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K H Gabbay

Publications and source records attributed to K H Gabbay.

At least 55 records · Page 3Linked to original sources
PubMed1988

T-cell-defined DR4 subtypes as markers for type 1 diabetes.

In most populations studied, HLA-DR4, a DRB1 (formerly DR beta I) allele, is increased in frequency among patients with insulin-dependent diabetes mellitus (IDDM). Using T-cells, one can distinguish five subtypes of DR4 (Dw4, Dw10, Dw13, Dw14, and Dw15). Two of these (Dw4 and Dw10) are IDDM-associated in the populations studied here. Therefore, Dw4 and Dw10 could be causative or merely markers for a linked diabetes allele. If they are causative, one might expect them to share some unique structural element or at least to associate consistently with IDDM in different populations. Published sequence data show no structural element unique to Dw4 and Dw10; moreover, the associations of these DR4-Dw subtypes with diabetes vary considerably in different populations. Thus the DRB1 locus probably cannot account for the DR4 association in IDDM. The strong linkage disequilibrium between IDDM and Dw4 and Dw10 suggests that the diabetes susceptibility locus should be in the vicinity of the DR region or the DQ region of the HLA complex. Alternative hypotheses are discussed, relating DR- and DQ-region alleles to IDDM. We further postulate that the evolutionary event that produced the Dw10 allele occurred on a Dw4 haplotype that happened to carry a diabetes susceptibility allele at another locus.

Adolescent↗
PubMed1986

Growth hormone regulates the abundance of insulin-like growth factor I RNA in adult rat liver.

Insulin-like growth factor I (IGF-I) is a mitogenic polypeptide present in the plasma of man and rat that is thought to mediate the actions of pituitary growth hormone on cartilage to promote skeletal elongation. In the rat, plasma levels of IGF-I show both developmental and hormonal regulation: levels are low at birth, increase with age, and are decreased in growth hormone-deficient adult animals. The present study demonstrates that these changes in plasma IGF-I reflect the abundance of IGF-I RNA in rat liver. A human IGF-I cDNA probe hybridized to multiple RNA species in adult rat liver with sizes 8.6, 4.6, 3.2, 2.1, and 1.0-1.4 kilobases. These RNA species were decreased by greater than 80% in neonatal (2- and 12-day-old) rat liver and by greater than 90% in liver from adult rats made growth hormone-deficient by hypophysectomy. Treatment of hypophysectomized rats with growth hormone increased the abundance of all species of IGF-I RNA. These results suggest that growth hormone regulates the expression of its physiological mediator by altering the synthesis, stability, or both of IGF-I RNA in rat liver.

Aging↗
PubMed1986

Secretion of an insulin-like growth factor-I-related protein by human breast cancer cells.

Somatomedin activity is required for proliferation of normal cells; recently somatomedin activity in the cellular environment was shown to be necessary for expression of the transformed phenotype. We demonstrate here that authentic serum-derived insulin-like growth factor-I (IGF-I) stimulates the proliferation of four human breast cancer cell lines, MCF-7, MDA-MB-231, ZR-75-1, and Hs578T in serum-free monolayer culture and that each of these lines produces and secretes an IGF-I-related growth factor. The two highly tumorigenic estrogen-independent cell lines, MDA-MB-231 and Hs578T, produced 2- to 10-fold more IGF-I than did two estrogen responsive cell lines, MCF-7 and ZR-75-1, which are not tumorigenic in the absence of estrogen. These breast cancer cells also secrete a Mr 50,000 binding activity which partially obscured detection of IGF-I by radioimmunoassay. Acid-ethanol extraction allowed dissociation of the high molecular weight complex; whereupon, fully immunoreactive IGF-I comigrated on acid gel exclusion chromatography with authentic human serum-derived IGF-I. Radioimmunoassay displacement curves for breast cancer cell line-derived IGF-I were parallel to those for authentic IGF-I. Northern blot analysis of mRNA from four breast cancer cell lines demonstrated specific hybridization with a human IGF-I probe corresponding to one of the two major transcripts seen in human liver mRNA. These data suggest that breast cancer cell line-derived IGF-I is similar to liver-synthesized, serum-derived IGF-I.

Breast Neoplasms↗
PubMed1985

A minor subset of HLA-DR3 haplotypes is preferentially increased in type 1 (insulin-dependent) diabetes.

We have been using human T-lymphocyte clones specifically sensitized to detect leucocyte antigens of Type 1 (insulin-dependent) diabetic patients in the hope of detecting novel HLA antigens associated with Type 1 diabetes. We previously described two such clones which define a new class II HLA antigen, Boston-1 (BO1). BO1 is found mainly on cells of persons with particular HLA-DR antigens and, of potential significance for diabetes, BO1 identifies a distinctive subset of DR3 haplotypes. We report here that BO1+ DR3 haplotypes are overrepresented in Type 1 diabetes. That is, significantly more of the DR3-positive subjects are BO1-positive in the patient group (31%) than in the control group (8%), suggesting that a diabetes-susceptibility gene may be more common on the BO1+ than on the BO1- DR3 haplotypes. Alternative interpretations are also discussed.

