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Primary Na+H+ exchanger dysfunction: A possible explanation for insulin resistance syndrome
Medical Hypotheses 1
1
Mdc,dHy@hws (1993) 41,186-189 OLQlpWQZOUpUKL3d1993
Primary Na+/H+ Exchanger Dysfunction: A Possible Explanation for Insulin Resistance Syndrome F. RUIZ-PALOMO and T. TOLEDO Medkina lnterna, Hospital Ramon y Cajai, Ctra Colmenar s/n, 28034 Madrid, Spain. Dote de Octubre, Madrid, Spain. (Reprint requests to FR-P)
l Hematobgia,
Hospital
Abstract-Insulin resistance has been recently distinguished as a syndrome associated with a clustering of metabolic disorders, including non-insulin dependent diabetes mellitus (NIDDM), obesity, hypertension, dyslipidemia and atherosclerosis. To date, it is thought that all of these disorders are the resulting consequences of primary insulin resistance. We propose that insulin resistance and the metabolic diseases mentioned can be caused by primary overactivity of the Na+/H+ exchange. This hypothesis has practical connotations for understanding the pathogenesis of the insulin resistance syndrome.
Introduction The insulin-resistancesyndrome Fasting hyperglycemia is the most relevant diagnostic criterion for non-insulin-dependent diabetes mellitus (NIDDM). NIDDM is commonly associated with peripheral insulin resistance and abnormal insulin secretion (1, 2). There is much evidence that insulin resistance is the first event in the development of NIDDM (3). At the beginning of the disease (preclinical stage), the glucose level remains normal because the secretory capacity of pancreatic P-cells is able to overcome the insulin resistance and, as a consequence, hyperinsulinemia appears (4). Progressively, the insulin secretion diminishes and the patient develops hyperglycemia and frank diabetes mellitus. Recently, Reaven (5) hypothesised that insulin resistance associates with glucose intolerance, hypertension, and
dyslipidemia in a distinct syndrome (syndrome X). Later, De Fronzo and Ferrannini described a clustering of metabolic disorders associated to insulin resislance, including NIDDM, obesity, hypertension, lipid abnormalities and atherosclerotic cardiovascular disease (6). In this paper, we hypothesise that all the metabolic disorders associated with insulin resistance (NIDDM, obesity, hypertension, atherosclerosis, dyslipidemia, and hyperinsulinemia) share a possible molecular disfunction: abnormal behaviour of the Na+/H+ exchanger. Na+IH+ exchanger The plasma membranes of numerous vertebrates contain a transport system which mediates the extrusion of protons, directly coupled to the influx of Na+ into the cell (7). The energy for this process does not re-
Date received 30 October 1992 Date accepted 4 December 1992
186
PRMARYNa+/H+EXCHANGERDYSFUN~ON
quire either ATP hydrolysis nor any other exergenic reaction; rather, energy for the extrusion of H+ is provided by the Na+ gradient (8). The prime physiological function of Na+/H+ exchanger is to regulate intracellular PH. The operation of Na+/H+ exchanger is electrically neutral and the stoichiometry of the process is 1:l. It has been demonstrated that Li+ and NH4 can be alternative substrates for the Na+/H+ antiporter. It appears that the cation affinity of the binding site is H+>Li+>NH@Na (8). Amiloride and its analogues have inhibitory properties on the plasma membrane Na+/H+ exchange. The system is allosteritally regulated by intracellular protons and it has been proposed that intracellular calcium activity might also be a modulator of Na+/H+ exchange. The physiological roles of the Na+/H+ exchanger include the regulation of intracellular pH, the control of cell proliferation, the stimulus-response coupling in platelets and white cells, the regulation of cell volume, the transepithelial transport of Na+, H+, Cl- , HC03- , and the metabolic responses to some hormones (7). ‘The pathophysiological capacities attributed, to date, to the dysfunction of sodium-proton exchanger include such different disorders as renal acid-base disturbances, cancer, organ hypertrophy, and arterial hypertension (7). Discussion Role of Na+lH+ exchanger in insulin secretion and action There are several common pathways in the intracellular signalling system that