Islet antibodies associated with pancreatic B-cell dysfunction at and 3 years after diagnosis of diabetes in subjects aged 35-64 years old: degree of impairment less severe than in those aged 0-34 years old.

AIMS: To determine differences in pancreatic B-cell function in relation to islet antibodies at diagnosis of diabetes and 3 years later in subjects aged 35-64 years old compared with those aged 0-34 years. METHODS: From a population-based diabetes register, 46 (0-34 years old) and 323 (35-64 years old) incident diabetic patients were investigated at diagnosis and 3 years later. Islet cell antibodies (ICA, GADA and IA-2A) and fasting plasma C-peptide were measured. RESULTS: Islet antibodies were found in 80% of the subjects aged 0-34 years and in 11% of those aged 35-64 years at diagnosis. ICA and GADA was the only combination of two islet antibodies detected in those aged 35-64 years and was, with or without IA-2A, associated with significantly lower median fasting C-peptide values than in those without or with only one antibody [0.35 nmol/l, interquartile range (IQR) 0.63 vs. 0.85 nmol/l, IQR 0.49; P = 0.0004]. However, fasting C-peptide in subjects aged 35-64 years old with multiple islet antibodies was higher than in those aged 0-34 years with islet antibodies (median 0 nmol/l, IQR 0.16, P = 0.0019). After 3 years' follow-up, fasting C-peptide was even lower in subjects aged 35-64 years old with three islet antibodies (median 0.14 nmol/l, IQR 0.27; P = 0.05). CONCLUSIONS: Islet antibodies were common in adults at diagnosis of diabetes. The combination of ICA and GADA indicates impaired B-cell function at diagnosis of diabetes in those aged 35-64 years old.

HLA-DQB1 genotypes, islet antibodies and beta cell function in the classification of recent-onset diabetes among young adults in the nationwide Diabetes Incidence Study in Sweden.

AIMS/HYPOTHESIS: The World Health Organization considers an aetiological classification of diabetes to be essential. The aim of this study was to evaluate whether HLA-DQB1 genotypes facilitate the classification of diabetes as compared with assessment of islet antibodies by investigating young adult diabetic patients. SUBJECTS AND METHODS: Blood samples were available at diagnosis for 1,872 (90%) of the 2,077 young adult patients (aged 15-34 years old) over a 5-year period in the nationwide Diabetes Incidence Study in Sweden. Islet antibodies were measured at diagnosis in 1,869 patients, fasting plasma C-peptide (fpC-peptide) after diagnosis in 1,522, while HLA-DQB1 genotypes were determined in 1,743. RESULTS: Islet antibodies were found in 83% of patients clinically considered to have type 1 diabetes, 23% with type 2 diabetes and 45% with unclassifiable diabetes. After diagnosis, median fpC-peptide concentrations were markedly lower in patients with islet antibodies than in those without (0.24 vs 0.69 nmol/l, p<0.0001). Irrespective of clinical classification, patients with islet antibodies showed increased frequencies of at least one of the risk-associated HLA-DQB1 genotypes compared with patients without. Antibody-negative patients with risk-associated HLA-DQB1 genotypes had significantly lower median fpC-peptide concentrations than those without risk-associated genotypes (0.51 vs 0.74 nmol/l, p=0.0003). CONCLUSIONS/INTERPRETATION: Assessment of islet antibodies is necessary for the aetiological classification of diabetic patients. HLA-DQB1 genotyping does not improve the classification in patients with islet antibodies. However, in patients without islet antibodies, HLA-DQB1 genotyping together with C-peptide measurement may be of value in differentiating between idiopathic type 1 diabetes and type 2 diabetes.

Long-term outcome of a large series of patients surgically treated for pheochromocytoma.

OBJECTIVE: To analyse the morbidity, mortality and long-term outcome in a consecutive series of surgically treated patients with pheochromocytoma (PC), or paraganglioma (PG), from the western region of Sweden between 1950 and 1997. PATIENTS: All patients (n = 121) who had been hospitalized and treated for PC/PG over 47 years. DESIGN: Retrospective review of patients with PC/PG regarding presenting symptoms, tumour characteristics, clinical management and long-term outcome after treatment. SETTING: One referral centre for all patients from the western region of Sweden. RESULTS: During an observation of 15 +/- 6 years, 42 patients died vs. 23.6 expected in the general population (P < 0.001). There was no intra- or post-operative mortality. Four patients with sporadic disease died of malignant PC and six with hereditary disease of associated neuroectodermal tumours. Five patients died of other malignancies, 20 of cardiovascular disease and seven of other causes. Besides older age at primary surgery, elevated urinary excretion of methoxy-catecholamines was the only observed risk factor for death (P = 0.02). At diagnosis 85% of the patients were hypertensive; one year after surgery more than half were still hypertensive. However, pre- and post-operative hypertension did not influence the risk for death versus controls. CONCLUSION: Pheochromocytoma/PG can be safely treated by surgery. Death of malignant PC/PG was unusual, but the patients as a group had an increased risk of death. We recommend life-long follow-up of patients treated for PC/PG with screening for recurrent tumour in sporadic cases and for associated tumours in hereditary cases. This strategy would also be helpful in diagnosing cardiovascular disease at an early stage.