Alleles↗
PubMed1984

Muscle capillary basement-membrane thickness and long-term glycemia in type I diabetes mellitus.

We explored the relation between the thickness of the quadriceps-muscle capillary basement membrane and the glycemia level in 102 young patients with Type I diabetes (median age, 17 years; range, 12 to 29). Membrane thickness was measured in serial biopsy specimens obtained after two consecutive 2 1/2-year observation periods, and glycemia was assessed in terms of glycosylated hemoglobin and fasting blood glucose levels determined at eight-week intervals. An association between membrane thickness and glycemia level was apparent in both cross-sectional and longitudinal analysis. Cross-sectional analysis of data on 39 postpubertal patients (growth less than 1.0 cm during the five years) showed a positive association of membrane thickness to glycosylated hemoglobin (r = 0.53, P = 0.0002) and blood glucose values (r = 0.37, P = 0.01) averaged over the antecedent 2 1/2-year period. By contrast, in 32 pubertal patients (growth greater than 7.5 cm) there was a significant negative association of membrane thickness to both glycosylated hemoglobin (r = -0.40, P = 0.01) and blood glucose (r = -0.42, P = 0.009). In longitudinal analysis, there was no correlation between changes in membrane thickness and average glycemia levels during the two follow-up periods in 32 pubertal patients (for glycosylated hemoglobin, r = 0.11; P = 0.25), but in the postpubertal group (n = 20) there was a significant positive covariation (r = 0.57, P = 0.0004). The data indicate that in postpubertal diabetic patients, the thickness of the muscle capillary basement membrane is positively related to the level of glycemia, but this relation does not obtain in the pubertal state.

Adolescent↗
PubMed1984

Extended major histocompatibility complex haplotypes in type I diabetes mellitus.

We have studied major histocompatibility complex markers in Caucasian patients with type I diabetes mellitus and their families. The frequencies of extended haplotypes that were composed of specific HLA-B, HLA-DR, BF, C2, C4A, and C4B allelic combinations, which occurred more commonly than expected, were compared on random diabetic and normal chromosomes in the study families. We demonstrated that all of the previously recognized increases in HLA-B8, B18, B15, DR3, and perhaps DR4 could be ascribed to the increase among diabetic haplotypes of a few extended haplotypes: [HLA B8, DR3, SC01, GLO2]; [HLA-B18, DR3, F1C30]; [HLA-B15, DR4, SC33]; and [HLA-BW38, DR4, SC21]. In fact, HLA-DR3 on nonextended haplotypes was "protective", with a relative risk considerably less than 1.0. There was a paucity or absence among diabetic patients of several extended haplotypes of normal chromosomes, notably [HLA-B7, DR2, SC31] and [HLA-BW44, DR4, SC30]. The extended haplotype [HLA-BW38, DR4, SC21] is found only in Ashkenazi Jewish patients, which suggests that extended haplotypes mark specific mutations that arise in defined ethnic groups. The data show that no known MHC allele, including HLA-DR3 and possibly HLA-DR4, is per se a marker for or itself a susceptibility gene for type I diabetes. Rather, extended haplotypes, with relatively fixed alleles, are either carriers or noncarriers of susceptibility genes for this disease. Thus, the increased frequency (association) or the decreased frequency (protection) of individual MHC alleles is largely explainable by these extended haplotypes.

Alleles↗
PubMed1984

HLA antigens of insulin-dependent diabetics. I. PLT colonies detecting Dw10 and a new class II determinant distinct from HLA-D, DR, MB(DC), MT, and SB.

We describe three human proliferating T cell colonies, derived from mixed leukocyte culture with a non-diabetic individual (DR3 + 4) as the source of responding cells and an insulin-dependent diabetic patient (also DR3 + 4) as the source of stimulating cells. One colony detects HLA-Dw10 or a closely related antigen, and two detect an antigen that we call BO1 (Boston 1). BO1 is found so far on cells of all persons with DR5, about half of those with DRw6, and a particular subset of those with DR3. Among DR3-positive subjects, BO1 is positively correlated with HLA-B18 and BfF1, and negatively correlated with HLA-B8. These findings suggest that BO1 occurs in linkage disequilibrium with DR5, DRw6, and the haplotype B18, BfF1, DR3, the latter being common in southern Europe and reported previously to be a marker for insulin-dependent diabetes. In limited testing (21 subjects), BO1 was completely included in the supertypic specificity MT2, BO1 is a Class II HLA antigen, as demonstrated by blocking with monoclonal antibodies, but is distinct from all known antigens of the DR, MB(DC), MT, and SB series. It could be located on the same polypeptide chain as one or more of these antigen groups, however, particularly DR and/or MT.

Adult↗
PubMed1983

Aldose reductase inhibition improves nerve conduction velocity in diabetic patients.

