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M J MacDonald

Publications and source records attributed to M J MacDonald.

At least 109 records · Page 6Linked to original sources
PubMed1988

Regulation of insulin release by factors that also modify glutamate dehydrogenase.

Leucine and monomethyl succinate initiate insulin release, and glutamine potentiates leucine-induced insulin release. Alanine enhances and malate inhibits leucine plus glutamine-induced insulin release. The insulinotropic effect of leucine is at least in part secondary to its ability to activate glutamate oxidation by glutamate dehydrogenase (Sener, A., Malaisse-Lagae, F., and Malaisse, W. J. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 5460-5464). The effect of these other amino acids or Krebs cycle intermediates on insulin release also correlates with their effects on glutamate dehydrogenase and their ability to regulate inhibition of this enzyme by alpha-ketoglutarate. For example, glutamine enhances insulin release and islet glutamate dehydrogenase activity only in the presence of leucine. This could be because leucine, especially in the presence of alpha-ketoglutarate, increases the Km of glutamate and converts alpha-ketoglutarate from a noncompetitive to a competitive inhibitor of glutamate. Thus, in the presence of leucine, this enzyme is more responsive to high levels of glutamate and less responsive to inhibition by alpha-ketoglutarate. Malate could decrease and alanine could increase insulin release because malate increases the generation of alpha-ketoglutarate in islet mitochondria via the combined malate dehydrogenase-aspartate aminotransferase reaction, and alanine could decrease the level of alpha-ketoglutarate via the alanine transaminase reaction. Monomethyl succinate alone is as stimulatory of insulin release as leucine alone, and glutamine enhances the action of both. Succinyl coenzyme A, leucine, and GTP are all bound in the same region on glutamate dehydrogenase, where GTP is a potent inhibitor and succinyl coenzyme A and leucine are comparable activators. Thus, the insulinotropic properties of monomethyl succinate could result from it increasing the level of succinyl coenzyme A and decreasing the level of GTP via the succinate thiokinase reaction.

Alanine↗
PubMed1988

Isolation and characterization of rat cDNA clones for two distinct thyroid hormone receptors.

Two distinct v-erbA-related cDNA clones representing the products of different genes were isolated from a rat liver cDNA library. The first, rc-erbA-alpha, was 82% identical to v-erbA and encoded a polypeptide with a calculated molecular mass of 45,000 daltons. This cDNA clone arises from the same gene product as a v-erbA-related cDNA isolated from rat brain by Thompson et al. (Thompson, C. C., Weinberger, C., Lebo, R., and Evans, R. (1987) Science 237, 1610-1614). The second cDNA clone, rc-erbA-beta, was 76% identical to v-erbA and encoded a polypeptide with a calculated molecular mass of 52,000 daltons. Both rc-erbA-alpha and rc-erbA-beta translational products bound 3,5,3'-triiodo-L-thyronine with affinities equal to each other (Kd approximately equal to 0.4 nM) and comparable to the nuclear thyroid hormone receptor extracted from rat liver. The relative affinities of a series of thyroid hormone analogs for both translational products were also identical. In various tissues and cell lines, the relative levels of rc-erbA-beta RNA, but not rc-erbA-alpha RNA, correlated with measurements of nuclear 3,5,3'-triiodo-L-thyronine binding sites. Based on this correlation, we suggest that rc-erbA-beta may encode the "classical" nuclear thyroid hormone receptor, whereas rc-erbA-alpha may encode an isoreceptor species with differing functional properties.

Amino Acid Sequence↗
PubMed1988

Regulation of malate dehydrogenase activity by glutamate, citrate, alpha-ketoglutarate, and multienzyme interaction.