contribute to both secretion and action of insulin. Therefore, it would be possible that in NIDDM a single common biochemical defect can explain deficiencies in both functions (secretion and action). It has been observed that phospholipase C (PLC) stimulates insulin release from pancreatic j3-cells in rats (9). PLC generates inositol triphosphate (IP3) and diacylglycerol (DAG) by means of hydrolysis of phosphoinositides (PIP9 (10). While IP3 induces release of Ca2+ from endoplasmatic reticulum (ER) to cytoplasm, the formed DAG activates the proteinkinase C (PKC) which excites the functioning of Na+/H+ exchanger and conduces to an increase of intracellular pH (11). The activation of Na+/H+ antiporter can also be carried out by tyrosine kinase stimulation or a direct PKC activation induced by phorbol esters (12). Another proposed mechanism which would contribute to islet cell activation is the
187 release of arachidonic acid (AA) during DAG degradation (13). It has been suggested that IP3 would have a role in the first phase of insulin release and the second phase (slower in onset but more sustained) would be mediated by PKC (13). Although the role of phospholipase A2 (PLA2) on insulin secretion is less known, there is evidence for thinking that both lipases (C and A2) accomplish synergic effects on the p-cell, whose results are both to mobilise Ca+ and to activate PKC (14). According to the above statements, the Na+iH+ exchanger would play a very important role in insulin release, due to prime actions that the antiporter exerts on the framework of the intracellular signalling system (see Figure for better understanding). Thus, the PKC (activated via PLC) would be able to stimulate the antiporter and, in consequence, to increase the intracellular pH (11). The Na+/H+ exchanger, besides extruding H+ from the cell, induces both calcium influx and mobilisation of Ca2+ from ER which activates to PLA2 and, subsequently, causes the release of AA (11). An overactivity of the Na+/H+ exchanger could create a vicious circle in which the elevation of Na+/H+ exchange provokes increase of cytoplasmatic calcium and consequent activation of PLA2. The result would be AA generation which originates further activation of PLC, contributing to a new mobilisation of Ca2+ and activation of PKC, and closing the circle by triggering Na+/H+ exchange (15). All these events can lead to elevation of insulin secretion (16). The augmented insulin levels promote overactivity of Na+/H+ exchanger (7) which results in raised cytosolit calcium levels. Since 1987, cumulative evidence about the relationship between sustained increases of intracellular calcium and insulin resistance have been published (17, 18). It seems there is an optimal range of cytosolic calcium required to achieve insulin action. This optimal range is between 140 and 370 nM of Ca2+ (19) and both lower and higher levels of intracellular Ca2+ diminish responsiveness to insulin. The mechanism whereby high levels of calcium provoke insulin resistance are under discussion, but intcrfemnce with insulin binding, reduction of tyrosine kinase activity of insulin receptor and decreased dephosphorylation of glucose transporter or insulin receptor have been advocated (18). We have shown how the dysfunction of Na+/H+ antiport can explain the simultaneous development of insulin resistance and hyperinsulinemia in patients with NIDDM in the early stages of the disease. Perhaps chronic hyperglycemia could lead to desensitisation of p-cells through the augmented synthesis of prostaglandins (20) (via AA) and/or chronic
@(if
CCa2+li>370nM)
Pig.F’mposed role
of Na+/H+ exchanger in the development of insulin resistance syndrome (the hatched region is the cellular membrane). Analogous routes can be used to secmte insulin or achieve its action. The ideal cell represented in the figme, therefore, can be a pancreatic be.ta cell or a target insulin-sensitive cell. Abbreviations: AA (arachidonic acid); ER (endoplasmatic reticulum); DAG (diacylglycerol): Gp (GTP-binding protein); IP3 (inositol triphosphate); PIP2 (phosphatidyl inositol biphosphate); PG (pmstaglandins); PKC @m&in kinase C); PLAz (phospholipase AZ); PLC @hospholipase C); R (receptor); + (stimulation); - (inhibition).
