Oral magnesium supplementation in insulin-requiring Type 2 diabetic patients.

Oral magnesium (Mg) supplementation can improve insulin sensitivity and secretion in patients with Type 2 diabetes mellitus (DM). We studied the effect of Mg supplementation on glycaemic control, blood pressure, and plasma lipids in insulin-requiring patients with Type 2 DM. Fifty moderately controlled patients were randomized to 15 mmol Mg or placebo daily for 3 months. Plasma Mg, glucose, HbA1c, lipids, erythrocyte Mg, Mg and glucose concentrations in 24-h urine, and systolic and diastolic pressure were measured before and after 3 months treatment. Plasma Mg concentration was higher after supplementation than after placebo (0.82 +/- 0.07 vs 0.78 +/- 0.08 mmol l(-1), p < 0.05), as was Mg excretion (5.5 +/- 1.9 vs 3.7 +/- 1.4 mmol 24 h(-1), p = 0.004) but erythrocyte Mg concentrations were similar. No significant differences were found in glycaemic control (glucose: 10.7 +/- 3.8 vs 11.6 +/- 6.2 mmol l(-1), p = 0.8; HbA1c: 8.9 +/- 1.6 vs 9.1 +/- 1.2%, p = 0.8), lipids or blood pressure. On-treatment analysis (34 patients: 18 on Mg, 16 on placebo) yielded similar results. An increase in plasma Mg concentration irrespective of medication was associated with a tendency to a decrease in diastolic pressure (increased plasma Mg vs no increase: -4.0 +/- 10.1 vs +2.5 +/- 12.0 mmHg, p = 0.059). Three months' oral Mg supplementation of insulin-requiring patients with Type 2 DM increased plasma Mg concentration and urinary Mg excretion but had no effect on glycaemic control or plasma lipid concentrations.

From medical history and biochemical tests to presymptomatic treatment in a large MEN 2A family.

An extensive study was published in 1959 in the Netherlands on a large family, which initially attracted attention because of a family history of attacks of shaking. Clinical investigation revealed phaeochromocytomas in four family members. In 1975, the family was identified to be a MEN 2A family, and since then, the members were examined annually using measurement of catecholamine metabolites in 24-h excreted urine and C-cell stimulation tests. In 1993, the RET proto-oncogene on chromosome 10q11 was found to be associated with MEN 2A and a specific mutation in this gene was identified in the family. In this family, 32 MEN 2A patients were detected. Since screening started in 1975, no patient died of phaeochromocytoma; however, two patients died of metastasized medullary thyroid carcinoma (MTC) (mean age 46 years). Twelve patients were operated on for phaeochromocytoma, and 13 for MTC. The results of DNA-analysis revealed the failures of the biochemical tests to identify affected family members. Six disease gene carriers with normal C-cell stimulation test results appeared to have small multifocal MTCs. Two carriers with normal excretion levels of catecholamines had a small phaeochromocytoma. DNA-analysis enables the unambiguous diagnosis of MEN 2A gene carrier-ship, allowing presymptomatic surgery for MTC.

Heterozygous familial hypercholesterolaemia is associated with pathological exercise-induced leakage of muscle proteins, which is not aggravated by simvastatin therapy.

The objective of this study was to assess the relationship between therapy with the HMG-CoA reductase inhibitor simvastatin and muscle damage and the possible causal role of hypercholesterolaemia. The exercise-induced release of muscle proteins as a parameter of muscle damage was studied in two equicholesterolaemic groups of male patients with heterozygous familial hypercholesterolaemia (FH); one group without treatment, the second group on simvastatin. To assess the role of cholesterol, a third group of healthy male volunteers was studied as well. The study took place at the Lipid Clinic of an 800-bed University Hospital. One group of 21 male patients with heterozygous FH did not receive treatment, except for a lipid-lowering diet. A second group of 13 male FH patients were treated with 40 mg simvastatin day-1 for at least 1 year and matched for cholesterol levels with the first group. A third group consisted of 25 normocholesterolaemic male controls. All subjects underwent a 45 min lean body mass (LBM) standardized ergometer muscle provocation test (2 Watt/kg LBM). Levels of creatine kinase (CK) and myoglobin (Mb) were assessed before and 1 and 8 h after exercise and compared with baseline levels. The exercise-induced release of muscle proteins is reflected by peak CK and Mb levels expressed as a percentage of baseline levels. The exercise-induced increase in Mb and CK levels did not differ between untreated and simvastatin-treated FH patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A.