Binding experiments indicate that mitochondrial aspartate aminotransferase can associate with the alpha-ketoglutarate dehydrogenase complex and that mitochondrial malate dehydrogenase can associate with this binary complex to form a ternary complex. Formation of this ternary complex enables low levels of the alpha-ketoglutarate dehydrogenase complex, in the presence of the aminotransferase, to reverse inhibition of malate oxidation by glutamate. Thus, glutamate can react with the aminotransferase in this complex without glutamate inhibiting production of oxalacetate by the malate dehydrogenase in the complex. The conversion of glutamate to alpha-ketoglutarate could also be facilitated because in the trienzyme complex, oxalacetate might be directly transferred from malate dehydrogenase to the aminotransferase. In addition, association of malate dehydrogenase with these other two enzymes enhances malate dehydrogenase activity due to a marked decrease in the Km of malate. The potential ability of the aminotransferase to transfer directly alpha-ketoglutarate to the alpha-ketoglutarate dehydrogenase complex in this multienzyme system plus the ability of succinyl-CoA, a product of this transfer, to inhibit citrate synthase could play a role in preventing alpha-ketoglutarate and citrate from accumulating in high levels. This would maintain the catalytic activity of the multienzyme system because alpha-ketoglutarate and citrate allosterically inhibit malate dehydrogenase and dissociate this enzyme from the multienzyme system. In addition, citrate also competitively inhibits fumarase. Consequently, when the levels of alpha-ketoglutarate and citrate are high and the multienzyme system is not required to convert glutamate to alpha-ketoglutarate, it is inactive. However, control by citrate would be expected to be absent in rapidly dividing tumors which characteristically have low mitochondrial levels of citrate.

Animals↗
PubMed1988

Speculation on the evolution of insulin-dependent diabetes genes.

A hypothesis about the evolution of insulin-dependent diabetes mellitus (IDDM)-susceptibility alleles is proposed. IDDM is known to be associated with two HLA-DR alleles, DR3 and DR4. DR3 is associated with IDDM in all ethnoracial groups including populations in which IDDM is rare, such as African and Asian populations, as well as whites in whom IDDM is common. However, in general, DR4 is associated with IDDM only in populations with white ancestry with high rates of IDDM. IDDM in American blacks illustrates the evolutionary patterns of the two diabetes alleles. The frequency of IDDM in American blacks relative to that in American whites (20% to 30%) approximates the frequency of the American black gene pool that is white-derived (also 20% to 30%), and DR4 is associated with IDDM in American blacks but not in African blacks. These data are consistent with the infusion of a dominant white-derived DR4-associated diabetes allele into the black gene pool. Recent studies of mitochondrial DNA suggest that modern humans evolved in Africa 200,000 to 300,000 years ago and that repeated migrations populated the world. The DR-population:IDDM-frequency relationships suggest that the DR3-associated diabetes allele evolved early (greater than or equal to 100,000 years ago) in Africa, whereas the DR4-associated diabetes allele evolved later (less than 15,000 years ago) in northern Europe. Recent data from studies of IDDM in families and populations which suggest that the DR4-associated allele has dominant characteristics and the DR3-associated allele has recessivelike characteristics fit into this hypothesis.

Alleles↗
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↗
PubMed1988

Glyceraldehyde phosphate and methyl esters of succinic acid. Two "new" potent insulin secretagogues.

We discovered that two physiologically occurring metabolic intermediates, glyceraldehyde phosphate and succinate, are potent insulin secretagogues. No other glycolytic intermediate besides glyceraldehyde phosphate was insulinotropic. Succinate, when added to islets as either its monomethyl or dimethyl ester to increase its cellular permeability, was also insulinotropic. In islets, as in other cell types, these esters are apparently hydrolyzed intracellularly to succinate. Unesterified succinate and other unesterified citric acid-cycle intermediates did not stimulate insulin release. Initiation of insulin release by esters of succinate suggests that mitochondrial metabolism alone is sufficient to initiate and support insulin release. However, this is specific for succinate in that esters of fumarate, pyruvate, and citrate were not insulinotropic.

Animals↗
PubMed1988

Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus.