overstimulation of membrane turnover with degradation of PIP2 and inositol depletion (13). The restorative effect of sodium salicylate on the insulin response to intravenous glucose administration in patients with NIDDM is the best confirmation of the role of prostaglandins in desensitisation of pancreatic p-cells (20). The result of this desensitisation would explain the reduction in both the fasting and glucosestimulated plasma insulin concentrations at the late stage of NIDDM. Role of Na+IH+ exchanger in obesity, hypertension, dyslipemia, and atherosclerosis
Some workers have described that erythrocyte sodium exchange can be stimulated by feeding of a meal (21) or during long term overfeeding (22). Obese subjects have a higher sodium pump activity which is not mediated by catecholamines or thyroid hormones, and could be the result of chronic hyperinsuhnemia and/or excessive calorie intake (22, 23). Furthermore, the overactivity of Na+/H+ exchanger can be responsible for adipocyte hypertrophy observed in obesity, since the cellular volume is regulated by the antiporter (7).
Overfunction of Na+/H+ exchanger (or Na+/Li+ exchanger) has been found in patients suffering hypertension (24). There is evidence that the increased activity of sodium pump is both a heritable trait and the only known genetic marker for hypertension (25). On the other hand, Na+/H+ overactivity is able to lead to cell growth and proliferation in vessel walls and increased smooth muscle contractility (7). It is very interesting to know that the most active vasoconstrictors present in man mqtire the activation of Na+/H+ pump to achieve their action (11,26,27). All of the factors mentioned above have relevant implications in the development of hypertension and atherosclerosis. Finally, NIDDM is commonly associated with elevation in very-low density lipoproteins (VLDL), total triglycerides concentration and with a reduction in high-density lipopro teins (HDL). Tobey et al (28) showed the relationship between changes in lipidic metabolism and insulin resistance. The role of the Na+/H+ pump in lipid metabolism needs further investigation but it has recently been demonstrati that hyperlipidemia is associated with raised sodium exchange (29). Nonno tensive relatives of hypertensive patients who had el-
lXlMARY Na+/H+ EXCHANGER DYSFUNCTION
evated sodium-lithium countertransportalso had abnormal lipids (raised cholesterol, triglycerides and LDL-cholesterol, and decreased HDL-cholesterol). On the other hand, relatives with normal function of Na+/Li+ pump had normal lipids (29). All those factors suggest that sodium-proton pump is associated to the inheritance of both hypertension and dyslipemia. Conclusion The Na+/H+ exchanger modulates the secretion and actions of insulin. Its primary dysfunction can lead to insulin resistance and also to a cluster of metabolic disturbances including NIDDM, obesity, hypertension, dyslipidemia and atherosclerosis (Fig.). The antiporterdysfunction can be inherited and predispose the subject to suffer the mentioned syndrome. However, the phenotypic expression of the metabolic disturbance would depend on environmental factors (i.e. excessive caloric intake in obesity, sodium ingestion in hypertension, etc) and/or the coexistence of a set of different genes which could interact with the gene responsible for the Na+/H+ exchanger abnormality (in those among the mentioned diseases with a polygenic mode of inheritance). Further research must be done to confirm or refute our hypothesis. Acknowledgements We thank Dr K. Mark for her review of the manuscript. This work was suppotted, in pan, by a grant from the Fondo de Investigaciones Sanitarias (FIS, no 9Om340).
