Hexose Anomers, Insulin Release, and Diabetes Mellitus A
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Biomedical Research l, 189--206 (1980) HEXOSE ANOMERS, INSULIN RELEASE, AND DIABETES MELLITUS A . ATSUSI-II NIKI and HATSUMI NIKI Department of Internal Medicine, School of Dentistry, Aichigakuin University, Chikusa-ku, Nagoya 464, Japan REVIEW A most fundamental problem concerning the mechanism of glucose-stimulated insulin release is the question as to whether glucose acts via its metabolism or via binding to a receptor, leading to two opposing hypotheses, the metabolism and glucoreceptor hypo- theses. The major arguments in support of either of these hypotheses are briefly review- ed. Special emphasis is laid on findings with respect to the insulinotropic actions of hexose anomers and their metabolism in pancreatic islets. Anomeric specificity in cel- lular processes other than insulin release are also summarized. Our current view is that adult-onset-type diabetes mellitus is, at least in some respects, due to a generalized disorder of glucoreceptors in the neuron-paraneuron system. INTRODUCTION creatic B cell recognizes glucose as a signal for insulin release. According to the metabolism Glucose is one of the most fundamental fuel substances for the majority of living cells. In hypothesis (the substrate-site hypothesis), the addition, in several cells, it serves as a signal to signal for insulin release is generated by the initiate a specific physiological response. An metabolism of glucose in the B cell in the form excellent example of this dual function of glu- of a metabolite or cofactor. In more general terms, stimulus recognition may be a function cose is its action on the pancreatic B cell where- by it acts to release insulin from the B cell and of energy, of phosphate or redox potentials, or to provide energy for the releasing process by of the intracellular pH as altered by the meta- being metabolized. Whether one can differenti- bolic process. In the glucoreceptor hypothesis ate the signal efiect of glucose from its role as (the regulator-site hypothesis), glucose is a fuel has been a major subject of investigation thought to combine with a specific receptor into the physiology and patho-physiology of molecule, possibly, but not necessarily, located pancreatic islets. We shall briefly review areas on the B-cell membrane. in which advances are being made in the under- Subtle models were even olfered to reconcile standing of the mechanism by which the pan- both hypotheses, postulating that the two creatic B cell recognizes glucose as a signal for mechanisms may function simultaneously. insulin release, with special emphasis upon As the major arguments in support of the metabolism hypothesis, Malaisse er al. adopted findings from the experiments using hexose anomers. the following (64). (i) The relative insulinotrop- ic capacity of different sugars (glucose, man- nose, fructose, galactose, sorbitol, erythrose, THE METABOLISM AND GLUCORECEP- and glyceraldehyde) correlates with their apti- TOR HYPOTHESES tude to be metabolized in the islet cells. (ii) Two major hypotheses have been proposed as The more marked insulinotropic capacity of n’- to the molecular mechanisms by which the pan- D-glucose, as distinct from ,3-D-glucose, coin- 190 A. NIKI and H. NIKI cides with a higher glycolytic rate due to the mit the message of altered substrate availability stereospecificity of the enzyme phosphoglucose and catabolism to the hormone releasing ma- isomerase for a"-D-glucose-6-phosphate. (iii) It chinery of the islet cell, since r.t-ketoisocapro- is possible to stimulate insulin release in the ate, the metabolism of which is unrelated to absence of extracellular glucose by provoking that of glucose, is as potent as glucose in stim- glycogenolysis and glycolysis from endogenous ulating insulin release (l27, 51). Such general stores of glycogen. -i metabolic parameters have been reviewed in (i) It is well established that only metaboliza— detail (4, 64). ble sugars can stimulate insulin release, while One main feature of the response of the pan- nonmetabolizable ones are poorly active (44, 4, creatic B cell to glucose is its rapidity. When 124). The dose-response curve for glucose- stimulated by a constant concentration of glu- induced insulin release is sigmoidal; the thresh- cose, the pancreas releases insulin biphasically old glucose concentration is 4-5 mM, and the (37, 64): the biphasic secretory response con- half-maximum and maximum responses to glu- sists of a rapid early insulin peak followed by cose occur at 8—l0 mM and l5—25 mM, respec- a more prolonged second phase persisting tively (5, 37, 64). Rates of glucose utilization, throughout the period of stimulation. Mat- glucose oxidation and lactate formation are re- schinsky er 01. (70) have argued against the ported to be closely related to rates of insulin metabolism hypothesis on the grounds that release with varying glucose concentrations most of the metabolites and cofactors measured (5, 64). However, limited association between in rat islets were unchanged during the first 5 metabolic and insulin releasing efficiency of