From 11 studies, a total of 1,792 Caucasian probands with insulin-dependent diabetes mellitus (IDDM) are analyzed. Antigen genotype frequencies in patients, transmission from affected parents to affected children, and the relative frequencies of HLA-DR3 and -DR4 homozygous patients all indicate that DR3 predisposes in a "recessive"-like and DR4 in a "dominant"-like or "intermediate" fashion, after allowing for the DR3/DR4 synergistic effect. Removal of DR3 and DR4 reveals an overall protective effect of DR2, predisposing effects of DR1 and DRw8, and a slight protective effect of DR5 and a predisposing effect of DRw6. Analysis of affected-parent-to-affected-child data indicates that a subset of DR2 may predispose. The non-DR3, non-DR4 antigens are not independently associated with DR3 and DR4; the largest effect is a deficiency of DR2, followed by excesses of DR1, DRw8, and DRw6, in DR4 individuals, as compared with DR3 individuals. HLA-B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. The presence or absence of Asp at position 57 of the DQ beta gene, recently implicated in IDDM predisposition, is not by itself sufficient to explain the inheritance of IDDM. At a minimum, the distinguishing features of the DR3-associated and DR4-associated predisposition remain to be identified at the molecular level. Risk estimates for sibs of probands are calculated based on an overall sibling risk of 6%; estimates for those sharing two, one, or zero haplotypes are 12.9%, 4.5%, and 1.8%, respectively. Risk estimates subdivided by the DR type of the proband are also calculated, the highest being 19.2% for sibs sharing two haplotypes with a DR3/DR4 proband.

Adolescent↗
PubMed1987

Potentiation by glucose metabolites of inositol trisphosphate-induced calcium mobilization in permeabilized rat pancreatic islets.

Saponin-permeabilized rat pancreatic islets degraded exogenously added inositol 1,4,5-trisphosphate (IP3), and degradation was inhibited in the presence of either fructose 1,6-bisphosphate or diphosphoglycerate. The addition of either fructose-1,6-P2 or diphosphoglycerate to 45Ca2+-labeled permeabilized islets potentiated 45Ca2+ release caused by IP3 (by either exogenously added IP3 or IP3 generated endogenously in the presence of carbachol or guanosine 5'-3-O-(thio)triphosphate (GTP gamma S). The effect of diphosphoglycerate and fructose-1,6-P2 on 45Ca2+ release correlated well with the effects of these agents on the recovery of radioactivity in IP3. These results further support our previous proposal that in pancreatic islets intracellular calcium mobilization may be sustained in part via the inhibition of IP3 degradation by metabolites produced during stimulation with insulinotropic concentrations of glucose (Rana, R.S., Sekar, M.C., Hokin, L.E., and MacDonald, M.J. (1986) J. Biol. Chem. 261, 5237-5240).

Animals↗
PubMed1987

Cooperative interaction between factor VII and cell surface-expressed tissue factor.

Assembly of the extrinsic pathway on cell surfaces was investigated by studying the binding and activity of factor VII on the bladder carcinoma cell line J82 which expressed 18,800 milliunits of tissue factor activity/10(6) cells. In binding studies, the association of factor VII to monolayers of cells was time-, temperature-, and calcium-dependent. The ligand binding was specific, reversible, and saturable. This interaction was inhibited by a monoclonal antibody to human brain tissue factor. Factor VII added to the cells was recovered as factor VII rather than factor VIIa when incubated in the presence of factor X neutralizing antibodies, suggesting that these cells produced factor X. Specific factor VII binding to the cell revealed a sigmoidal binding isotherm with half-maximal binding occurring at 314 +/- 145 pM to 38,300 +/- 14,300 sites/cell. Hill plots of the binding data indicated an average slope of 2.1. Binding parameters were also determined kinetically. At maximal factor VII-tissue factor complex formation the apparent Km for factor X was 274 nM, the Vmax was 4.15 nM/min, and the kcat was estimated to be 14 s-1. In the presence of excess tissue factor and factor X, increasing amounts of factor VII added to the J82 cells demonstrated a sigmoidal relationship with the rate of factor Xa formation. Hill plots indicated a slope of 2.0 at the lower factor VII concentrations which changed to 1.0 at the higher input amounts of factor VII. Hanes plots were used to determine the apparent dissociation constant of the interaction (222 +/- 85 pM). The Vmax was 5.54 +/- 1.04 nM/min for the cleavage of factor X. These data are consistent with factor VII binding to at least two sites on tissue factor (receptor) with positive cooperativity. Because at saturation the stoichiometry of the factor VII-tissue factor complex is 1:1, tissue factor must be expressed as a dimer on the surface of the J82 cells.