References 1. Halter J B, Porte D Jr. Mechanisms of impaired acute insulin release in adult onset diabetes: studies with isoproterenol and secretin. Clin Endoctin Metab 1978; 46: 952 2. Olefsky J M. The insulin receptor: its role in insulin resistance of obesity and diabetes. Diabetes 1976; 25: 1154. 3. Golay A, Felber J P, Jequier E, De Fronxo R A, Ferrannini E. Metabolic basis of obesity and non-insulin dependent diabetes meUitus. Diabetes Metab Rev 1988; 4: 727. 4. De. Frotuo R A. Lilly lecture 1987: the triumvirate: @cell, muscle liver: a collusion responsible for NIDDM. Diabetes 1988; 37: 667. 5. Reaven G M. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595. 6. De Fronx.o R A, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM. obesity, hypettension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173. I. Mahnensmith R L, Aratson P S. The plasma membrane sodium-hydrogen exchanger and its role in physiological and pathophysiological processes. Circ Res 1985; 57: 773. 8. Wamock D G, Pollock A S. Na+/H+ exchange in excitable cells. In: Grinstein S, ed. Na+/H+ exchange. Boca Raton, Florida: CRC Press Inc. 1988: 77. 9. Metx S A. Lipoxygenase inhibitors reduce insulin secretion without impairing calcium mobilization. Endocrinology 1987;
189 120: 2534. 10. Benidge M J, Irvine R F. Inositol trispbospltate, a novel second messenger in cellular signal transduction. Nature 1984; 312: 315. Na+/H+ exchange 11. Decker K. Dieter P. The stimulus-activated in macrophages, neutrophils and plateless. In: Hattssinger D, ed. pH Homeostasis. London, Academic Press, 1988: 79. 12. Pouyssegur J, Franchi A, Paris S. Sardet C. Mechanisms of activation and molecular genetics of the mammalian Na+/H+ antipotter. In: Haussinger D, ed. pH Homeostasis. Londar: Academic Press, 1988: 61. 13. Metx S A. Membrane phospholipid turnover as an intermediary step in insulin secretion. Am J Med 1988; 85 (Suppl5A): 9. 14. Metx S A. Arachidonic acid and its metabolites: evolving roles as transmembrane signals for insulin release. Prostaglandins Leukot Essent Fatty Acids 1988: 32: 187. 15. Siffert W. Akkennan J W N. Protein kinase C enhances Ca2+ mobii&n in human platelets by activating Na+/H+ exchange. J Biol Chem 1988; 263: 4223. 16. Efendic S, Kindmark H. Berggren P 0. Mechanisms involved in the regulation of the insulin secretory process. J hem Med 1991; 229 (Sttppl2): 9. 17. Draznin B, Lewis D, Houder N et al. Mechanism of insulin resistance induced by sustained levels of cytosolic free calcium in rat adipocytes. Endocrinology 1989; 125: 2341. 18. Dramin B. Cytosolic calcium: A new factor in insulin resisrance. Diabetes Res Clin Pratt 1991; 11: 141. 19. Dramin B, Sussman K, Kao M, Lewis D, Sherman N. The existence of an optimal range of cytosolic free calcium for insulin-stimulated glucose transport in rat adipocytes. J Biol Chem 1987; 262: 14385. 20. Robertson R P. Type II diabetes, glucose ‘non-sense’ and islet desensitization. Diabetes 1989; 38: 1501. 21. Mir M A. Charalambous B M, Morgan K, Evans P J. Erythrocyte sodium-potassium-ATPase and sodium transport in obesity. N Engl J Me-d 1981; 305: 1264. 22. Fagerberg B, Herlitx H, Jonsson 0 et al. Increased etythrocyte sodium efflux during overfeeding whiteout evidence of mediation by circulating catecholamines or thyroid hormones. Metabolism 1984; 33: 994. 23. Ng L L. Hockaday T D R. The effect of oral glucose on the leucocyte sodium pump in normal and obese subjects. Clin Endocrinol 1987; 27: 345. 24. Livne A. Veitch R, Grinstein S, Balfe J W, Marquez-Julio A, Rothstein A. Increased platelet Na+/H+ exchange rates in essential hypertension: application of a novel test. Lancet 1987; 1: 533. 25. Woods J W, Falk R J, Pittman A W, Klemmer P J, Watson B S, Nambodiri K. lncteased red-cell sodium-lithium countertranspon in normotensive sons of hypertensive parents. N Engl J Med 1982; 306: 593. 26 Toledo T, Ruiz-Palomo F, Hockaday T D R. The Na+/H+ exchange is required for platelet aggregation induced by AVP (Arginine-Vasopressin). thrombosis Research 1989; 55: 389. 27. Griendling K K, Berk B C. Alexander R W. Evidence that Na+/H+ exchange regulates angiotensin II-stimulated diacylglycerol accumulation in vascular smooth muscle cells. J Biol Chem 1988; 263: 10620. 28 Tobey T A, Greenfield M. Kraemer R, Reaven G M. Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics and plasma triglyceride levels in nonn&igly&idemic man. Metabolism 1981; 30: 165. 29 Can S J. Thomas T H. Laker M F. Wilkinson R. Elevated sodium-lithium countertransport: a familial marker of hyperlipidaemia and hypertension? J Hypertens 1990; 8: 139.