BACKGROUND: Multiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes parathyroid adenoma. Missense mutations in the RET proto-oncogene are associated with MEN-2A. Their detection by DNA analysis allows the identification of carriers of the gene, in whom the risk of medullary thyroid carcinoma is 100 percent. We compared the reliability of biochemical tests with that of DNA analysis in identifying carriers of the MEN2A gene. METHODS: Starting in 1975, we screened 300 subjects in four large families with MEN-2A for expression of the disease, using measurements of plasma calcitonin after stimulation with pentagastrin or calcium and urinary excretion of catecholamines and catecholamine metabolites. We tested for carrier status by DNA analysis, including linkage analysis, and more recently by analysis of mutations in the RET gene. RESULTS: Of 80 MEN2A gene carriers (in 61 of whom carrier status was proved by DNA analysis), 66 had abnormal plasma calcitonin values and medullary thyroid carcinoma. Fourteen young carriers had normal results of plasma calcitonin tests. In 8 of these 14, thyroidectomy revealed small foci of medullary thyroid carcinoma; the remaining 6 have not yet been operated on. Of the other 220 family members, 68 were found by DNA analysis not to carry the MEN2A gene. None of these 68 subjects had medullary thyroid carcinoma or pheochromocytoma; 6 had elevated plasma calcitonin concentrations and underwent thyroidectomy but had only C-cell hyperplasia. CONCLUSIONS: Unlike biochemical tests, DNA analysis permits the unambiguous identification of MEN2A gene carriers.

Increasing incidence of type I diabetes in The Netherlands. The second nationwide study among children under 20 years of age.

OBJECTIVE: A nationwide retrospective study was conducted to assess the incidence of type I diabetes in The Netherlands among children < 20 years of age in 1988-1990. The first study with a similar design covered 1978-1980. RESEARCH DESIGN AND METHODS: The capture-recapture census method was chosen for analysis of the data. A questionnaire was sent to all Dutch pediatricians and internists, and for the ascertainment, a similar questionnaire was sent out separately to members of the Dutch Diabetes Association, which is the national patient association. RESULTS: The average achieved ascertainment rate was 81%. The ascertainment-adjusted annual incidence was 13.2/100,000 for 0- to 19-year-old children, indicating an increase of 23% compared with the 1978-1980 survey; for 0- to 14-year-olds, the increase amounted to 17%. CONCLUSIONS: This study suggests a sustained increase of type I diabetes in The Netherlands because the cumulative incidence studied previously in the 1960-1970 birth cohorts of male army conscripts 18 years of age was also found to rise. In contrast to Northern European countries, an increase in incidence for the age category 0-4 years could not be found.

The clinical implications of a positive calcitonin test for C-cell hyperplasia in genetically unaffected members of an MEN2A kindred.

C-cell hyperplasia precedes the development of medullary thyroid carcinoma in multiple endocrine neoplasia type 2A (MEN2A). Identification of abnormal calcitonin levels after a provocative stimulus is a technique that has been widely used to diagnose this preneoplastic condition in an early stage during the development of medullary thyroid carcinoma, when total thyroidectomy is likely to be curative. In a MEN2A kindred, we identified seven individuals with abnormal calcitonin test results, whose carrier state was questionable. Five of these people were thyroidectomized, and C-cell hyperplasia was diagnosed. Four of these individuals were the offspring of a mother who is at risk for the development of MEN2A but who has had normal calcitonin test results throughout the years and of a father who is not at risk but who has had abnormal test results over a period of 10 years, without evidence of progressive elevation. None of these people developed other manifestations of MEN2A. DNA analysis using markers linked to the MEN2A gene demonstrated, with > 99% likelihood, that none of the individuals who could be genotyped was a gene carrier. C-cell hyperplasia due to some mechanism other than the presence of the MEN2A gene may also occur in MEN2A kindreds. DNA analysis offers an important additional tool for proper diagnosis in the clinical management of MEN2A families.

Successful dissolution of cholesterol gallstone during treatment with pravastatin.

This case report describes a 51-year-old hypercholesterolemic male patient who had a large solitary cholesterol gallstone. The patient was treated with the 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin, 40 mg/day. After 3 months of therapy, serum cholesterol level normalized (7.7 mmol/L before and 5.2 mmol/L during treatment), and biliary cholesterol saturation index decreased from 1.3 before to 0.8 during treatment. Repeatedly performed ultrasonography showed complete gallstone dissolution. Pravastatin may be valuable in the nonsurgical treatment of cholesterol gallstone disease particularly when there is an additional indication for HMG-CoA reductase inhibitors because of hypercholesterolemia.

Long-term follow-up in four large MEN 2 families in The Netherlands.

Results of follow-up studies in four large multiple endocrine neoplasia type 2A families (total of 95 patients affected) have shown a positive effect on the course of the disease since early screening and intervention were initiated in 1974.

Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation.

We report on two male and two female relatives with intestinal lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial anomalies; seizures; mild growth retardation; and moderate mental retardation. Main facial anomalies are a flat face, flat nasal bridge, hypertelorism, small mouth, tooth anomalies, and ear defects. Their parents are consanguineous. This disorder probably is an hitherto undescribed autosomal recessive syndrome.

Development of multiple endocrine neoplasia type 2A does not involve substantial deletions of chromosome 10.