Antibodies, Monoclonal↗
PubMed1987

Seasonality in glycosylated hemoglobin in normal subjects. Does seasonal incidence in insulin-dependent diabetes suggest specific etiology?

Seasonality in the diagnosis of insulin-dependent diabetes mellitus (IDDM), i.e., increased incidence in winter, was the impetus for this study of seasonality in glycosylated hemoglobin levels in nondiabetics. Glycosylated hemoglobin levels of 35 nondiabetic children and adults were highest at the ends of autumn and winter and lowest at the ends of spring and summer (P less than 10(-4)). This result is consistent with reports of seasonal variation in blood glucose, with the highest levels occurring in winter, as well as reports that suggest an internal milieu of increased counterinsulin action in winter due to seasonality in counterinsulin hormones, dietary factors, body weight, amount of exercise, growth rates in children, and ambient temperature. IDDM is caused by the gradual destruction of the pancreatic insulin-producing cells via lymphocytic infiltration--a process that may occur over years. We conclude that a decreased carbohydrate tolerance associated with winter can explain the seasonal variation in the incidence of IDDM and that this seasonality is caused by the precipitation of overt carbohydrate intolerance in individuals with already seriously compromised insulin secretory capacity. This implies that seasonality is not very formative about the cause of the destruction of pancreatic insulin-producing cells.

Adolescent↗
PubMed1987

Canine diabetes mellitus has a seasonal incidence: implications relevant to human diabetes.

A 3 year survey of practicing veterinarians in the State of Wisconsin revealed a strong seasonal variation (peak incidence in January and February) for spontaneous canine diabetes mellitus (SCDM) in pet dogs. This seasonal incidence was quite similar to that observed in insulin-dependent diabetes mellitus (IDDM) in humans. SCDM is etiologically heterogeneous, it has dissimilar etiologies as compared to IDDM, and it is unlikely that viral infections play a causal role. For these reasons, it is concluded that the finding of a similar seasonal incidence in SCDM and IDDM suggests that the seasonal incidence of IDDM most likely represents the effects of, as yet undefined, stresses which precipitate the diabetic state in humans and dogs with pre-existent islet dysfunction of varying causes.

Animals↗
PubMed1986

A possible role for glucose metabolites in the regulation of inositol-1,4,5-trisphosphate 5-phosphomonoesterase activity in pancreatic islets.

Rat pancreatic islets demonstrate inositol-1,4,5-trisphosphate 5-phosphomonoesterase activity which is 3 times higher than that in the exocrine pancreas. This enzyme has several features in common with the erythrocyte and hepatocyte enzymes: it is located primarily in the plasma membrane, it has a similar Km for inositol trisphosphate (IP3) (16 microM), and it requires Mg2+. The activity of the islet enzyme is inhibited by several diphosphorylated glucose metabolites: 2,3-bisphosphoglycerate, fructose 1,6-bisphosphate, fructose 2,6-bisphosphate, and glucose 1,6-bisphosphate. Monophosphorylated and unphosphorylated metabolites have little or no effect on its activity. Several reports show that stimulation of islets with glucose raises the concentrations of various glucose metabolites including fructose 1,6-bisphosphate, glucose 1,6-bisphosphate, and 2,3-bisphosphoglycerate to concentrations that are in the range that inhibit the islet inositol-1,4,5-trisphosphate 5-phosphomonoesterase. Other reports show that IP3 mobilizes calcium when added to permeabilized insulin-secreting cells. It is possible that the increase in cytosolic calcium known to occur during glucose-induced insulin secretion may be sustained in part by higher IP3 levels resulting from the inhibition of inositol-1,4,5-trisphosphate 5-phosphomonoesterase by some of the diphosphorylated glucose metabolites.