1
Mdc,dHy@hws (1993) 41,186-189 OLQlpWQZOUpUKL3d1993
Primary Na+/H+ Exchanger Dysfunction: A Possible Explanation for Insulin Resistance Syndrome F. RUIZ-PALOMO and T. TOLEDO Medkina lnterna, Hospital Ramon y Cajai, Ctra Colmenar s/n, 28034 Madrid, Spain. Dote de Octubre, Madrid, Spain. (Reprint requests to FR-P)
l Hematobgia,
Hospital
Abstract-Insulin resistance has been recently distinguished as a syndrome associated with a clustering of metabolic disorders, including non-insulin dependent diabetes mellitus (NIDDM), obesity, hypertension, dyslipidemia and atherosclerosis. To date, it is thought that all of these disorders are the resulting consequences of primary insulin resistance. We propose that insulin resistance and the metabolic diseases mentioned can be caused by primary overactivity of the Na+/H+ exchange. This hypothesis has practical connotations for understanding the pathogenesis of the insulin resistance syndrome.
Introduction The insulin-resistancesyndrome Fasting hyperglycemia is the most relevant diagnostic criterion for non-insulin-dependent diabetes mellitus (NIDDM). NIDDM is commonly associated with peripheral insulin resistance and abnormal insulin secretion (1, 2). There is much evidence that insulin resistance is the first event in the development of NIDDM (3). At the beginning of the disease (preclinical stage), the glucose level remains normal because the secretory capacity of pancreatic P-cells is able to overcome the insulin resistance and, as a consequence, hyperinsulinemia appears (4). Progressively, the insulin secretion diminishes and the patient develops hyperglycemia and frank diabetes mellitus. Recently, Reaven (5) hypothesised that insulin resistance associates with glucose intolerance, hypertension, and
dyslipidemia in a distinct syndrome (syndrome X). Later, De Fronzo and Ferrannini described a clustering of metabolic disorders associated to insulin resislance, including NIDDM, obesity, hypertension, lipid abnormalities and atherosclerotic cardiovascular disease (6). In this paper, we hypothesise that all the metabolic disorders associated with insulin resistance (NIDDM, obesity, hypertension, atherosclerosis, dyslipidemia, and hyperinsulinemia) share a possible molecular disfunction: abnormal behaviour of the Na+/H+ exchanger. Na+IH+ exchanger The plasma membranes of numerous vertebrates contain a transport system which mediates the extrusion of protons, directly coupled to the influx of Na+ into the cell (7). The energy for this process does not re-
Date received 30 October 1992 Date accepted 4 December 1992
186
PRMARYNa+/H+EXCHANGERDYSFUN~ON
quire either ATP hydrolysis nor any other exergenic reaction; rather, energy for the extrusion of H+ is provided by the Na+ gradient (8). The prime physiological function of Na+/H+ exchanger is to regulate intracellular PH. The operation of Na+/H+ exchanger is electrically neutral and the stoichiometry of the process is 1:l. It has been demonstrated that Li+ and NH4 can be alternative substrates for the Na+/H+ antiporter. It appears that the cation affinity of the binding site is H+>Li+>NH@Na (8). Amiloride and its analogues have inhibitory properties on the plasma membrane Na+/H+ exchange. The system is allosteritally regulated by intracellular protons and it has been proposed that intracellular calcium activity might also be a modulator of Na+/H+ exchange. The physiological roles of the Na+/H+ exchanger include the regulation of intracellular pH, the control of cell proliferation, the stimulus-response coupling in platelets and white cells, the regulation of cell volume, the transepithelial transport of Na+, H+, Cl- , HC03- , and the metabolic responses to some hormones (7). ‘The pathophysiological capacities attributed, to date, to the dysfunction of sodium-proton exchanger include such different disorders as renal acid-base disturbances, cancer, organ hypertrophy, and arterial hypertension (7). Discussion Role of Na+lH+ exchanger in insulin secretion and action There are several common pathways in the intracellular signalling system that contribute to both secretion and action of insulin. Therefore, it would be possible that in NIDDM a single common biochemical defect can explain deficiencies in both functions (secretion and action). It has been observed that phospholipase C (PLC) stimulates insulin release from pancreatic j3-cells in rats (9). PLC generates inositol triphosphate (IP3) and diacylglycerol (DAG) by means of hydrolysis of phosphoinositides (PIP9 (10). While IP3 induces release of Ca2+ from endoplasmatic reticulum (ER) to cytoplasm, the formed DAG activates the proteinkinase C (PKC) which excites the functioning of Na+/H+ exchanger and conduces to an increase of intracellular pH (11). The activation of Na+/H+ antiporter can also be carried out by tyrosine kinase stimulation or a direct PKC activation induced by phorbol esters (12). Another proposed mechanism which would contribute to islet cell activation is the
