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Biomedical subjects

S S Fajans

Publications and source records attributed to S S Fajans.

At least 37 records · Page 2Linked to original sources
PubMed1993

Administration of sulfonylureas can increase glucose-induced insulin secretion for decades in patients with maturity-onset diabetes of the young.

OBJECTIVE: To ascertain whether the effect of sulfonylureas on glucose-mediated insulin release persists for years to decades in patients with maturity-onset diabetes of the young. RESEARCH DESIGN AND METHODS: The effect of sulfonylurea treatment on glucose-induced insulin secretion was ascertained prospectively for up to 33 yr in 12 diabetic patients of the maturity-onset diabetes of the young RW pedigree, who are genetically homogeneous because they share DNA markers on chromosome 20q. In 7 of these patients, paired glucose tolerance tests, given while the patients were on and off sulfonylureas, were performed after 7-31 yr. RESULTS: Glucose-induced insulin secretion showed an average increase of 68% in diabetic patients who remained responsive to chlorpropamide after having been on and off the drug for decades. In most patients, however, glucose-induced insulin secretion declines over time (1-4%/yr). Some patients become unresponsive to sulfonylureas after 3-25 yr and then have very small or no increases in glucose-induced insulin secretion and require treatment with insulin to normalize fasting hyperglycemia. CONCLUSIONS: Increase in glucose-induced insulin secretion remains the most important mechanism of the action of sulfonylureas during long-term administration.

Adolescent↗
PubMed1992

A microsatellite polymorphism associated with the PLC1 (phospholipase C) locus: identification, mapping, and linkage to the MODY locus on chromosome 20.

A highly polymorphic (dC-dA)n.(dG-dT)n dinucleotide repeat at the PLC1 locus on human chromosome 20 has been identified. Primers flanking the dinucleotide repeat were used for PCR amplification of the repeat region in 37 informative kindreds from the Centre d'Etude du Polymorphisme Humain. Two-point linkage analysis indicates that PLC1 is closely linked to several chromosome 20 markers, including D20S16 (Zmax = 41.25; theta = 0.07), D20S17 (Zmax = 42.81; theta = 0.09), and ADA (Zmax = 57.24; theta = 0.05). Multipoint linkage analysis places the PLC1 locus between D20S18 and D20S17, 11.2 and 6.6 cM, respectively, from these loci (sex-averaged distances). In addition, the PLC1 gene shows linkage to the maturity-onset diabetes of the young (MODY) locus on chromosome 20 with a lod score of 4.57 at theta = 0.089.

Base Sequence↗
PubMed1992

Identification of genetic markers flanking the locus for maturity-onset diabetes of the young on human chromosome 20.

A systematic search for genetic linkage with maturity-onset diabetes of the young (MODY) as expressed in the R.-W. pedigree has been carried out. Evidence for linkage was found with restriction-fragment-length polymorphism loci that map to human chromosome 20. Two-point linkage analysis with CRI-L1214 (D20S16) and MODY gave a log of the odds (lod) score of 4.16 at theta = 0.08. Multipoint linkage analysis with nine restriction-fragment-length polymorphism loci resulted in a lod score of 4.81 with the MODY locus in an approximately 20-cM region bounded by D20S16 and D20S14-D20S18. Examination of the pattern of MODY segregation suggests that additional factors, possibly genetic could be involved in the age of onset of the disease.

Adult↗
PubMed1992

Mapping diabetes-susceptibility genes. Lessons learned from search for DNA marker for maturity-onset diabetes of the young.

During our search for a marker for non-insulin-dependent diabetes mellitus (NIDDM) in a large multigenerational family with a form of NIDDM termed maturity-onset diabetes of the young (MODY), we learned a great deal that may serve to streamline the search for diabetes-susceptibility genes in other families. We describe here our experience and suggest strategies that may enhance the search for markers for other diabetes susceptibility genes with genetic linkage approaches.

Chromosome Mapping↗
PubMed1991

Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q.

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus characterized by an early age of onset, usually before 25 years of age, and an autosomal dominant mode of inheritance. The largest and best-studied MODY pedigree is the RW family. The majority of the diabetic subjects in this pedigree has a reduced and delayed insulin-secretory response to glucose, and it has been proposed that this abnormal response is the manifestation of the basic genetic defect that leads to diabetes. Using DNA from members of the RW family, we tested more than 75 DNA markers for linkage with MODY. A DNA polymorphism in the adenosine deaminase gene (ADA) on the long arm of chromosome 20 was found to cosegregate with MODY. The maximum logarithm of odds (lod score) for linkage between MODY and ADA was 5.25 at a recombination fraction of 0.00. These results indicate that the odds are greater than 178,000:1 that the gene responsible for MODY in this family is tightly linked to the ADA gene on chromosome 20q.

Adenosine Deaminase↗
PubMed1990

Scope and heterogeneous nature of MODY.