2,3-Diphosphoglycerate↗
PubMed1986

Enzymes of phospholipid metabolism in rat pancreatic islets: subcellular distribution and the effect of glucose and calcium.

The effect of glucose and calcium on the activities of the phosphatidylinositol cycle enzymes, CDP-diglyceride inositol transferase, diacylglycerokinase, and lysophosphatidylcholine 2-acyltransferase in rat pancreatic islets was studied. Calcium inhibited the activity of CDP-diglyceride inositol transferase but had no effect on lysophosphatidylcholine 2-acyltransferase and diacylglycerokinase activities. Upon preincubation of islets in a concentration of glucose known to stimulate insulin release, the activity of lysophosphatidylcholine 2-acyltransferase, but not that of diacylglycerokinase or the CDP-diglyceride inositol transferase, was stimulated. Subcellular fractionation of pancreatic islets showed that secretory granule membranes were enriched in CDP-diglyceride inositol transferase, whereas lysophosphatidylcholine 2-acyltransferase activity was highest in the microsomal membranes. The activation of 2-acyltransferase by incubating islets in insulinotropic glucose, and the calcium sensitivity of CDP-diglyceride inositol transferase, suggest that these enzymes may have roles in regulation of insulin secretion.

Acyltransferases↗
PubMed1986

Secretagogue-responsive and -unresponsive pools of phosphatidylinositol in pancreatic islets.

The effect of glucose on phosphatidylinositol turnover was studied. Phosphatidylinositol of rat pancreatic islets was labeled with myo[2-3H]inositol in the presence of various secretagogues (16.7 mM D-glucose, 22 mM D-mannose, 20 mM D-glyceraldehyde) and nonsecretagogues (3.3 mM D-glucose, 20 mM pyruvate, 16.7 mM D-galactose, 16.7 mM L-glucose). Upon subsequent stimulation with 16.7 mM D-glucose, only the islets that were labeled in the presence of secretagogues showed a loss of radioactivity from phosphatidylinositol. No loss of radioactivity from phosphatidylinositol occurred in the presence of 3.3 mM D-glucose even after labeling in the presence of secretagogues. A comparison of the subcellular distribution of labeled phosphatidylinositol in islets before and after stimulation with insulinotropic glucose revealed a loss of radioactivity from the plasma membrane fraction as judged by subcellular fractionation with a sucrose gradient. These results support a hypothesis advanced previously that pancreatic islets contain a unique pool of phosphatidylinositol that undergoes rapid turnover only in the presence of insulinotropic concentrations of D-glucose or other secretagogues [R. S. Rana, R. J. Mertz, A. Kowlura, J. F. Dixon, L. E. Hokin, and M. J. MacDonald (1985) J. Biol. Chem. 260, 7861-7867]. On the basis of the subcellular fractionation studies reported here, the secretagogue-responsive phosphatidylinositol pool appears to be located primarily in the plasma membrane of pancreatic islets.

Animals↗
PubMed1986

Phosphatidylinositol kinase in rat pancreatic islets: subcellular distribution and sensitivity to calcium.

Plasma membrane of pancreatic islets contains a calcium sensitive phosphatidylinositol kinase. This enzyme catalyzes the first reaction in the pathway leading to the production of inositol trisphosphate, which is believed to cause a redistribution of intracellular calcium. Since the activity of this enzyme is inhibited by calcium (K0.5 = 10 microM), a loss of calcium from plasma membrane (the site of PI kinase) may be necessary for activation of the enzyme in vivo.

1-Phosphatidylinositol 4-Kinase↗