187 release of arachidonic acid (AA) during DAG degradation (13). It has been suggested that IP3 would have a role in the first phase of insulin release and the second phase (slower in onset but more sustained) would be mediated by PKC (13). Although the role of phospholipase A2 (PLA2) on insulin secretion is less known, there is evidence for thinking that both lipases (C and A2) accomplish synergic effects on the p-cell, whose results are both to mobilise Ca+ and to activate PKC (14). According to the above statements, the Na+iH+ exchanger would play a very important role in insulin release, due to prime actions that the antiporter exerts on the framework of the intracellular signalling system (see Figure for better understanding). Thus, the PKC (activated via PLC) would be able to stimulate the antiporter and, in consequence, to increase the intracellular pH (11). The Na+/H+ exchanger, besides extruding H+ from the cell, induces both calcium influx and mobilisation of Ca2+ from ER which activates to PLA2 and, subsequently, causes the release of AA (11). An overactivity of the Na+/H+ exchanger could create a vicious circle in which the elevation of Na+/H+ exchange provokes increase of cytoplasmatic calcium and consequent activation of PLA2. The result would be AA generation which originates further activation of PLC, contributing to a new mobilisation of Ca2+ and activation of PKC, and closing the circle by triggering Na+/H+ exchange (15). All these events can lead to elevation of insulin secretion (16). The augmented insulin levels promote overactivity of Na+/H+ exchanger (7) which results in raised cytosolit calcium levels. Since 1987, cumulative evidence about the relationship between sustained increases of intracellular calcium and insulin resistance have been published (17, 18). It seems there is an optimal range of cytosolic calcium required to achieve insulin action. This optimal range is between 140 and 370 nM of Ca2+ (19) and both lower and higher levels of intracellular Ca2+ diminish responsiveness to insulin. The mechanism whereby high levels of calcium provoke insulin resistance are under discussion, but intcrfemnce with insulin binding, reduction of tyrosine kinase activity of insulin receptor and decreased dephosphorylation of glucose transporter or insulin receptor have been advocated (18). We have shown how the dysfunction of Na+/H+ antiport can explain the simultaneous development of insulin resistance and hyperinsulinemia in patients with NIDDM in the early stages of the disease. Perhaps chronic hyperglycemia could lead to desensitisation of p-cells through the augmented synthesis of prostaglandins (20) (via AA) and/or chronic
@(if
CCa2+li>370nM)
Pig.F’mposed role
of Na+/H+ exchanger in the development of insulin resistance syndrome (the hatched region is the cellular membrane). Analogous routes can be used to secmte insulin or achieve its action. The ideal cell represented in the figme, therefore, can be a pancreatic be.ta cell or a target insulin-sensitive cell. Abbreviations: AA (arachidonic acid); ER (endoplasmatic reticulum); DAG (diacylglycerol): Gp (GTP-binding protein); IP3 (inositol triphosphate); PIP2 (phosphatidyl inositol biphosphate); PG (pmstaglandins); PKC @m&in kinase C); PLAz (phospholipase AZ); PLC @hospholipase C); R (receptor); + (stimulation); - (inhibition).
overstimulation of membrane turnover with degradation of PIP2 and inositol depletion (13). The restorative effect of sodium salicylate on the insulin response to intravenous glucose administration in patients with NIDDM is the best confirmation of the role of prostaglandins in desensitisation of pancreatic p-cells (20). The result of this desensitisation would explain the reduction in both the fasting and glucosestimulated plasma insulin concentrations at the late stage of NIDDM. Role of Na+IH+ exchanger in obesity, hypertension, dyslipemia, and atherosclerosis
Some workers have described that erythrocyte sodium exchange can be stimulated by feeding of a meal (21) or during long term overfeeding (22). Obese subjects have a higher sodium pump activity which is not mediated by catecholamines or thyroid hormones, and could be the result of chronic hyperinsuhnemia and/or excessive calorie intake (22, 23). Furthermore, the overactivity of Na+/H+ exchanger can be responsible for adipocyte hypertrophy observed in obesity, since the cellular volume is regulated by the antiporter (7).