Random C-peptide in the classification of diabetes.

OBJECTIVE: To clarify whether random C-peptide is a valuable test in the classification of diabetes. RESEARCH DESIGN AND METHODS: All C-peptide measurements conducted in the diabetic population of Skaraborg (280,539 inhabitants and 3.2% diabetes) between 1995 and 1998 (3,115 samples) were considered, but only patients with well-defined diabetes type (1,449 samples from 1,093 patients) were analyzed for the correlation between diabetes type and C-peptide concentration. Serum C-peptide was measured after fasting over night (fCP), after glucagon stimulation (gCP), and randomly (rCP) without considering previous meals at an ordinary visit to the diabetic clinic (rCP). Receiver Operating Characteristic (ROC) curves were constructed to illustrate the power of the different C-peptide protocols and to determine the optimal cut-off values. RESULTS: Although all three tests had high discriminative power, the ROC curves demonstrated that rCP was superior to fCP and gCP in discriminating type 1 from type 2 diabetes. The optimal cut-off value for rCP was 0.50 nmol/L, for fCP 0.42 nmol/L, and for gCP 0.60 nmol/L. CONCLUSIONS: rCP is more powerful than fCP and gCP in distinguishing type 1 from type 2 diabetes and can therefore be recommended as a classification tool, particularly in outpatients.

Incidence, prevalence, and mortality of diabetes in a large population. A report from the Skaraborg Diabetes Registry.

OBJECTIVE: Our objective was to analyze the prevalence, incidence, and mortality of diabetes in a population of 280,539 inhabitants. RESEARCH DESIGN AND METHODS: The incidence, prevalence, and deaths from diabetes at all ages of a population have been prospectively followed in the county of Skaraborg, Sweden, since 1991. RESULTS: The annual incidence of diabetes per 100,000 inhabitants in 1991-1995 was (mean +/- 95% CI) 14.7 +/- 3.2 for type 1 diabetes (diagnosed at 24.1 +/- 2.2 years of age) and 265.6 +/- 16.1 for type 2 diabetes (diagnosed at 66.6 +/- 0.6 years of age). The incidence of type 2 diabetes was significantly (P < 0.001) higher among men. There was no significant change in the age at diagnosis of diabetes. Although the incidence rate and the age at diagnosis were constant, the prevalence of diabetes increased by 6% each year. The relative mortality risk for diabetic patients was almost four times higher than expected. The median age at death, however, increased significantly, from 77.2 to 80.2 years (P < 0.05), during the study. CONCLUSIONS: The prevalence but not the incidence rate of diabetes increased during the years 1991-1995. Although diabetic patients showed a high relative mortality, increased survival apparently explains the increase in prevalence of diabetes in the country of Skaraborg.

The prevalence of diabetes in a Swedish population of 280,411 inhabitants. A report from the Skaraborg Diabetes Registry.

OBJECTIVE: To estimate the prevalence of known diabetes in a Swedish county (Skaraborg) and to evaluate capture-recapture methods for validation of the diabetes prevalence. RESEARCH DESIGN AND METHODS: Four sources were used to find known diabetic patients: 1) the Skaraborg Diabetes Registry (SDR), a case-finding inventory, 2) an administrative hospital registry, 3) a registry for the retinopathy screening program, and 4) a pharmacy prescription inventory. The capture-recapture method was applied to various combinations of sources to determine the prevalence of diabetes. RESULTS: The completeness of the SDR was 88.4 +/- 1.3%, indicating a diabetes prevalence of 3.20 +/- 0.08%. When the SDR was not used as one of the sources, the estimated prevalence varied between 2.2 and 4.5%. CONCLUSIONS: A case-finding registry is important in reliably estimating the prevalence of diabetes.

QRS amplitudes, QTc intervals and ECG abnormalities in pheochromocytoma patients before, during and after treatment.