In MEN2A both familial and sporadic cases are known. The familial cases show a dominant pattern of inheritance. In these respects, MEN2A resembles other tumors in whose etiology so-called tumor suppressor genes play a decisive role. The MEN2A locus has been assigned to chromosome 10 by linkage studies. Analysis of tumor DNA from 42 patients shows that markers on chromosome 10 were lost in only one tumor. Thus, these results contrast with previous studies which show that tumor development is generally associated with the loss of the whole or substantial parts of the chromosome on which the putative tumor suppressor gene is located.

Evolutionary pathways of the calcitonin (CALC) genes.

Recombinant DNA techniques have made it possible to establish the structure of various genes encoding polypeptide hormones. Comparison of nucleotide sequences of the calcitonin (CALC) genes in man has revealed surprising similarities and variations. These findings and the homologies among the sequences in different species offered an opportunity for speculation about relationships between these genes and about their evolutionary origin. The first gene (CALC-I) directing the synthesis of calcitonin (CT) or CT gene-related peptide (CGRP) comprises six exons and gives rise to two mRNAs by an alternative RNA-processing mechanism. The homology between CGRP and CT reflects their common origin. The human genome contains a second gene (CALC-II) that is structurally related to the CALC-I gene. The CALC-II RNA transcripts do not appear to be differentially processed, as only preproCGRP-II mRNA and not preproCT-II is detected. The first and second CT/CGRP genes probably have evolved from a common ancestor gene early in evolution. Meanwhile, a third genomic locus containing nucleotide sequences highly homologous to exons 2 and 3 of both CALC genes was detected and probably generated by duplication of a part of CALC-II. This locus is not likely to encode a CT- or CGRP-related polypeptide hormone. The CALC genes and this last (pseudo) gene are located on the short arm of chromosome 11. Recently, islet- or insulinoma-amyloid polypeptide (IAPP) was isolated as a major constituent of amyloid present in human insulinoma and in pancreatic islet amyloid in noninsulin-dependent diabetes mellitus. IAPP shows 46% amino acid sequence homology with human CGRP-II.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple endocrine neoplasia syndrome type 2: the value of screening and central registration. A study of 15 kindreds in The Netherlands.

Since 1975, 10 families with the multiple endocrine neoplasia (MEN)-2A syndrome and five with the MEN-2B syndrome, making a total of 101 patients, have been identified in The Netherlands. Twenty-three of the MEN-2A patients died before the start of the screening program. The average age of the patients whose death was due to pheochromocytoma (n = 11) or medullary thyroid carcinoma (n = 12) was 34.9 and 49.2 years, respectively. Eighty-seven patients with the MEN-2A syndrome and eight with the MEN-2B syndrome underwent thyroidectomy for C-cell hyperplasia and/or medullary thyroid carcinoma. Eighteen patients had signs or symptoms caused by MEN-2A (group A), 60 were relatives of these patients who had been found to be affected at the first screening of the family (group B), and nine relatives had had negative screening results that later became positive (group C). Five patients had signs or symptoms due to MEN-2B (group A) and three were relatives of these patients who had been found to be affected at the initial screening (group B). To assess the effect of screening, we compared these groups with respect to the occurrence of metastatic medullary thyroid carcinoma at thyroidectomy and the results of the postoperative calcitonin tests. Among the MEN-2A families, 72 percent of group A, 33 percent of group B, and none of group C were found to have metastatic medullary thyroid carcinoma at surgery. In the MEN-2B families, all five patients in group A and one of the three patients in group B had metastatic disease. The "cure rates" in these three groups with MEN-2A, as determined by stimulated calcitonin assessment, were 11, 57, and 100 percent, respectively. One of the five patients with MEN-2B in group A and two of the three patients in group B showed normalization of the stimulated calcitonin value after surgery. From these results, it may be concluded that screening can lead to the detection of medullary thyroid carcinoma in an earlier stage, which in turn may permit curative treatment and improvement of both prognosis and life expectancy. The need for supervision of affected families by central registration to promote periodic examination and to guarantee the continuity of such screening is discussed.

Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome).

Two kindreds with the multiple endocrine neoplasia type 2A syndrome were studied. Of one of these we examined 150 members, 20 of whom were treated with thyroidectomy for medullary carcinoma and nine with bilateral adrenalectomy for pheochromocytoma. Of the second kindred 50 members were examined, seven of whom were thyroidectomized and seven treated with bilateral adrenalectomy. Pheochromocytomas were invariably found on both sides, even in four cases in which the adrenals on one side appeared to be completely normal, not only at preoperative roentgenologic examination but also on inspection during the operation. The microscopic finding of micronodules and a cluster of abnormal medullary cells identical with those found in pheochromocytomas in one of the apparently normal adrenals represents a first stage in the development of diffuse medullary hyperplasia as well as nodular hyperplasia. This is in accordance with the fact that in the MEN type 2A syndrome pheochromocytomas are always multicentric and multiple in origin. On the basis of these findings we conclude that all patients with the MEN 2A syndrome who show symptoms and signs of active pheochromocytoma should be subjected to bilateral adrenalectomy, even when one or both of the adrenals appear to be normal at roentgenologic investigation.