Overfunction of Na+/H+ exchanger (or Na+/Li+ exchanger) has been found in patients suffering hypertension (24). There is evidence that the increased activity of sodium pump is both a heritable trait and the only known genetic marker for hypertension (25). On the other hand, Na+/H+ overactivity is able to lead to cell growth and proliferation in vessel walls and increased smooth muscle contractility (7). It is very interesting to know that the most active vasoconstrictors present in man mqtire the activation of Na+/H+ pump to achieve their action (11,26,27). All of the factors mentioned above have relevant implications in the development of hypertension and atherosclerosis. Finally, NIDDM is commonly associated with elevation in very-low density lipoproteins (VLDL), total triglycerides concentration and with a reduction in high-density lipopro teins (HDL). Tobey et al (28) showed the relationship between changes in lipidic metabolism and insulin resistance. The role of the Na+/H+ pump in lipid metabolism needs further investigation but it has recently been demonstrati that hyperlipidemia is associated with raised sodium exchange (29). Nonno tensive relatives of hypertensive patients who had el-
lXlMARY Na+/H+ EXCHANGER DYSFUNCTION
evated sodium-lithium countertransportalso had abnormal lipids (raised cholesterol, triglycerides and LDL-cholesterol, and decreased HDL-cholesterol). On the other hand, relatives with normal function of Na+/Li+ pump had normal lipids (29). All those factors suggest that sodium-proton pump is associated to the inheritance of both hypertension and dyslipemia. Conclusion The Na+/H+ exchanger modulates the secretion and actions of insulin. Its primary dysfunction can lead to insulin resistance and also to a cluster of metabolic disturbances including NIDDM, obesity, hypertension, dyslipidemia and atherosclerosis (Fig.). The antiporterdysfunction can be inherited and predispose the subject to suffer the mentioned syndrome. However, the phenotypic expression of the metabolic disturbance would depend on environmental factors (i.e. excessive caloric intake in obesity, sodium ingestion in hypertension, etc) and/or the coexistence of a set of different genes which could interact with the gene responsible for the Na+/H+ exchanger abnormality (in those among the mentioned diseases with a polygenic mode of inheritance). Further research must be done to confirm or refute our hypothesis. Acknowledgements We thank Dr K. Mark for her review of the manuscript. This work was suppotted, in pan, by a grant from the Fondo de Investigaciones Sanitarias (FIS, no 9Om340).
