Asthma and diabetes mellitus: A biochemical basis for antithetical features

Medical Hypotheses (1987) 23, 9ilO6 fJ Longman Group UK Ltd 1987

ASTHMA AND DIABETES MELLITUS: ANTITHETICAL FEATURES E. Lasser, California, California

A BIOCHEMICAL

Department of Radiology, M-032, San Diego, School of Medicine, 92093

BASIS

FOR

University La Jolla,

of

ABSTRACT

Diabetes mellitus and asthma have .many antipodal features. Although both are common disorders, concurrence occurs less often than would be predicted. When co-existence does occur, the cases are generally mild, and effective treatment of one disease frequently The hypothesis is advanced that exacerbates the other. basilar membrane concentrations of heparan sulfate differ in these two diseases and that this difference may account for the antithetical features. An experimental basis for postulating increased concentrations of extracellular heparan sulfate in asthma and diminished concentrations in diabetes is cited. A rationale for tying these differences to the polar activities of cholinergic transmission and atherogenesis in the two diseases is advanced. Diminished heparan sulfate concentrations in diabetes may down-regulate the transmission of vagal impulses to insulin-producing pancreatic cells, and thereby impair both the continued vitality of these cells, and the acetylcholine modulated potentiation of glucose-induced insulin release.

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INTRODUCTION Both asthma and diabetes mellitus are common diseases, and concurrence would correspondingly be expected to occur commonly. Most published studies, however, indicate that the incidence of asthma in diabetic patients, and vice versa, is less than the incidence of these respective diseases in the residual population (l-4). When co-existence does occur, the cases are frequently "mild" in nature (3). While asthma is characterized by bronchospasm, increased parasympathetic activity (5-8), and a presumed diminution in atherosclerosis (g-11), diabetes is characterized by hyperglycemia, diminished parasympathetic activity incidence of atherosclerosis (12), and an increased (13,14). Spontaneous or induced improvement in one disease is frequently accompanied by an antithetical change in the other (1,3). I should now like to propose a comprehensive pathophysiologic mechanism for this apparent antagonism. The pivotal feature in this mechanism is a predicated difference in concentrations of heparan sulfate that occupy endothelial areas, basilar membranes and synaptic junctions in these two diseases. Heparan sulfate, like heparin, is a sulfated polyanionic linear electrolyte. Like heparin, heparan sulfate is composed of repeating disaccharide groups of uranic acid and glucosamine. In heparin, the hexosamine groups contain N-sulfate, while in heparan sulfate the hexosamine groups contain either N-sulfate or N-acetyl. Heparin, then, is more highly sulfated than heparan sulfate, and in heparan sulfate there may be considerable variation in the ratio of uranic acid to glucosamine, and varying degrees of While sulfation or acetylation of the amino groups. anticoagulant activity is associated chiefly with heparin, some heparin-like species of heparan sulfate have been identified in the vascular tree (15). In mammalian tissues, these glycosaminoglycans are covalently bonded to proteins, and, thus, are correctly classified as proteoglycans (16). Asthmatics demonstrate a mean increase in the level of a circulating anticoagulant that has a number of the functional and biochemical characteristics of heparin, but most likely represents a special subset of This material probably derives heparan sulfate (17-19). from vascular endothelium (15,17,18), and increased circulating concentrations suggest either saturated availability via endothelial binding sites, increased

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hyperactive releasing mechanisms, diminished catabolic clearance rates (20-22). In rates, or diminished subsequent sections of this article, this material will sulfate" [H/HS]. be referred to as "heparin/heparan Diabetics have demonstrated a diminished concentration of heparan sulfate in capillary basement the reduced heparan membranes (23). In human diabetes, sulfate component has been accompanied by evidence of over-production and abnormal packing of collagen polyIn diabetics, peptide chains in the membrane (23). nephropathy, retinopathy, or neuropathy is characterized pathologically by thickening of capillary basement membranes, and physiologically, by an increased permeability to the passage of macromolecules. Animal models of experimental diabetes have also demonstrated reduced synthesis of basement membrane heparan sulfate It has been postulated that the diminution of (24). heparan sulfate in these circumstances may be responsible for the increased transcapillary passage of macromolecules. This is thought to occur by virtue of a diminished anionic shielding and/or steric hindrance ascribed to the loss of the proteoglycan (24,25). In fact, the reduced capillary heparan sulfate concentration that results from the infusion of heparinase (25), or from the binding of an infused in polycation (26), will result in massive proteinuria experimental animals. Experimental data, then, exists for a diminution in endothelialand/or connective tissue-derived heparan sulfate in diabetes mellitus, and there is presumptive evidence for an increase in this component in asthma. The reduction in heparan sulfate in diabetic tissues is apparently not confined to endothelial basement membranes (27). It has been demonstrated, for example, that the heparan sulfate found in diabetic intestinal epithelial cells in streptozotocin-induced rat diabetes has a diminished sulfate content (28). Heparan Sulfate Concentrations Clinical Features -in Diabetes

