic osteomalacia was assisted by demonstration of inhibitory activity of the patient's serum in a renal cell phosphate bioassay that provided an impetus for total body MR imaging.

Power and self-perceived health in blind diabetic and nondiabetic individuals.

AIMS: The aims of this study were: (1) to explore perceptions of power in blind individuals and relate presence or absence of power to self-perceived health and (2) to compare self-perceived health in blind individuals with that of the general population. BACKGROUND: The theoretical framework of this study was Barrett's Power theory, which is based on The Rogerian nursing theory. Power is defined as being aware of what one is choosing to do, feeling free to doing it, and do it intentionally. METHODS: Thirty-nine blind subjects at three adjacent ophthalmology centres agreed to participate in the study. Of those 23 had become blind because of late complications of diabetes. Power was explored during semi-structured interviews and self-perceived health was measured with the Swedish health-related quality of life questionnaire. Data on socio-economic, rehabilitative and diabetes-related variables were also collected. FINDINGS: Power was experienced by 19 of the 39 respondents and was more frequently found in nondiabetic subjects than in diabetic subjects. Those experiencing power reported a better emotional and general health compared with individuals lacking power. The perception of having power was not significantly related to any other of the studied variables. When compared with age- and gender-matched controls from the general population, nondiabetic blind subjects scored higher in positive feelings and lower in physical functioning. In contrast diabetic subjects experienced poorer general health, less satisfaction with physical health and more negative feelings, but they reported that they did not experience limitation as a result of these emotions. CONCLUSION: One way of improving health in diabetic blind individuals could be to increase the subject's perception of power.

Family characteristics and life events before the onset of autoimmune type 1 diabetes in young adults: a nationwide study.

OBJECTIVE: To elucidate whether family characteristics and stressful life events were associated with onset of autoimmune type 1 diabetes in young adults. RESEARCH DESIGN AND METHODS: This investigation was based on a nationwide study (Diabetes Incidence Study in Sweden) of newly diagnosed patients aged 15-34 years. Patients clinically classified as type 1 diabetic with antibodies to islet cells and/or to GAD65 were compared with age- and sex-matched control subjects via questionnaire. The questionnaire covered diabetes heredity, social environment, educational level, and life events experienced during the 12 months before diagnosis. RESULTS: The rate of response was 82% for the diabetic patients and 65% for the control subjects. Questionnaires from 349 diabetic patients and 979 control subjects were considered. Diabetes in relatives was more frequent in the patients (odds ratio [OR]2.6) who were born in Sweden and whose mothers were of Swedish origin. No major stress factors were detected in the diabetic patients; however, in comparison with the control subjects, the diabetic patients had experienced fewer conflicts with their parents and had less often broken contacts with friends. CONCLUSIONS: Young adults with recent-onset type 1 diabetes were more exposed to heredity for diabetes, but no major prediabetic stress factors were detected. Our study does not directly support the concept that psychosocial stressful life events are involved in the development of autoimmune type 1 diabetes in young adults.

Increased mortality in diabetes during the first 10 years of the disease. A population-based study (DISS) in Swedish adults 15-34 years old at diagnosis.

OBJECTIVES: To study, prospectively, in young adult patients, the mortality during the first years after the diagnosis of diabetes. DESIGN: The Diabetes Incidence Study in Sweden (DISS) aims to register all incident cases aged 15-34 years. During a 10-year period all deaths were identified by record linkage to the national Cause of Death Registry. SUBJECTS: During the period, 4097 new cases were registered and classified as type 1 diabetes (73%), type 2 (16%), secondary (2%) and unclassified (9%). The median follow-up was 5 years (21 001 person-years). MAIN OUTCOME MEASURES: Calculation of the standardized mortality ratio (SMR) and 95% confidence interval (CI). Evaluation of all deceased by scrutiny of clinical records, death certificates and autopsy protocols. RESULTS: Fifty-eight patients died, corresponding to an SMR of 3.5 (CI=2.7-4.5), which increased from 1.5 at 15-19 years to 4.1 at 30-34 years. SMR was 2.7 in primary diabetes: 2.3 (1.6-3.3) in type 1 and 4.1 (2.6-6.7) in type 2. In secondary diabetes, alcohol-associated pancreatitis a common cause, SMR was 32 (CI=24-45). Evidence of alcohol or drug misuse, mental dysfunction or suicide was found in 40 of all 58 deceased cases. Less often, hypoglycaemia (n=7) or hyperglycaemia-ketoacidosis (n=11) was present at death. Unexplained 'dead in bed' was found once. CONCLUSIONS: In the investigated population-based cohort the early mortality was about threefold increased. Hypoglycaemia and ketoacidosis per se played a relatively small role compared with a heavy impact from social and mental dysfunction, and from careless use of alcohol or drugs.

Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations.

AIMS/HYPOTHESIS: The aim of this study was to examine the putative role of mutations in the insulin promoter 1 (IPF1) gene in early-onset diabetes. METHODS: We carried out mutation screening of the IPF1 gene in 115 Scandinavian families with at least two members with onset of diabetes younger than 40 years. The allele frequencies were also tested in 183 unrelated patients with late-onset Type II (non-insulin-dependent) diabetes mellitus and in 92 non-diabetic control subjects. RESULTS: Two novel IPF1 variants (G212R and P239Q) and one previously reported (D76N) IPF1 variant were identified in the 115 families (3.5%). The D76N variant was found in one MODY3 family (S315fsinsA of HNF1alpha) and also in two families with late-onset Type II diabetes. The P239Q variant was identified in two families with early-onset diabetes including one with MODY3 (R272C of HNF1alpha) and in three families with late-onset Type II diabetes. Despite the fact that the variants did not segregate completely with diabetes, the non-diabetic carriers of the IPF1 variants had increased blood glucose concentrations (p < 0.05) and reduced insulin:glucose ratios (p < 0.05) during an oral glucose tolerance test compared with non-diabetic family members without these variants. In addition, when the G212R and P239Q variants were expressed in cells without IPF1 i.e.. Nes2y cells, both variants showed about a 50% reduction in their ability to activate insulin gene transcription compared to wild-type IPF1, as measured by reporter gene assay. CONCLUSION/INTERPRETATION: Although mutations in the IPF-1 gene are rare in early- (3.5 %) and late-onset (2.7 % ) Type II diabetes, they are functionally important and occur also in families with other MODY mutations.

The effect of smoking on glucose homeostasis and fetal growth in pregnant women.

OBJECTIVE: To examine the relationship between maternal blood glucose levels, cigarette smoking in pregnancy and fetal growth. DESIGN: A prospective study of healthy parous women from early pregnancy and their infants. SETTING: Three Scandinavian university hospitals covering all deliveries from well defined geographical areas. SUBJECTS: Study groups of non-smoking (150), light smoking (131) and heavily smoking mothers (218), para 1 and 2 and with > 37 weeks of gestational length. MAIN OUTCOME MEASURES: Oral glucose tolerance test performed in pregnancy week 37, glycated hemoglobin measured the 3rd day post partum and neonatal anthropometric parameters including skinfold measurements. RESULTS: Among heavily smoking mothers 12.4% displayed a 2-hour glucose value in the range of gestational diabetes (> 8.5 mmol/l) compared to 9.2% among light smokers and 6.0% among nonsmokers (p < 0.05). Heavily smoking mothers also had significantly (p < 0.05) higher glycated hemoglobin compared to nonsmokers, 5.01 v.s. 4.86. These changes in glucose parameters in smokers were not associated with higher birthweights. CONCLUSIONS: Smoking in pregnancy affects parameters of glucose homeostasis in the direction of gestational diabetes. The retarding effect of smoking on fetal growth abolished any expected growth stimulation from the higher blood glucose levels seen in the smokers.

Ketoacidosis in young adults is not related to the islet antibodies at the diagnosis of Type 1 diabetes mellitus--a nationwide study.

