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Biomedical subjects

F M Matschinsky

Publications and source records attributed to F M Matschinsky.

At least 127 records · Page 7Linked to original sources
PubMed1983

Identification and significance of glucokinase in transplantable insulinomas.

Glucose 6-phosphotransferases were investigated in two transplantable rat insulinoma tumor lines. Homogenates of tumors contained glucose phosphorylating activities of both high (e.g. supernatant Km = 0.060 mM and pellet Km = 0.077 mM) and low (Km = 7.6 mM) affinities for glucose. Chromatography of supernatants (105,000 X g) of insulinomas on DEAE-Cibacron Blue F3GA agarose evidenced glucose 6-phosphotransferase activity which eluted similarly to glucokinase from rat liver. Kinetic studies of insulinoma glucokinase also indicated similarity with liver glucokinase, i.e. cooperative rate dependence on glucose concentration and comparable Km values for glucose, and it did not phosphorylate N-acetylglucosamine. These characteristics of glucose 6-phosphotransferase in insulinomas are similar to those of the enzyme found in islets of Langerhans. Since glucokinase is thought to serve as glucose sensor of insulin secretory pancreatic beta-cells, these transplantable insulinomas offer great promise for biochemical and biophysical studies of the nature of glucose-induced insulin release.

Adenoma, Islet Cell↗
PubMed1983

Isolation and chemical analysis of neuron soma samples from the cat cochlear nucleus.

Pieces of neuron somata were dissected from the cochlear nuclei of two cats and analyzed for activity of malic dehydrogenase, an important enzyme of oxidative metabolism. Based on location, size and shape the somata were identified as those of spherical bushy cells, octopus cells, and fusiform cells. Somata of cerebellar Purkinje cells were analyzed for comparison. The results suggest that the large cochlear nucleus neurons have malic dehydrogenase activities higher than those of most other neurons so far studied. Also, the octopus and fusiform somata had higher malic dehydrogenase activities than those of the spherical bushy cells.

Animals↗
PubMed1983

Chromatographic resolution and kinetic characterization of glucokinase from islets of Langerhans.

Glucokinase (ATP:D-glucose 6-phosphotransferase, EC 2.7.1.2) from rat islets of Langerhans was partially purified by chromatography on DEAE-Cibacron blue F3GA agarose. The enzyme eluted in two separate peaks. Sigmoidal rate dependence was found with respect to glucose (Hill coefficient = 1.5) for both enzyme fractions. Km values for glucose were 5.7 mM for the major fraction and 4.5 mM for the minor fraction. Neither fraction phosphorylated GlcNAc. A GlcNAc kinase (ATP:2-acetamido-2-deoxy-D-glucose 6-phosphotransferase, EC 2.7.1.59)-enriched fraction, prepared by affinity chromatography on Sepharose-N-(6-aminohexanoyl)-GlcNAc, had a Km of 25 microM for GlcNAc. Islet tissue also contained hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1) eluting in multiple peaks. The results are consistent with the concept that glucokinase serves as the glucose sensor of pancreatic beta cells.

Animals↗
PubMed1983

Effect of spontaneous diabetes on hormone release in BB/Phi rats: comparison between the isolated perfused pancreas/stomach/duodenum/spleen and the isolated perfused pancreas.