May Produce and Asthma

Antithetical

The production of proteoglycans by body cells involves, in part, the utilization of glucose (29). Diminished insulin levels inhibit general cellular glucose utilization. Persistent high glucose levels may diminish the potential of endothelial cells to synthesize and secrete heparan sulfate into the surrounding extracellular matrix (29). In animal models of diabetes, it was found that heparan sulfate synthesis

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could be restored by sufficient insulin to normalize blood glucose levels (24).

administration

The increased concentration of H/HS that may be found in the plasma of asthmatics has the potential to both initiate and/or potentiate the contact cascade of plasma proteins (17,30). Activation of these proteins results in the liberation of bradykinin from plasma high molecular weight kininogen (31). In vitro studies indicate that prekallikrein in the plasma of asthmatics, when exposed to a soluble contact system activator and released from inhibitor influences, will show an accelerated production of kallikrein (17) [and putative bradykinin]. Bradykinin can produce bronchospasm directly (31), and/or indirectly, via the liberation of membrane arachidonic acid that then becomes available for the production of bronchospastic leukotrienes (32). The level of systemic bradykinin, once this material appears in the circulation, is controlled in large part by the presence of endogenous kininases (33,34). Principal among these is a substance known alternatively as kininase II or angiotensin converting enzyme [ACE] This material is found in high concentrations (33,34). in pulmonary vascular endothelium, and has the dual capacity to both hydrolyze bradykinin and to convert renin-derived angiotensin I, to the powerful vasoThus, the increased constrictor angiotensin II (33,34). bradykinin levels that might be engendered in asthmatics by the presence of circulating H/HS will be modulated in normal circumstances by the powerful degradative influence exerted by ACE as bradykinin passes through Any substance that inhibits the pulmonary circulation. the activity of-ACE will potentiate the increase in the plasma concentration of bradykinin, while concurrently Both diminishing the formation of angiotensin II. synthetic and endogenous inhibitors of ACE have been Among the endogenous inhibitors are listed described. Other the B chain of insulin and insulin (33,34). recognized endogenous inhibitors are glutathione and The inhibiting actions of these bradykinin itself (33). While peptides have been studied in vitro and in situ. it is not yet known whether these substances will also inhibit the enzyme in vivo, it is known that insulin is the most active of the endogenous inhibitors recognized more than 75% of subthus far, 1 x 10 M inhibiting strate bradykinin in vitro (34). In patients with both diabetes mellitus and one can postulate asthma, where diabetes predominates, that the diminished availability of insulin will limit the cellular potential to utilize glucose for the

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production of heparan sulfate and, hence, will minimize the possibilities for circulating release of this substance from endothelial (or other cellular) .binding This will result in an attendant diminished sites. potential for contact activation and, hence, bradykinin If, in this circumstance, insulin is formation. administered to correct the hyperglycemia, one can anticipate the reemergence of asthma, since the ability to both activate the contact system with subsequent bradykinin formation and to inhibit the restraining influences exerted by kininases on bradykinin will be restored. From experi-mental data, it appears that insulin restoration of this potential will occur in a matter of several hours (24). In patients with both diabetes and asthma, where asthma predominates, sufficient H/HS may be produced to permit release of this anticoagulant into the circulation with consequent contact activation and In these patients, a subsequent bronchospasm. sufficient amount of insulin must have been available to permit tissue utilization of glucose in the production and to limit the development of of the proteoglycan, clinical diabetes. If conditions change and the diabetes becomes sufficiently severe to require exogenous insulin therapy, the subsequent abatement of the diabetes is frequently accompanied by a In a number of such recrudescence of asthma (1,3,16). it has been noted that the onset of bronchoinstances, spasm coincides with the maximal insulin effect at the nadir of the blood glucose level. In these cases, we postulate that insulin therapy activated latent asthma a) by permitting the cellular utilization of glucose necessary for the production of H/HS and b) by inhibiting ACE, thus potentiating any bradykinin formation initiated by H/HS (or by other circulating soluble contact activators). In the context of polar concentrations of endothelial H/HS, it is not difficult to understand the presence of increased atherosclerosis in diabetes in asthma (9-11). (13,14), and its reported diminution A protective role of H/HS against atheroscleroris can be readily assigned when cunsideration is given to the known functions of heparin-like substances which include the following: Heparin mobilizes lipoprotein lipase and thus aids in the clearance of elementary and hepatically synthesized triglycerides (35); the binding of heparin to endothelial cell surfaces acts as a localized anticoagulant in these areas (36); heparin minimizes platelet adhesion to damaged vascular endothelium (37);