AIMS: To test the hypothesis that there is lower prevalence of islet antibodies in subjects with newly diagnosed Type 1 diabetes mellitus in young adulthood than in children is associated with less severe diabetes at time of diagnosis. METHODS: This investigation was based on a nationwide study (Diabetes Incidence Study in Sweden) of 15-34-year-old newly diagnosed diabetic subjects. During 1992-1993, all diabetic subjects (excluding secondary and gestational diabetes) were reported on standardized forms, with information about clinical characteristics at diagnosis. The study examined islet cell antibodies (ICA) by indirect immunofluorescence, and autoantibodies to glutamic acid decarboxylase (GADA), tyrosine phosphatase-like antigen (IA-2A) and insulin (IAA) as well as C-peptide by radioimmunoassay. RESULTS: Blood samples were available from 78 patients with diabetic ketoacidosis (DKA) and 517 non-acidotic patients. The prevalence of ICA (63% vs. 57%), GADA (63% vs. 66%), IA-2A (35% vs. 44%) and IAA (20% vs. 15%) were very similar in patients with or without DKA. The median levels of the four autoantibodies did not differ between the two groups. High blood glucose (P < 0.001) and low C-peptide levels (P < 0.001) were the only parameters found to be related to DKA. CONCLUSIONS: The similarities in findings of newly diagnosed diabetic patients with or without DKA regarding ICA, GADA, IA-2A and IAA suggest that there is no relationship between the expression of antigenicity and the severity of beta-cell dysfunction. The lower prevalence of the four autoantibodies in 15-34-year-old diabetic subjects compared with previous findings in children is not explained by misclassification of diabetes type.

Prognostic factors for the course of beta cell function in autoimmune diabetes.

This study presents a 2-yr follow-up of 281 patients, aged 15-34 yr, diagnosed with diabetes between 1992 and 1993. At diagnosis, 224 (80%) patients were positive for at least one of the following autoantibodies: islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADAs), or tyrosine phosphatase antibodies (IA-2As); the remaining 57 (20%) patients were negative for all three autoantibodies. At diagnosis, C-peptide levels were lower (0. 27; 0.16-0.40 nmol/L) in autoantibody-positive patients compared with autoantibody-negative patients (0.51; 0.28-0.78 nmol/L; P: < 0. 001). After 2 yr, C-peptide levels had decreased significantly in patients with autoimmune diabetes (0.20; 0.10-0.37 nmol/L; P: = 0. 0018), but not in autoantibody-negative patients. In patients with autoimmune diabetes, a low initial level of C-peptide (odds ratio, 2. 6; 95% confidence interval, 1.7-4.0) and a high level of GADAs (odds ratio, 2.5; 95% confidence interval, 1.1-5.7) were risk factors for a C-peptide level below the reference level of 0.25 nmol/L 2 yr after diagnosis. Body mass index had a significant effect in the multivariate analysis only when initial C-peptide was not considered. Factors such as age, gender, levels of ICA or IA-2A or insulin autoantibodies (analyzed in a subset of 180 patients) had no effect on the decrease in beta-cell function. It is concluded that the absence of pancreatic islet autoantibodies at diagnosis were highly predictive for a maintained beta-cell function during the 2 yr after diagnosis, whereas high levels of GADA indicated a course of decreased beta-cell function with low levels of C-peptide. In autoimmune diabetes, an initial low level of C-peptide was a strong risk factor for a decrease in beta-cell function and conversely high C-peptide levels were protective. Other factors such as age, gender, body mass index, levels of ICA, IA-2A or IAA had no prognostic importance.

High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes.

AIMS/HYPOTHESIS: To investigate the contribution of mutations in maturity-onset diabetes of the young (MODY) and mitochondrial genes to early-onset diabetes with a strong family history of diabetes in a cohort with a high prevalence of Type I (insulin-dependent) diabetes mellitus. METHODS: Screening for sequence variants in the hepatocyte nuclear factor (HNF)-4alpha (MODY1), glucokinase (MODY2), HNF-1alpha (MODY3) genes and mitochondrial DNA was carried out in 115 Finnish and Swedish patients with early-onset (

Negative association between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is attenuated with age at onset. Swedish Childhood Diabetes Study Group.