We have studied the effects of spontaneous diabetes in BB/Phi rats on hormone release in response to amino acids (15 mM) and to amino acids (15 mM) plus glucose (10 mM) from isolated perfused pancreas/stomach/duodenum/spleen (PSDS) and from isolated perfused pancreas (P) preparations. In the PSDS preparation, diabetes reduced total integrated insulin output by 97% (from 1146 +/- 198 to 40 +/- 24 ng/65 min, P less than 0.001), and glucagon output by about 50% (from 51.6 +/- 13.1 to 24.0 +/- 3.7 ng/65 min, P less than 0.05), whereas somatostatin output did not change (105.5 +/- 48.1 to 110.1 +/- 36.9 ng/65 min). In the P preparation, integrated glucagon output fell by 91% (from 97.9 +/- 26.8 to 8.6 +/- 4.8 ng/65 min, P less than 0.01) whereas integrated somatostatin output more than doubled (from 28.1 +/- 7.5 to 69.6 +/- 14.2 ng/65 min, P less than 0.05). Intestinal glucagon and somatostatin contributions were estimated by comparing hormone release from the PSDS with that from the P preparations. We conclude that in our nondiabetic BB/Phi rats, the pancreas was the only source for the release of glucagon and that the intestinal tract secreted more somatostatin than the pancreas. In the diabetic BB/Phi rats, pancreatic glucagon and insulin release was virtually abolished while glucagon secretion from the intestinal tract increased and somatostatin secretion decreased.

Animals↗
PubMed1983

Mannose phosphorylation by glucokinase from liver and transplantable insulinoma. Cooperativity and discrimination of anomers.

Glucokinase from rat liver or transplantable, radiation-induced insulinomas was partially purified by ion exchange chromatography using DEAE-Cibacron Blue F3GA agarose. Phosphorylation of alpha,beta-D-mannose by glucokinase occurred with cooperative rate dependence on mannose concentration (nH: 1.50). Half-maximal phosphorylation rate occurred at 14 mM alpha,beta-D-mannose. The alpha- and beta-anomers of mannose were phosphorylated with sigmoidal kinetics (nH: 1.57 and 1.42, respectively). The affinity of glucokinase for alpha-D-mannose is higher than for beta-D-mannose (S0.5: 12 mM versus 19 mM). The maximum phosphorylation rate is slightly higher, about 10%, with beta-D-mannose than with alpha-D-mannose. Islet glucokinase has previously been shown to be chromatographically and kinetically identical to glucokinase from insulinoma and liver; therefore, evidence that glucokinase from these two tissues phosphorylates mannose with cooperative rate dependence and differentiates mannose anomers supports the glucokinase-glucose sensor hypothesis.

Adenoma, Islet Cell↗
PubMed1982

Quantitative histochemical resolution of the oxidation-reduction and phosphate potentials within the simple hepatic acinus.

Glycerin-3-P, commonly known as alpha-glycerophosphate and dihydroxyacetone phosphate (DHAP) were measured in well defined microscopic samples of the simple liver acinus allowing a comparison of the glycerin-3-P/dihydroxyacetone-P-ratios of Zones 1 and 3 as a measure of the free NAD+/NADH ratio. The ATP/ADP X Pi quotients were determined in these same microscopic areas of the liver acinus as a measure of the phosphate potential. Brief ischemia was used to disturb the system. The results indicate that the oxidation-reduction and phosphate potentials are uniform throughout the entire liver lobule.

Animals↗
PubMed1982

Distribution of myo-inositol in the cat cochlear nucleus.

The distribution of myo-inositol, a substance that has been implicated in synaptic transmission, has been mapped within sections of the cat cochlear nucleus as well as some nearby regions. Highest values in the cochlear nucleus were found in regions of granule cells along the periphery of the anteroventral subdivision of the nucleus. Highest values overall were found in the molecular layer of the cerebellar flocculus. A fairly good correlation was found between myo-inositol levels and activities of the enzymes of acetylcholine metabolism in the cat cochlear nucleus, supporting the possibility that myo-inositol may be involved in cholinergic synaptic transmission. No positive correlation was found between myo-inositol levels and the levels of glutamate, aspartate, glycine, or gamma-aminobutyric acid (GABA). The most striking gradient of myo-inositol levels within a region was found in the auditory nerve, where different myo-inositol levels might be related to nerve fibers innervating different parts of the cochlea. The distribution of scyllo-inositol, a stereoisomer of myo-inositol, was also examined, and found to parallel closely the distribution of myo-inositol, with levels 4--5% as high.

Acetylcholinesterase↗
PubMed1982

Metabolic and underlying causes of diabetes mellitus.