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heparin and heparan sulfate inhibit smooth muscle proliferation resulting from vascular injury (39); heparin inhibits complement activation capable of mediating endo-thelial cell injury (39). In fact, in experimental animal models of atherosclerosis, the administration of either heparin or heparan sulfate has demonstrated striking protective effects (40). Asthma patients, with their increased plasma content of H/HS, should develop less atherosclerosis, on the average, than diabetic patients who have normal, or less than normal, quantities of this endothelial protective substance. In a preliminary study comparing atherosclerosis in asthmatic patients over the age of 45 with age- and sexmatched controls, we found a significant diminution in the extent of atherosclerosis as judged by the radiographic degree of large artery intimal calcification (41). Finally, some postulations may be made regarding the presence of increased cholinergic activity in asthma, and diminished cholinergic activity in diabetes. In recent years, it has become evident that the three principal functional components of cholinergic nerve . . transmission--i.e., the neurotransmitter acetylcholine, the acetylcholine modulating substance cholinesterase, and the receptor proteins for acetylcholine are, in varying degrees, bound to heparan sulfate in situ (42While these studies have been conducted in . . iziclfic animal species , other work in this area would suggest that the results are probably applicable to most mammalian tissues. Heparan sulfate has been identified as a specific core component of cholinergic synaptic vesicles in the electric organ of Torpedo Marmorata. The proteoglycan is a major component of these vesicle's, The antiamounting to 20% on a dry weight basis (44). serum used to identify heparan sulfate in these determinations also cross-reacts with antigens present in the cholinergic nerve terminals of mammalian tissue (44). of acetylcholine receptors In other animals, aggregates were found to be closely associated with plaques of a It has basal lamina heparan sulfate proteoglycan (45). been suggested that these heparan sulfate plaques may contribute to both the immobilization of synaptic elements and to the transmission of inductive signals It is of further between nerve and muscle (45). interest that axon outgrowth itself appears to be linked This is to the presence of heparan sulfate (43). additional evidence that heparan sulfate proteoglycans at the muscle surface are of particular regulatory and that the ability to effectively significance, transmit cholinergic impulses depends in large part on

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Finally, the presence and extent of this proteoglycan. it has been reported that asymmetric forms of cholinesterase are bound to heparan sulfate in the basal In this lamina of the neuromuscular junction (47,48). particular form of cholinesterase binding occurs via a represent a collagen tail, but such forms evidently relatively minor fraction of the total cholinesterase content (50). In the light of these considerations, a final In asthma, where there postulation can be entertained. appears to be a sufficiently abundant production of cellular H/HS to permit released material to appear in the circulation one might expect that abundant acetylcholine and acetylcholine receptors would likewise be available to facilitate cholinergic nerve transmission. In diabetes, the opposite might be expected. In this respect, it is interesting to bear in mind the fact that acetylcholine is a strong potentiator of glucose-induced insulin release (51-56) and that long-term trophic influences on insulin- producing cells may be exerted by diminished cholinergic activity, as suggested by B-cell atrophy in atropine-injected mice (57). Thus, the concentration of H/HS available to facilitate cholinergic mechanisms might even play a fundamental role in the control and/or genesis of diabetes, per se.

CONCLUSIONS The antithetical clinical findings in diabetes mellitus and asthma, recognized in many earlier reports, may be explicable in the light of experimental data suggesting a diminished production of heparan sulfate in diabetes mellitus, and an increased production in asthma. Increased bradykinin levels in asthma, engendered or potentiated by the presence of H/HS in the can reach the point of clinical penetrance circulation, if the hydrolysis of bradykinin in the pulmonary circuit is depressed. Insulin is a potent endogenous depressant of bradykinin hydrolysis, and a paucity of insulin in diabetes would thereby be expected to potentiate bradykinin hydrolysis, and thus minimize the likelihood of emergent bronchospasm attributable to this peptide. On the other hand, a sufficiency of insulin would permit normal rates of carbohydrate utilization for proteoglycan formation, and would also impose a damping effect on bradykinin kininases, allowing increased levels of bradykinin to develop. This would explain the emergence of latent asthma in diabetics receiving insulin therapy. Other antithetical features of these two diseases--

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namely, the occurrence of decreased cholinergic activity and increased atherosclerosis in diabetes versus increased cholinergic activity and decreased atherosclerosis in asthma, may correspondingly depend upon the divergent concentrations of ubiquitous heparan sulfate, predicated for each of these diseases. Finally, the possibility that a diminished availability of heparan sulfate could down-regulate cholinergic transmission to insulin-producing cells, and thereby diminish the potentiating effect of acetylcholine on glucose-induced insulin release has also been considered.

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