HLA-associated relative risks of type 1 (insulin-dependent) diabetes mellitus were analysed in population-based Swedish patients and controls aged 0-34 years. The age dependence of HLA-associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB1*0201-A1*0502/B1*0302-A1*0301 (DQ2/8) genotype (P = 0.02) and the negatively associated DQB1*0602-A1*0102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype other than 2, 8 or 6.2, were not significantly age-dependent. An exploratory analysis of DQ haplotypes other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB1*0604-A1*0102 (DQ6.4) and that the peak risk for the negatively associated DQB1*0301-A1*0501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB1*0303-A1*0301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA-DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2-positive individuals.

Appearance of islet cell autoantibodies after clinical diagnosis of diabetes mellitus.

Islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies (GAD65Ab) are often present at diagnosis of insulin dependent diabetes mellitus (type I diabetes) and are supposed to decline in level and frequency during the first years of disease. We have analysed ICA and GAD65Ab at onset and after one year in 395 population based randomly selected 15-34 year old patients newly diagnosed with diabetes mellitus, to study how these autoantibodies persist, disappear and appear and their relation to C-peptide levels. Of the 395 samples 212 (54%) were positive for ICA, 250 (63%) were positive for GAD65Ab and 170 (43%) were positive for both. At follow up after one year, 27/183 (15%) of the ICA negative patients and 25/145 (17%) of the GAD65Ab negative patients had converted to positivity. Among the 103 patients negative for both ICA and GAD65Ab, 16 turned positive for one or both antibodies after one year. Patients converting to positivity for one or the other antibody after one year, had lower C-peptide levels after one year than patients who initially were and remained negative, supporting the hypothesis that these patients have a genuine type I diabetes. In conclusion, newly diagnosed patients may be negative for autoantibodies at diagnosis but develop these antibodies later on during the disease.

Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment. A cohort study in young adults whose disease was initially labeled as type 2 or unclassifiable diabetes.

OBJECTIVE: To clarify the predictive value of islet cell antibody (ICA) and GAD65 antibody (GADA) present at diagnosis with respect to the need for insulin treatment 6 years after diagnosis in young adults initially considered to have type 2 or unclassifiable diabetes. RESEARCH DESIGN AND METHODS: The patient material was representative of the entire Swedish population, consisting of patients who were 15-34 years old at diagnosis of diabetes in 1987-1988 but were not considered to have type 1 diabetes at onset. At follow-up, 6 years after the diagnosis, it was noted whether the patient was treated with insulin. The presence of ICA was determined by an immunofluorescence assay, and GADAs were measured by a radioligand assay. RESULTS: Six years after diagnosis, 70 of 97 patients were treated with insulin, and 27 of 97 patients were treated with oral drugs or diet alone. At diagnosis, ICAs and GADAs were present in 41 (59%) of 70 patients and 41 (60%) of 68 patients, respectively, of those now treated with insulin, compared with only 1 (4%) of 26 patients and 2 (7%) of 27 patients who were still not treated with insulin. For either ICA or GADA, the corresponding frequencies were 50 (74%) of 68 for patients who were later treated with insulin and 3 (12%) of 26 for those who were still not treated with insulin, respectively. The sensitivity for later insulin treatment was highest (74%) for the presence of ICA or GADA, and the specificity was highest (100%) for ICA and GADA. The positive predictive value was 100% for the combination of ICA and GADA, 98% for ICA alone, and approximately 95% for GADA alone. CONCLUSIONS: Determination of the presence of ICA and GADA at diagnosis of diabetes improves the classification of diabetes and predicts the future need of insulin in young adults.

Diazoxide treatment at onset preserves residual insulin secretion in adults with autoimmune diabetes.

Twenty islet cell antibody (ICA)-positive patients, aged 19-38 years, with IDDM were randomized at onset to treatment with either diazoxide, a K+ channel opener that inhibits the release of insulin, or placebo for 3 months, in addition to multiple insulin injection therapy. The patients who were given diazoxide displayed higher residual insulin secretion than the placebo group after 1 year (basal C-peptide level, 0.40 +/- 0.04 vs. 0.25 +/- 0.04 [mean +/- SE] nmol/l; P < 0.021) and at an 18-month follow-up (0.37 +/- 0.06 vs. 0.20 +/- 0.01 nmol/l, P < 0.033). Metabolic control did not differ between the two groups. During the course of the study, no differences in islet cell or GAD autoantibodies were detected between the two groups. The results of this study warrant further trials to explore the potential of inducing target cell rest in order to halt the loss of insulin-producing cells during the early course of the disease.