It is emphasized that animal models should be used to study specific genotypic or phenotypic expressions associated with diabetes rather than assuming a single animal model can reflect diverse forms of the human disease. Diabetic and normal animals are reviewed on the basis of their usefulness as models of genetic, viral, and chemically induced diabetes, including the often associated immune phenomena. Characteristics of spontaneously diabetic animals with and without obesity are also described with an emphasis on both genetics and metabolic derangements. Recommendations for future animal experimentation include: more longitudinal studies evaluating the role of sex, prenatal environment, diet, and viral or chemical attack on B-cell function; characterization of the immune phenomena associated with B-cell lesions (and insulitis) in diabetic and immunologically incompetent lines; clarification of relationships between obesity and islet-cell function with emphasis on the role of fuel metabolism, vitamins, and minerals; and, finally, the development of new models with specific genetic aberrations placed in normal or diabetic lines.

Alloxan↗
PubMed1981

Effects of starvation and obesity on somatostatin, insulin, and glucagon release from an isolated perfused organ system.

We have studied the effects of starvation and of obesity on somatostatin, insulin, and glucagon release from an isolated perfused organ system in fed and 3- and 5-day fasted Holtzman rats and in obese (fa/fa) and lean (Fa/?) Zucker rats. Fasting for 3 days significantly decreased basal (-71%) and amino acid-stimulated (-62%) somatostatin output. After 5 days of starvation, there was a significant increase over the 3-day level in somatostatin output stimulated by amino acid plus glucose (+540%) and by amino acids plus tolbutamide (+238%). Three and five days of starvation severely depressed insulin output while having no statistically significant effects on glucagon secretion. Somatostatin output from obese Zucker rats was significantly greater than that from lean controls in response to amino acids (41.2 +/- 13.2 vs. 16.3 +/- 10.3 ng/25 min, P less than 0.05). Insulin output was greatly increased from obese compared to lean Zucker rats, whereas there were no statistically significant differences in glucagon output. These data show that fasting decreases and obesity increases both somatostatin and insulin release. They suggest that altered stimulation by nutrients was primarily responsible for changes in somatostatin and insulin release observed in starving and obese rats.

Amino Acids↗
PubMed1981

Quantitative distribution of choline acetyltransferase and acetylcholinesterase activities in the rat cochlear nucleus.

Within the cochlear nucleus of the rat, as well as some nearby regions, quantitative histochemical mapping procedures were used to construct maps of the distributions of choline acetyltransferase and acetylcholinesterase activities. The results were in some ways consistent with results previously reported for cat, e.g., very low activities of both enzymes were found in the auditory nerve root, and also in the vestibular nerve root, except where acetylcholinesterase-positive centrifugal fibers are located, very high activities were found in the facial nerve system. In many ways, however, the results for the rat cochlear nucleus contrasted with those for the cat. Notably, choline acetyltransferase activities in some regions of the rat cochlear nucleus were as much as 30- to 60-fold higher than for the comparable regions in the cat, and both enzymes had much more uniform distributions in the rat cochlear nucleus than in the cat. The more prominent cholinergic system in the rat cochlear nucleus might relate to a proportionately larger population of cholinergic interneurons, or, more probably, a more significant innervation by cholinergic, centrifugal pathways, or both, as well as, perhaps, generally higher choline acetyltransferase activities in cholinergic neurons of rat.

Acetylcholinesterase↗
PubMed1981

Regulation of glucose metabolism in pancreatic islets.