References 1. Halter J B, Porte D Jr. Mechanisms of impaired acute insulin release in adult onset diabetes: studies with isoproterenol and secretin. Clin Endoctin Metab 1978; 46: 952 2. Olefsky J M. The insulin receptor: its role in insulin resistance of obesity and diabetes. Diabetes 1976; 25: 1154. 3. Golay A, Felber J P, Jequier E, De Fronxo R A, Ferrannini E. Metabolic basis of obesity and non-insulin dependent diabetes meUitus. Diabetes Metab Rev 1988; 4: 727. 4. De. Frotuo R A. Lilly lecture 1987: the triumvirate: @cell, muscle liver: a collusion responsible for NIDDM. Diabetes 1988; 37: 667. 5. Reaven G M. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595. 6. De Fronx.o R A, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM. obesity, hypettension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173. I. Mahnensmith R L, Aratson P S. The plasma membrane sodium-hydrogen exchanger and its role in physiological and pathophysiological processes. Circ Res 1985; 57: 773. 8. Wamock D G, Pollock A S. Na+/H+ exchange in excitable cells. In: Grinstein S, ed. Na+/H+ exchange. Boca Raton, Florida: CRC Press Inc. 1988: 77. 9. Metx S A. Lipoxygenase inhibitors reduce insulin secretion without impairing calcium mobilization. Endocrinology 1987;
189 120: 2534. 10. Benidge M J, Irvine R F. Inositol trispbospltate, a novel second messenger in cellular signal transduction. Nature 1984; 312: 315. Na+/H+ exchange 11. Decker K. Dieter P. The stimulus-activated in macrophages, neutrophils and plateless. In: Hattssinger D, ed. pH Homeostasis. London, Academic Press, 1988: 79. 12. Pouyssegur J, Franchi A, Paris S. Sardet C. Mechanisms of activation and molecular genetics of the mammalian Na+/H+ antipotter. In: Haussinger D, ed. pH Homeostasis. Londar: Academic Press, 1988: 61. 13. Metx S A. Membrane phospholipid turnover as an intermediary step in insulin secretion. Am J Med 1988; 85 (Suppl5A): 9. 14. Metx S A. Arachidonic acid and its metabolites: evolving roles as transmembrane signals for insulin release. Prostaglandins Leukot Essent Fatty Acids 1988: 32: 187. 15. Siffert W. Akkennan J W N. Protein kinase C enhances Ca2+ mobii&n in human platelets by activating Na+/H+ exchange. J Biol Chem 1988; 263: 4223. 16. Efendic S, Kindmark H. Berggren P 0. Mechanisms involved in the regulation of the insulin secretory process. J hem Med 1991; 229 (Sttppl2): 9. 17. Draznin B, Lewis D, Houder N et al. Mechanism of insulin resistance induced by sustained levels of cytosolic free calcium in rat adipocytes. Endocrinology 1989; 125: 2341. 18. Dramin B. Cytosolic calcium: A new factor in insulin resisrance. Diabetes Res Clin Pratt 1991; 11: 141. 19. Dramin B, Sussman K, Kao M, Lewis D, Sherman N. The existence of an optimal range of cytosolic free calcium for insulin-stimulated glucose transport in rat adipocytes. J Biol Chem 1987; 262: 14385. 20. Robertson R P. Type II diabetes, glucose ‘non-sense’ and islet desensitization. Diabetes 1989; 38: 1501. 21. Mir M A. Charalambous B M, Morgan K, Evans P J. Erythrocyte sodium-potassium-ATPase and sodium transport in obesity. N Engl J Me-d 1981; 305: 1264. 22. Fagerberg B, Herlitx H, Jonsson 0 et al. Increased etythrocyte sodium efflux during overfeeding whiteout evidence of mediation by circulating catecholamines or thyroid hormones. Metabolism 1984; 33: 994. 23. Ng L L. Hockaday T D R. The effect of oral glucose on the leucocyte sodium pump in normal and obese subjects. Clin Endocrinol 1987; 27: 345. 24. Livne A. Veitch R, Grinstein S, Balfe J W, Marquez-Julio A, Rothstein A. Increased platelet Na+/H+ exchange rates in essential hypertension: application of a novel test. Lancet 1987; 1: 533. 25. Woods J W, Falk R J, Pittman A W, Klemmer P J, Watson B S, Nambodiri K. lncteased red-cell sodium-lithium countertranspon in normotensive sons of hypertensive parents. N Engl J Med 1982; 306: 593. 26 Toledo T, Ruiz-Palomo F, Hockaday T D R. The Na+/H+ exchange is required for platelet aggregation induced by AVP (Arginine-Vasopressin). thrombosis Research 1989; 55: 389. 27. Griendling K K, Berk B C. Alexander R W. Evidence that Na+/H+ exchange regulates angiotensin II-stimulated diacylglycerol accumulation in vascular smooth muscle cells. J Biol Chem 1988; 263: 10620. 28 Tobey T A, Greenfield M. Kraemer R, Reaven G M. Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics and plasma triglyceride levels in nonn&igly&idemic man. Metabolism 1981; 30: 165. 29 Can S J. Thomas T H. Laker M F. Wilkinson R. Elevated sodium-lithium countertransport: a familial marker of hyperlipidaemia and hypertension? J Hypertens 1990; 8: 139.