This review summarizes aspects of the phenotypic expression, natural history, recognition, pathogenesis, and heterogeneous nature of maturity-onset diabetes of the young (MODY), which is inherited in an autosomal-dominant pattern. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among White pedigrees. In MODY patients with low insulin responses, there are delayed and decreased insulin and C-peptide secretory responses to glucose from childhood or adolescence even before glucose intolerance appears, which may represent the basic genetic defect. When followed for decades, nondiabetic siblings have normal insulin responses. The fasting hyperglycemia of some MODY patients has been treated successfully with sulfonylureas for up to 30 yr. In a few patients, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they resemble those of early insulin-dependent diabetes mellitus. The progression of the insulin secretory defect over time distinguishes between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose, despite glucose intolerance and fasting hyperglycemia similar to that seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient beta-cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, a structurally abnormal mutant insulin molecule that is biologically ineffective is secreted. No associations have been found between specific HLA antigens and MODY in White, Black, and Asian pedigrees. Linkage studies of the insulin gene, insulin-receptor gene, erythrocyte/HepG2 glucose-transporter locus, and apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional non-insulin-dependent diabetes mellitus. Because of autosomal-dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in non-insulin-dependent diabetes mellitus, including the use of genetic linkage strategies to identify diabetogenic genes.

Adult↗
PubMed1989

Maturity-onset diabetes of the young (MODY).

This review summarized aspects of the widening scope, phenotypic expression, natural history, recognition, pathogeneses, and heterogenous nature of maturity-onset diabetes of the young (MODY), an autosomal dominant inherited subtype of NIDDM, which can be recognized at a young age. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among Caucasian pedigrees. In MODY patients with low insulin responses, there is a delayed and decreased insulin and C-peptide secretory response to glucose from childhood or adolescence, even before glucose intolerance appears; it may represent the basic genetic defect. The nondiabetic siblings have had normal insulin responses for decades. The fasting hyperglycemia of some MODY has been treated successfully with sulfonylureas for more than 30 years. In a few, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they may resemble those of early Type I diabetes. The rate of progression of the insulin secretory defect over time does distinguish between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose despite glucose intolerance and fasting hyperglycemia similar to those seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient beta cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, an insulin is secreted which is a structurally abnormal, mutant insulin molecule that is biologically ineffective. No associations have been found between specific HLA antigens and MODY in Caucasian, black, and Asian pedigrees. Linkage studies of the insulin gene, the insulin receptor gene, the erythrocyte/Hep G2 glucose transporter locus, and the apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional NIDDM. Because of autosomal dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in NIDDM, including the use of genetic linkage strategies to identify diabetogenic genes.

Adolescent↗
PubMed1989

Insulin-producing islet cell tumors.

The types of islet cell pathology and the history and clinical course are presented for 82 patients with proven islet B-cell disease with hyperinsulinism. They form the basis for the recognition of the patient suspected of harboring this syndrome. Among laboratory tests and procedures for recognition of inappropriate hyperinsulinism, the evaluation of plasma levels of glucose (G) and immunoreactive insulin (IRI) on fasting is the most important, with calculation of the IRI/G ratio, if necessary. The determination of the concentration of basal proinsulin and C-peptide is also helpful. Suppression tests and provocative tests are used infrequently. Attempts at preoperative localization are recommended. Ultrasonography and arteriography are helpful, while transhepatic percutaneous portal venous sampling is the only procedure that can differentiate localized (solitary insulinoma) from diffuse hyperinsulinism caused by adenomatosis, hyperplasia, and nesidioblastosis (present in 18% of our patients). Intraoperative ultrasonographic localization may visualize nonpalpable tumors and exclude multiple tumors. Treatment of benign B-cell disease is primarily surgical, but a variety of drugs may be useful for temporary or more prolonged therapy.

Adenoma, Islet Cell↗
PubMed1988

Effects of secretin on the normal and pathological beta-cell.

Secretin is a gastrointestinal hormone that stimulates insulin secretion and enhances the insulin response to glucose. The mechanism by which secretin acts on the beta-cell has not been extensively studied. The plasma insulin responses to secretin (2 U/kg), expressed as the percent increase relative to basal plasma insulin concentrations, were similar in normal (n = 23) and obese subjects with normal glucose tolerance (n = 12), but were decreased in obese subjects with abnormal glucose tolerance (n = 11). The insulin response to secretin was directly proportional to the basal insulin concentration in these three groups. The effects of secretin on beta-cell function was not altered by propranolol (n = 6), atropine (n = 8), or surgical vagotomy (n = 10). Patients with single islet cell tumors secreting insulin (n = 18) had no plasma insulin response to secretin, whereas patients with noninsulin-secreting pancreatic tumors (gastrinomas; n = 6) and patients in whom single insulinomas had been removed (n = 7) responded normally. Two adult patients with multiple B-cell adenomas and hyperplasia (not associated with multiple endocrine neoplasia type I) hyperresponded to secretin, whereas patients with multiple endocrine neoplasia, type I, without hyperinsulinism responded normally. One patient with nesidioblastosis had no response to secretin, indicating that the pathophysiology of this entity is distinct from that of other forms of islet hyperplasia. These data suggest that secretin stimulates beta-cells directly rather than through cholinergic, adrenergic, or vagal peptidergic neural mechanisms. In addition, the ability to respond to secretin appears to be lost in patients with single insulinomas and nesidioblastosis, but not in those with multiple B-cell adenomas and hyperplasia. The lack of a plasma insulin response in patients with single insulinomas and the high normal or exaggerated response in patients with multiple B-cell adenomas and hyperplasia may prove useful in differentiating these entities.