We evaluated the possible role of islet glucokinase in controlling the rate of islet glucose metabolism, and thereby the rate of glucose-induced insulin release. The activities of glucokinase, hexokinase, P-fructokinase, and glyceraldehyde-P dehydrogenase were quantitated in sonicated or isotonically homogenized islet preparations using pyridine nucleotide-dependent fluorometric assays. In sonicates, about 1/4 of the islet glucose phosphorylating activity was due to an enzyme with kinetic properties similar to glucokinase; 3/4 of the activity was due to hexokinase. The procedure for determining islet glucokinase activity was improved by centrifuging isotonic islet homogenates at 12,000 x g. The supernatant fraction was enriched for glucokinase. About 1/2 of the glucose phosphorylating activity in this fraction was due to glucokinase and 1/2 was due to hexokinase. The glucokinase activity in islet homogenates was !23 of the activity of hexokinase, 1/40 of the activity of P-fructokinase, and 1/400 of the activity of glyceraldehyde-P dehydrogenase. Detailed concentration dependency curves of glucose and mannose utilization were also obtained with intact isolated pancreatic rat islets. Glucose and mannose usage in islets was governed by two superimposed hyperbolic systems differing in Km and Vmax. A high Km system (Km for glucose 11 mM and for mannose 21 mM) predominated. A low Km system (Km for glucose 215 and for mannose 530 microM) contributed about 15% to the total activity. The available data with intact islets could be rationalized by the existence of two distinct hexose phosphorylating enzymes with differing capacities and kinetic properties. These enzymes, tentatively identified as glucokinase and hexokinase, could coexist in the same cell or could be distributed among different cell types. The possible physiologic significance of these results is discussed, emphasizing the idea of dual control of glycolysis and insulin release by glucokinase and hexokinase. An earlier proposal that glucokinase serves as glucoreceptor of beta-cells [J. Biol. Chem. 243:2730 (1968)] is greatly strengthened by the present studies.

Animals↗
PubMed1981

Adaptation of glycolytic enzymes: glucose use and insulin release in rat pancreatic islets during fasting and refeeding.

Starvation refeeding experiments were conducted in rats to test the hypothesis that adaptation of glucokinase (the high Km component of glucose phosphorylation) could be the major determinant of glucose metabolism of pancreatic islet cells and of glucose-stimulated insulin release. It was found that glucokinase of islet homogenates, glucose use by intact isolated islets, and glucose-induced insulin release as studied in a perifusion system were decreased after 24 h of fasting, whereas P-fructokinase and 3-P-glyceraldehyde DH were unaltered. After extended fasting (e.g., 120 h) all three enzymes were decreased but glucose use did not change any further. Refeeding normalized all parameters. These and previous results support the concept that glucokinase serves as the adaptive beta-cell glucoreceptor relating blood glucose to insulin release.

Animals↗
PubMed1980

Adaptations of alpha2- and beta-cells of rat and mouse pancreatic islets to starvation, to refeeding after starvation, and to obesity.

The effects of starvation and refeeding and of obesity on pancreatic alpha2- and beta-cell responses to glucose or tolbutamide were studied with the isolated rat or mouse pancreas perfused with an amino acid mixture in the presence and absence of glucose. It was observed that the physiological adaptation to a regimen of fasting and realimentation and to obesity differed greatly in the two types of endocrine cells. Whereas beta-cells of rats showed a dramatic reduction of glucose- and tolbutamide-stimulated insulin release during starvation that was reversed by refeeding, alpha2-cells preserved their response to stimulators and inhibitors during this experimental manipulation. Amino acid stimulation of glucagon release occurred equally well with the pancreas from fed and starved rats and was suppressed efficiently by glucose and tolbutamide in both nutritional states. Surprisingly, the rate of onset of glucose suppression of alpha2-cells was significantly higher in the fasted than in the fed state. This glucose hypersensitivity was apparent 2 d after after food deprivation and had disappeared again on the 2nd d of refeeding. In the pancreas from animals starved for 3 d, glucose and tolbutamide suppression of alpha2-cells took place in the absence of demonstrable changes of insulin release. In the isolated perfused pancreas taken from the hyperphagic obese hyperglycemic mouse (C57 Black/6J; ob/ob), the observed rate of insulin secretion as a result of a combined stimulus of amino acids and glucose and of glucagon release stimulated by amino acids was about four times higher than achieved by the pancreas of lean controls. However, glucose was unable to suppress the alpha2-cells in the pancreas of obese animals, in spite of the hypersection of the beta-cells, again in contrast to the alpha2-cells of controls that were readily inhibited by glucose. These data imply that the acute suppression of alpha2-cells by glucose is largely independent of a concomitant surge of extracellular insulin levels and that the adaptation of the islet organ to starvation leads to decreased glucose sensitivity of beta-cells, which contrasts with an improved glucose responsiveness of alpha2-cells. However, hyperphagia, which is assumed to be the primary abnormality in the ob/ob mouse, leads to overproduction of insulin and glucagon by the pancreas while greatly reducing the alpha2-cell sensitivity to glucose. An attempt is made to incorporate these data on starvation, refeeding, and obesity, as well as previous results with experimental diabetes, in a comprehensive picture describing a regulative principle underlying the glucose responsivness of alpha2-cells.