Patient administrative system as a tool to validate the ascertainment in the diabetes incidence study in Sweden (DISS).

The aim of this study was to evaluate the degree of ascertainment in a nationwide prospective registration of incident cases of diabetes mellitus in the age group 15-34 years (The Diabetes Incidence Study in Sweden (DISS)). Incident cases of diabetes mellitus in DISS during a five year period were compared with inpatients, with the diagnosis of diabetes mellitus, registered in a routine computer-based administrative register. The Patient Administrative System-Inpatient Care (PAS-IC). To clarify this issue the two-sample capture-recapture phenomena was employed in the two southernmost counties in Sweden, Malmöhus and Kristianstad, covering 9.2% of the total of 2.3 million people aged 15-34 years in Sweden. The results showed that the ascertainment level in DISS was 0.86 for insulin dependent diabetes mellitus (IDDM). Hence, the DISS registry is a valid tool to monitor the incidence of IDDM in young (15-34 years) adult subjects.

Health-related quality of life in relation to metabolic control and late complications in patients with insulin dependent diabetes mellitus.

To investigate important factors with respect to health-related quality of life (HRQOL) in patients with longstanding insulin dependent diabetes mellitus, a patient cohort was followed prospectively for 10 years. The degree of metabolic control and the presence of late complications was assessed and HRQOL was measured with a 61-item questionnaire (SWEDQUAL) in which reference values have been obtained in a population sample. The results indicate that diabetic patients (n = 108) experienced a quality of life as good as a general population. When patients were divided into four groups based on metabolic control, those with poor control (HbA1c > or = 9%) rated their physical and emotional functioning significantly lower than those with lower HbA1c values. Nearly 15% of the patients reported 1-5 hypoglycaemic episodes during the latest 6 months. Despite a lower HbA1c they rated their general health as being poorer than patients without severe hypoglycaemia. Of the 108 patients 39% appeared to be free from late complications of diabetes. These patients rated their general health as better than patients who already had developed late complications. We conclude that a satisfactory metabolic control with a minimum of hypoglycaemic episodes is desirable not only to prevent late complications but also because poor metabolic control seems to be one reason why diabetic patients experience a poorer quality of life.

Difficulties in classifying diabetes at presentation in the young adult.

All newly diagnosed diabetic patients in Sweden aged 15-34 years have been registered since 1983. In this study the clinical characteristics initially and after 2.5-3 years were evaluated by a questionnaire to the patient's physician and by non-fasting C-peptide. The study comprised patients registered 1983-84, and for 281 patients (37%), complete information was obtained. At diagnosis 75% were classified as Type 1, 19% as Type 2, and 6% as secondary diabetes or as uncertain by their physician. Twenty patients (7.1%) were reported to have ketoacidosis. Seventy-five percent were treated with insulin, 7% with oral hypoglycaemic agents (OHG), and 18% with diet alone. At follow-up 71% were classified as Type 1, 21% as Type 2, and 8% as secondary or uncertain while treatment was 82% insulin, 8% OHG, and 9% diet. During the follow-up period 42% of the initially non-insulin-treated patients were put on insulin whereas only a few stopped insulin treatment. Patients treated with diet or OHG at follow-up were older, had higher percent desirable weight, and lower blood glucose at diagnosis than patients treated with insulin. All except one patient had measurable random C-peptide at follow-up and mean values were for patients treated with insulin 0.55, OHG 1.41 and diet alone 1.29 nmol l-1. Random blood glucose results were similar. In conclusion the majority of newly diagnosed patients in the age group 15-34 years have the characteristics of Type 1 diabetes and Type 2 diabetes is rare before 25-30 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of smoking on maternal glucose metabolism.

Maternal smoking, studied in late pregnancy, was found to be associated with lower blood glucose values, both during fasting and after an intravenous glucose load. As a correlation between blood glucose levels and infant birth weight has been reported, it is possible that smoking during pregnancy might reduce fetal growth through an effect on maternal glucose metabolism.