QRS amplitudes (S1 + R5), Minnesota Code ECG abnormalities and QTc intervals were analyzed in ECGs from 31 pheochromocytoma patients on admission to hospital, after 17 +/- 7.2 (SD) days of preoperative phenoxybenzamine therapy in a dosage of 148 +/- 45.0 (SD) mg/day and after a mean postoperative follow-up of 6 years. QRS voltage decreased significantly from 3.37 +/- 1.48 on admission, to 2.26 +/- 0.69 mV at postoperative follow-up (p less than 0.001). The prevalence of total Minnesota Code changes increased or was unchanged on the different occasions. Severe to moderate changes, however, became less prevalent, while mild changes increased. The QTc interval was 0.44 +/- 0.04 s on admission and 0.41 +/- 0.02 s at follow-up (p less than 0.01). No significant differences were observed during treatment with phenoxybenzamine. Pathological ECGs are common findings in patients with pheochromocytoma and significant improvements occur after surgery. Significant effects of phenoxybenzamine therapy were only found in patients with sustained hypertension.

Long-term results in 64 patients operated upon for pheochromocytoma.

During the years 1956-1982, 64 pheochromocytoma patients were operated upon without mortality. Twenty-eight patients had sustained hypertension and 29 paroxysmal hypertension only. In two patients high blood pressure was not related to pheochromocytoma and five subjects were normotensive. In two women the pheochromocytoma demonstrated malignancy by widespread metastases. Sixteen patients also had neuroectodermal manifestations other than pheochromocytoma. Preoperatively, heart disease was found in most of the hypertensive patients aged 50 years or more at operation, but was uncommon in the others. In these subjects, heart disease persisted after surgery. Young subjects with sustained hypertension were not less affected by preoperative cerebrovascular accidents than older subjects. After surgery, hypertension persisted in 12 patients, and was easily controlled by drug therapy in eight. Nine patients died 7 months-18 years after surgery. In no case was the death directly associated with the pheochromocytoma disease. Three died from other neuroectodermal abnormalities. The 55 surviving patients have been followed up for a mean of 12 years after surgery. During the observation time the survival of the pheochromocytoma patients was similar to that of the normal population. At the end of the study, 44 out of the 55 surviving patients were free from symptoms.

Urinary excretion of 3-methylhistidine and creatinine and plasma concentrations of amino acids in hyperthyroid patients following preoperative treatment with antithyroid drug or beta-blocking agent: results from a prospective, randomized study.

The aim of this investigation was to compare the effects of a beta 1-selective adrenoceptor blocking agent and an antithyroid drug on urinary excretion of creatinine (Cr) and 3-methylhistidine (3-MH) and plasma concentrations of amino acids in hyperthyroid patients. beta-adrenoceptor blocking agents are increasingly used in the treatment of hyperthyroid patients, and the effects on clinical signs and symptoms mainly reflect beta 1-adrenoceptor blockade. The consequences of this treatment on metabolic alterations in hyperthyroidism are not fully known. In the present study, 30 hyperthyroid patients were randomized to preoperative treatment with the antithyroid drug methimazole + thyroxine (group I) or the beta 1-selective adrenoceptor blocking agent metoprolol (group II). Urinary excretion of Cr and 3-MH and plasma concentrations of amino acids were measured at the time of diagnosis, following preoperative treatment and 6 months postoperatively. Serum triiodothyronine (T3) was comparably elevated in the two groups of patients at the time of diagnosis and was normalized during preoperative treatment in group I but remained elevated during preoperative treatment in group II. Urinary excretion of creatinine was lower at the time of diagnosis than postoperatively, suggesting reduced muscle mass during hyperthyroidism. Urinary excretion of Cr increased during preoperative treatment in group I but was not significantly altered during treatment with metoprolol. The 3-MH/Cr ratio, which was higher at the time of diagnosis than postoperatively, indicating accelerated protein breakdown in skeletal muscle during hyperthyroidism, was reduced during preoperative treatment in group I but not in group II.(ABSTRACT TRUNCATED AT 250 WORDS)

The selective beta 1-blocking agent metoprolol compared with antithyroid drug and thyroxine as preoperative treatment of patients with hyperthyroidism. Results from a prospective, randomized study.