Adaptation, Physiological↗
PubMed1980

Effect of intervening lesions on amino acid distributions in rat olfactory cortex and olfactory bulb.

Levels of the proposed neurotransmitter amino acids glutamate, aspartate, gamma-aminobutyric acid (GABA), and glycine were measured within the layered structures of the olfactory bulb and olfactory cortex following unilateral transections of the lateral olfactory tract or of virtually all fiber tracts of the olfactory peduncle. Distributions of the amino acids on both lesion and control sides were examined and compared by means of a mapping procedure. The results suggest: 1) Glutamate and aspartate are specifically associated with mitral (and presumably also tufted) cell axons and terminals in the piriform cortex. The distribution of aspartate in the olfactory bulb is further suggestive of a specific association of aspartate with mitral cell dendrites and somata. 2) Glutamate might be specifically associated with some centrifugal fibers traveling to the olfactory bulb in or near the anterior commissure. 3) GABA might be specifically related to some certrifugal fibers to the olfactory bulb in addition to its prominent association with granule cells of the bulb. 4) Glycine is unlikely to play a prominent neurotransmitter role in either the olfactory bulb or olfactory cortex.

Amino Acids↗
PubMed1980

Pirogliride: an oral hypoglycemic drug which accelerates glucose usage and insulin secretion by islets of Langerhans.

Pirogliride potentiates glucose-induced insulin secretion from isolated islets. This effect is accompanied by a facilitated glucose metabolism. Pirogliride partially prevents the known inhibitory effects of mannoheptulose on glucose-induced secretion and utilization. Pirogliride might be useful not only to probe the underlying mechanism of stimulated insulin secretion but also in the therapy of those diabetics who have an impaired beta-cell responsiveness to glucose.

Animals↗
PubMed1979

Metabolism and insulin-releasing capabilities of glucosamine and N-acetylglucosamine in isolated rat islets.

The ability of glucosamine and N-acetylglucosamine to stimulate insulin secretion from perifused rat islets and the suitability of these hexoses to be metabolized in a static incubation was studied under various conditions. N-Acetylglucosamine alone stimulated insulin release with a threshold of 10 mM, with half-maximal effect at approx. 16 mM, and maximally at 20 mM. With higher concentrations stimulation was slightly diminished. Release caused by 20 mM-N-acetylglucosamine was unaffected by 30 mM-mannoheptulose, but was blocked by 2-deoxyglucose or iodoacetate (1 mM). At moderate concentrations, (2.75--20 mM), the metabolism of N-acetyl[1-3H]glucosamine was similar to that of [1-3H]glucose and secretion rates paralleled the corresponding rates of metabolism with these hexoses. Glucosamine (27.5 mM) alone weakly stimulated insulin secretion, which was unaltered by 30 mM-mannoheptulose but blocked by 2-deoxyglucose or iodoacetate. A lower rate of [1-3H]glucosamine metabolism appeared to account for its weaker stimulatory efficacy. Insulin release caused by 27.5 mM-glucosamine or 27.5 mM-N-acetylglucosamine in the presence of basal (2.75 mM) glucose was accurately predicted based on the summed metabolic rates of these compounds. The data strengthen the theory proposing that metabolites or cofactors generated during metabolism are essential for triggering insulin secretion.

Acetylglucosamine↗