min of glucose stimulation, even though insulin glucose was also reported, and methodological release could be detected within l min after problems in metabolic studies were discussed injecting glucose. Other studies, however, do (126). Results with a number of inhibitors of not support this contention. Rapid changes in sugar metabolism show that blockade of glyco- concentration of hexose phosphates (6, 52) and lytic flux is accompanied by inhibition ofinsulin in pyridine nucleotide fluorescence (92) have release. For example, D-mannoheptulose which been reported in islets exposed to high concen- inhibits glucose phosphorylation blocks in par- trations of glucose. Thus, available data, but allel the metabolism and insulin-releasing ac- not all, on kinetics of changes in metabolic par- tions of glucose (5). The eflects of other inhib- ameters in islets are consistent with the meta- itors on the release of insulin are also well cor- bolism hypothesis. related with their effects on glucose metabolism (ii) Anomeric specificity of the secretory re- (127, 4). The theoretical possibility that the in- sponse to glucose will be discussed in the fol- hibitors similar in structure to glucose might lowing section. prevent binding of glucose to the putative re- (iii) Insulin release due to glycogenolysis in ceptors, however, remains to be determined. glucose-deprived islets was demonstrated by D-Glyceraldehyde and dihydroxyacetone en- Malaisse er al. (67). When pancreatic islets are ter the glycolytic pathway at the triose phos- preincubated for 20 hr in the presence of glu- phate level, and their metabolism in islets is cose (83.3 mM) and thereafter transferred to a not inhibited by D-mannoheptulose or 2-deoxy- glucose-free medium, theophylline provokes an D-glucose but inhibited by iodoacetate. Insulin immediate and dramatic stimulation of insulin release stimulated by these trioses, with or with- release. The release of insulin is not suppressed out inhibitors, reflects their metabolism ( 127, by mannoheptulose and abolished in calcium- l24, 4). These observations are not easily ex- depleted media. The theophylline-induced in- plicable in terms of the glucoreceptor hypothe- crease in glycogenolysis coincides with a higher sis without the unattractive mosaic construct rate of both lactate output and oxidation of of a site (s) for triose (s) distinct from that for endogenous “C-labelled substrate. These data glucose. Sugden and Ashcroft (l l2) observed suggest that stimulation of glycolysis from en- parallel elfects of glucose and glyceraldehyde dogenous stores of glycogen is suflflcient to pro- on insulin release and islet phosphoenolpyru- voke insulin release even in glucose-deprived vate content. The authors suggested that phos- islets, as if the binding of extracellular glucose phoenolpyruvate could mediate effects of sug- to hypothetical plasma membrane glucorecep- ars on insulin release. tors is not an essential feature of the stimulus- However, emphasis has recently shifted away secretion coupling process. from searching for specific metabolites to more Although there is now little doubt that the general metabolic parameters that might trans- glucose-recognizing capability of the pancreatic HEXOSE ANOMERS, INSULIN RELEASE AND DIABETES 191 B cell is closely related to the capacity of the B On the basis of these findings, Davis and cell to catabolize glucose, the glucoreceptor Lazarus have postulated a ‘cascade’ theory of hypothesis needs to be kept in reserve in order insulin release (Fig. l). Glucose initiates insulin to explain sets of data that do not fit the meta- release first by interaction with a receptor on bolism hypothesis. the plasma membrane and simultaneously en- There are now three kinds of evidence that ters the B cell to be metabolized. The meba- suggest the existence of membrane glucorecep- tolites may stimulate the protein kinase and tors of the B cell [the lecture by S. J. H. Ash- thereby initiate and augment the release of in- croft entitled ‘Insulin release: The substrate- sulin. site and regulator-site hypotheses’, at the panel Other types of support for the glucoreceptor symposium in the Xth Congress of the Inter- hypothesis, (ii) the anomeric specificity of hex- national Diabetes Federation (Vienna, Austria, ose stimulation of insulin release, and (iii) the Sept. l3, 1979) and the report of ‘Hormone Se- interactions of alloxan, ninhydrin, and hexoses cretion’ workgroup (Chairman: F. M. Matsch- on insulin release, will be discussed in the fol- insky) at the National Conference on Diabetes lowing section. (Reston, U. S. A., Oct. 9-l2, 1979)]. (i) Studies on insulin release in a cell-free reconstituted system. (ii) The anomeric specificity of hexose Outside Plasma membrane Inside stimulation of insulin release. (iii) The inter- Gmcagon Second phase actions of alloxan, ninhydrin, and hexoses on insulin release. l x ‘ (i) Davis and Lazarus (23, 24) have develop- CAMP ed an in virro secreting system utilizing plasma Phospho membranes prepared from the cod endocrine diesterase pancreas and incubating these with insulin AMP granules isolated from mouse or rabbit pan- creatic islets.