Adenoma↗
PubMed1987

Linkage analysis of the human insulin receptor gene and maturity onset diabetes of the young.

The cloning of the insulin receptor cDNA has permitted the definition of restriction fragment length polymorphisms at that locus. These polymorphisms were used to study the role of the insulin receptor in four pedigrees with maturity onset diabetes of the young through linkage analyses. When each pedigree was individually analysed, no linkage was demonstrated in the two larger pedigrees, implying that an insulin receptor defect was not responsible for the predisposition to diabetes in these pedigrees. One of these pedigrees was known to be hypoinsulinaemic, while insulin levels were unavailable in the second pedigree. In the two smaller pedigrees, however, a single haplotype cosegregated with diabetes. One of these pedigrees is known to be hyperinsulinaemic. The small size of the pedigrees which demonstrated cosegregation precluded statistical proof of linkage. Nonetheless, the presence of an uncommon insertional polymorphism which cosegregated with diabetes in both pedigrees was improbable and suggested that this insertion could be responsible for diabetes in these families. This study thus may be additional evidence for heterogeneity in maturity onset diabetes of the young. For the two larger pedigrees, the insulin gene and HLA region have already been eliminated as genetic markers. This study provides data which eliminate a third candidate gene in these two pedigrees.

Diabetes Mellitus, Type 2↗
PubMed1985

Heterogeneity within type II and MODY diabetes.

The heterogeneity within Type II diabetes (NIDDM) and within Maturity-Onset type Diabetes of Young people (MODY), a subset of NIDDM which is inherited in an autosomal dominant fashion, is discussed. Aspects of the definition and phenotypic expression of MODY are reviewed. Within NIDDM there are differences in patterns of inheritance between subgroups. HLA antigen associations are not found in most NIDDM populations but exist in three specific population groups with Type II diabetes. Within NIDDM and within MODY there are differences in the magnitude of insulin responses to glucose, differences in target tissue responsiveness to insulin in vivo, and differences in receptor and post-receptor effects of insulin. Structurally abnormal variant and biologically defective insulin molecules have been found in some Type II diabetic patients and in members of certain MODY families. The presence or absence of obesity may mark heterogeneous groups of Type II diabetic patients, in addition to the importance of obesity in uncovering an insulin secretory defect by causing insulin resistance. There is heterogeneity in susceptibility to vascular disease within NIDDM and MODY. The natural history of carbohydrate metabolism and of insulin secretory responses to glucose in early Type I diabetes and in MODY with low insulin secretory responses are illustrated and similarities and dissimilarities compared and contrasted. Failure to recognize young patients with MODY may contribute to incorrect diagnosis, management, and assignment of prognosis of this form of diabetes in the young by many practicing physicians. The recognition that Type I or insulin-dependent diabetes (IDDM) and Type II or noninsulin-dependent (NIDDM) differ from each other not only phenotypically but also in etiology and pathogenesis led the National Diabetes Data Group (NDDG) to devise the present nomenclature and classification of diabetes mellitus. These were adopted by the World Health Organization. As suggested by the NDDG report, the classification should be reexamined periodically to reflect improved understanding of the disease, to stimulate further research, and to be of help to practicing physicians.

Adult↗
PubMed1985

Hormonal studies in a patient with PP-producing tumors.

Five years after the removal of pure pancreatic polypeptide (PP) producing tumors, concentrations of circulating levels of PP, insulin, glucagon, and growth hormone in the basal state, after insulin-induced hypoglycemia, and after a protein-rich meal were determined in a patient with previous truncal vagotomy and Billroth II gastrectomy. Basal plasma levels of PP ranged between 2180 and 2660 pg/ml suggesting persistence or recurrence of PP producing tumors. Concentrations of the other hormones were within normal values. After insulin injection (0.1 U/Kg) levels of PP and glucagon were not modified while those of GH rose from 3.2 to 22.6 ng/ml. After a protein meal (450 gms. of cooked ground beef meat) a sharp rise of plasma PP was observed to a peak of 11310 pg/ml at 10 min. Moreover, plasma levels of immunoreactive insulin also showed an equally prompt rise to a peak of 532 microU/ml while plasma glucagon rose simultaneously to 448 pg/ml. The cause of the abnormal PP, insulin and glucagon responses could not be ascertained but we postulate that they are derived from pancreatic tumors of mixed cell type.

Blood Glucose↗