Despite the increasing use of beta-blocking agents alone as preoperative treatment of patients with hyperthyroidism, there are no controlled clinical studies in which this regimen has been compared with a more conventional preoperative treatment. Thirty patients with newly diagnosed and untreated hyperthyroidism were randomized to preoperative treatment with methimazole in combination with thyroxine (Group I) or the beta 1-blocking agent metoprolol (Group II). Metoprolol was used since it has been demonstrated that the beneficial effect of beta-blockade in hyperthyroidism is mainly due to beta 1-blockade. The preoperative, intraoperative, and postoperative courses in the two groups were compared, and patients were followed up for 1 year after thyroidectomy. At the time of diagnosis, serum concentration of triiodothyronine (T3) was 6.1 +/- 0.59 nmol/L in Group I and 5.7 +/- 0.66 nmol/L in Group II (reference interval 1.5-3.0 nmol/L). Clinical improvement during preoperative treatment was similar in the two groups of patients, but serum T3 was normalized only in Group I. The median length of preoperative treatment was 12 weeks in Group I and 5 weeks in Group II (p less than 0.01). There were no serious adverse effects of the drugs during preoperative preparation in either treatment group. Operating time, consistency and vascularity of the thyroid gland, and intraoperative blood loss were similar in the two groups. No anesthesiologic or cardiovascular complications occurred during operation in either group. One patient in Group I (7%) and three patients in Group II (20%) had clinical signs of hyperthyroid function during the first postoperative day. These symptoms were abolished by the administration of small doses of metoprolol, and no case of thyroid storm occurred. Postoperative hypocalcemia or recurrent laryngeal nerve paralysis did not occur in either group. During the first postoperative year, hypothyroidism developed in two patients in Group I (13%) and in six patients in Group II (40%). No patient had recurrent hyperthyroidism. The results suggest that metoprolol can be used as sole preoperative treatment of patients with hyperthyroidism without serious intra- or postoperative complications. Although the data indicate that the risk of postoperative hypothyroidism is higher after preoperative treatment with metoprolol than with an antithyroid drug, a longer follow-up period than 1 year is needed to draw conclusions regarding late results.

Effects of thyroid hormone and beta-adrenoceptor blocking agents on urinary excretion of 3-methylhistidine and plasma amino acids in man.

The aim of this investigation was to study the effect of beta-adrenoceptor blockade on alterations in protein metabolism induced by administration of 3,5,3'-triiodothyronine (T3) to man. Urinary excretion of 3-methylhistidine and plasma concentrations of amino acids were measured in seven healthy subjects following 1 weeks's administration of T3 alone or T3 in combination with the selective beta 1-adrenoceptor blocking agent metoprolol or the non-selective beta-adrenoceptor blocking agent propranolol. Urinary excretion of 3-methylhistidine and plasma concentrations of valine, methionine, lysine, tyrosine, phenylalanine, isoleucine, leucine, and total essential and branched chain amino acids increased following administration of T3, probably in part reflecting accelerated muscle proteolysis. Neither metoprolol nor propranolol normalized 3-methylhistidine excretion or plasma concentrations of amino acids during T3 treatment. The results indicate that metabolic alterations induced by T3 and giving rise to enhanced 3-methylhistidine excretion and elevated concentrations of plasma amino acids are not normalized by beta-adrenoceptor blockade.

Pheochromocytoma in Sweden 1958-1981. An analysis of the National Cancer Registry Data.

An epidemiological study of 439 cases (184 males, 255 females) of pheochromocytoma (paraganglioma) diagnosed in Sweden from 1958-81 is presented. From the mid 1960's an average of 22 cases have been diagnosed each year. In 255 cases, the pheochromocytoma was diagnosed by clinical examination and/or surgery. In 184 cases (40%), the diagnosis was achieved by autopsy and out of which 60 (14% of all cases) were reported as incidental findings. Ninety-five pheochromocytomas (22%) were located outside the adrenals. The average (+/- SD) age at diagnosis for the total study population was 55.8 +/- 17.7 years. Clinically diagnosed tumour cases were significantly younger (48.5 +/- 16.3 years) compared to cases diagnosed at autopsy (65.8 +/- 14.0). Pheochromocytomas were more common among women than among men. The age specific incidence rate increased continuously for both sexes from the youngest to the oldest age groups. The average incidence of pheochromocytoma in the 24 counties of Sweden was 2.1 cases per million inhabitants per year, range 0.9-5.3. A North to South gradient was noted with a higher incidence in the Southern parts of the country. Whether this is due to a real geographical variation of incidence, to a larger number of unreported cases in the Northern parts, or to presence of families with Sipple's syndrome in the South is unclear.

Evaluation of platelet reactivity in diabetes mellitus.

Seventeen patients with insulin-dependent diabetes mellitus, all below the age of 45 years, were studied. Five of them had retinopathy but no other micro- or macrovascular diabetic complications. None of them had any other concurrent disorder or were on any medication but insulin. The results were compared to those of 17 healthy volunteers of comparable age. There was no difference between the two groups in venous platelet counts, serum production of thromboxane B2 (TXB2), ADP-induced platelet aggregation or bleeding times. As compared to the controls, the diabetics had significantly elevated blood glucose and glycosylated hemoglobin values. The mean plasma values of beta-thromboglobulin, platelet factor 4 and TXB2 were significantly lower in the patients than in the controls. Thus, our results do not lend support to the current concept that platelet reactivity is enhanced in diabetes mellitus.