To assess the potential role of polyol-pathway activity in diabetic neuropathy, we measured the effects of sorbinil--a potent inhibitor of the key polyol-pathway enzyme aldose reductase--on nerve conduction velocity in 39 stable diabetics in a randomized, double-blind, cross-over trial. During nine weeks of treatment with sorbinil (250 mg per day), nerve conduction velocity was greater than during a nine-week placebo period for all three nerves tested: the peroneal motor nerve (mean increase [+/- S.E.M.], 0.70 +/- 0.24 m per second, P less than 0.008), the median motor nerve (mean increase, 0.66 +/- 0.27, P less than 0.005), and the median sensory nerve (mean increase, 1.16 +/- 0.50, P less than 0.035). Conduction velocity for all three nerves declined significantly within three weeks after cessation of the drug. These effects of sorbinil were not related to glycemic control, which was constant during the study. Although the effect of sorbinil in improving nerve conduction velocity in diabetics was small, the findings suggest that polyol-pathway activity contributes to slowed nerve conduction in diabetics. The clinical applicability of these observations remains to be determined, but they encourage further exploration of this approach to the treatment or prevention of diabetic neuropathy.

Adult↗
PubMed1981

Kinetics of an orally absorbed aldose reductase inhibitor, sorbinil.

Kinetics of sorbinil, an orally absorbed reductase inhibitor, were examined in man. Peak plasma concentrations were 0.95 micrograms/ml after a single 50-mg oral dose and 3.6 micrograms/ml after a 250-mg dose. The apparent volume of distribution was 840 ml/kg. Elimination from plasma was slow with a terminal half-life between 6 and 24 hr after dose of 34 to 52 hr and a renal clearance of 6.0 ml/min/1.73 m2. Administration of 50 mg/day for 5 days induced a mean peak serum concentration of 1.9 micrograms/ml. A dose of 250 mg/day for 10 days induced a peak serum concentration of 10.6 micrograms/ml. A mean of one-third of the dose was ultimately recovered unchanged in urine. Sorbinil kinetics make it suitable for once-a-day dosing.

Administration, Oral↗
PubMed1980

Formation of biologically active peptides.

Many small biologicaly active peptides are derived from larger precursor forms which fulfil a variety of roles in the synthesis, segregation and intracellular migration of secretory products. Limited proteolysis may occur at several stages during this process, giving rise to products that are either degraded (e.g. the prepeptides) or discharged coordinately from their cells of origin during exocytosis (e.g. insulin and C-peptide). Molecular defects have recently been found to occur at cleavage sites in proinsulin as well as in other proproteins, and these point mutations may, in some instances, be responsible for familial metabolic disorders. The nature and cell specificity of the proteolytic enzymes involved in the conversion of the various precursor forms remains unresolved. Recent studies in our laboratory have led to the identification of precursors of glucagon and somatostatin in rat islets of Langerhans. Analysis of tryptic maps of these precursors has shown that a trypsin-like enzyme would be sufficient to cleave the C-terminally located somatostatin sequence from its precursor (relative molecular mass 12,500), but that both trypsin-like and carboxypeptidase B-like enzymes would be necessary to cleave the internal glucagon sequence from its prohormone (relative molecular mass 18,000). Molecular cloning techniques have provided valuable new approaches to analysing the structures of a variety of precursor forms, including those for insulin, gastrin, growth hormone, adrenocorticotropic hormone and the endorphins, and in the future will undoubtedly shed more light on the structures of their chromosomal genes, the mechanisms regulating their expression, and their evolutionary origins.

Amino Acid Sequence↗
PubMed1980

Hyperglycemia and plasma lipid levels: a prospective study of young insulin-dependent diabetic patients.

We explored the relation of plasma lipid levels to the degree of blood glucose control in young, insulin-dependent diabetic patients. Levels of total plasma cholesterol and triglyceride, of their lipoprotein subfractions, and of hemoglobin A, and fasting blood glucose were measured repeatedly over a one-year period in 105 patients. Lipid levels were also measured in 74 nondiabetic siblings. Increasingly poor control of diabetes, reflected by levels of hemoglobin A1 or of fasting blood glucose, was associated with statistically significant increases in total cholesterol (P less than or equal to 0.01), total triglyceride (P less than or equal to 0.007), and lipoprotein subfractions except for high-density lipoprotein cholesterol. Diabetic patients in best control had lipid levels similar to those in their nondiabetic siblings. These data on the relation of plasma lipid levels to diabetic control lend credence to the hypothesis that poor control of blood glucose is conducive to accelerated atherosclerosis in diabetes mellitus.

Adolescent↗
PubMed1980

Human pancreatic polypeptide: studies in fasting and in the growth hormone deficient state.

Human pancreatic polypeptide (hPP) was measured in eight normal subjects and six growth hormone deficient dwarfs after insulin-induced hypoglycemia. hPP concentrations increased similarly in both groups with induction of hypoglycemia. In eight normal subjects fasted for 72 hours, no significant elevation of hPP occurred. This is contrary to a previous report indicating such a relationship. Despite the rationale that hPP might play a role in the metabolism of fasting and that its secretion might be altered by growth hormone, no evidence for these relationships could be documented in man.

Fasting↗