review salicylates as hypoglycemic agents - diabetes care

Review

salicylates as Hypoglycemic AgentsSTEVEN H. BARON

Salicylates lower blood sugar and enhance glucose-stimulated insulin secretion in normal and diabeticman. Although the hypoglycemic effect appears to be mediated by enhanced insulin secretion, extra-pancreatic mechanisms cannot be excluded. The mechanism of the enhanced insulin secretion appearsto be mediated by prostaglandin synthesis inhibition. The effect of salicyiates on insulin secretion me-diated by other secretagogues is imprecisely known. In addition to their glucose lowering action, salicy-lates have been reported to lower free fatty acids, triglycerides, and cholesterol. Salicylates have beenimprecisely evaluated as hypoglycemic and hypolipidemic agents. Knowledge of their mechanism of ac-tion may provide further insight into the pathogenesis of diabetes mellitus and hyperlipidemic states.DIABETES CARE 5: 64-71, JANUARY-FEBRUARY 1982.

Some of the least appreciated pharmacologic effectsof salicylates are their ability to lower blood sugarand enhance insulin secretion. This review will sum-marize the clinical and animal literature pertaining

to these phenomena and offer a perspective as to future de-velopments in this field. In addition, the effect of salicylateson glucagon secretion and on free fatty acid, triglyceride,and cholesterol metabolism will be discussed.

CLINICAL STUDIES ON THE EFFECT OF SALICYLATES ON GLYCEM1AAND INSULIN SECRETION

The earliest observations of the hypoglycemic effect of sali-cylates were made over 100 years ago by a number of Germanphysicians who noted a diminution of glycosuria in diabeticpersons ingesting large quantities of sodium salicylate.1'2 Oneof the earliest records in the English literature of the effectsof salicylates was made by Williamson,3 who noted markedlydiminished glycosuria, weight gain, and a sense of well-beingin mild diabetic patients. This astute clinician also notedthat the occasional diabetic patient did not respond to salicy-lates, that high doses were required for a sustained effect, andthat salicylates were not efficacious in relieving severe symp-toms. Probably for these reasons, as well as the discovery ofinsulin, salicylates never became popular as hypoglycemicagents.

In the late 1950s, a resurgence occurred in the use of sali-cylate in clinical diabetes. The key observation was made byReid and his associates, who noted that a young insulin-

treated diabetic patient, who was ingesting more than 6 g ofaspirin daily for acute rheumatic fever, had normalization ofblood sugar, even during oral glucose testing, without theneed of exogenous insulin.4 Observations in seven additionaldiabetic patients of varying severity confirmed the hypogly-cemic action of aspirin and also established that the agenthad a hypoketonuric effect. In another publication, Reid andLightbody demonstrated that aspirin could replace insulin asa hypoglycemic agent in reasonably controlled insulin-re-quiring diabetic persons, but only at the cost of salicylatetoxicity.5

No doubt stimulated by the experience of Reid, other in-vestigators utilized aspirin in mild and insulin-requiring dia-betes and reported favorable results, with a minimum of ad-verse effects and with no episodes of hypoglycemia. Twolarge-scale studies are particularly relevant. Hecht andGoldner administered a minimum of 4.8 g of aspirin daily for1-3 wk to 13 nondiabetic and 12 diabetic inpatients andfound a moderate, though substantial, hypoglycemic effectin most instances in both groups.6 In the nondiabetic group,8 of 13 patients responded with an average diminution of thefasting blood sugar by 23 mg/dl, and in 7 of 10 patients givenan oral glucose challenge, a lowering of all values of the gly-cemic curve was observed. In the diabetic patients, who wereconcomitantly treated with diet, sulfonylureas, and/or insu-lin, 9 of 12 patients responded with an average decrease ofthe fasting blood sugar by 59 mg/dl, and two were able to becontrolled with salicylates only. Similarly, Anderson andThompson, administering aspirin in doses from 1.8 to 4.5 g

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SALICYLATES AS HYPOGLYCEMIC AGENTS/STEVEN H. BARON

daily for 3-42 wk to a geriatric population of 23 inpatients,found a consistent blood sugar lowering effect.7 In 3 of 5 pa-tients taking insulin and salicylates, insulin was discontin-ued, and another had a substantially lower insulin require-ment. Of the 23 patients, 5 had to discontinue aspirinbecause of complications, although none could be directlyattributed to aspirin.

Unfortunately, the precise role of aspirin in these uncon-trolled reports is difficult to ascertain. In particular, in nei-ther study is the role of diet and body weight adequately ac-counted for, although the latter may not have been a majorfactor, as evidenced by patients in both studies with im-proved glucose control despite weight gain. Furthermore, inneither study is it possible to decipher the respective hypo-glycemic effects of concomitantly administered insulinand/or oral agents as compared with aspirin.

In a controlled study using 6 g of aspirin daily in six dia-betic subjects, Gilgore reported a decrement of the meanfasting blood sugar from 371 mg/dl before aspirin treatmentto 128 mg/dl after 10 days of treatment.8 Five days after aspi-rin was discontinued, the mean fasting blood sugar rose to254 mg/dl. While on aspirin, four patients lost 1-4 lb, whilethe other two gained 3 and 4 lb, respectively. Four of thesubjects experienced adverse effects from aspirin, but it didnot necessitate discontinuing the drug nor cause diminishedfood intake. In a case report, Gilgore and Rupp relate thetreatment of an elderly diabetic woman who failed an initialcourse of tolbutamide and had been well maintained on 6 gof aspirin daily for a 28-mo period.9

A number of clinical studies have been reported demon-strating improved glucose tolerance and enhanced insulin re-sponse to a glucose load following the administration of vari-ous salicylate derivatives, either orally or intravenously. Ithas been demonstrated repeatedly that intravenous sodiumsalicylate decreases serum glucose in diabetic subjects10"15

and that this drug and lysine acetylsalicylate enhance the se-cretion of immunoreactive insulin.12'13'15"17 Using 3-methylsalicylic acid, Lightbody and Reid found that this drug had ahypoglycemic effect in diabetic subjects comparable to thatof aspirin at similar serum salicylate levels.18 Following theadministration of the same drug, Hyams et al. noted an en-hanced insulin response to glucose in both normal and dia-betic subjects, but improvement in glucose tolerance was in-consistent in the latter.19 Micossi et al. have shown both animproved glucose tolerance and enhanced insulin responseto oral glucose with moderate doses of aspirin in both types ofsubjects.20'21 In addition, both they21 and others14'22 haveobserved the restoration of the acute insulin response in typeII (non-insulin-dependent) diabetic subjects, as well as anaugmentation of the acute insulin response in normals21"24

following a 3-day administration of aspirin or an infusion ofsodium salicylate.

Prince and co-workers have further defined the sal icy late-induced insulin response to glucose by characterizing theirdiabetic subjects1 as C-peptide negative or positive. In C-pep-tide negative subjects, no change in serum levels of basal glu-cose or.of glucose during a glucose infusion occurred follow-

ing aspirin ingestion, while in similarly treated C-peptidepositive subjects, significant decreases in serum glucose fol-lowing aspirin treatment occurred, but without concomitantchanges in C-peptide levels. These results, coupled with aglucose clamp experiment in which glucose infusion follow-ing aspirin led to enhanced C-peptide levels, were inter-preted as evidence in support of salicylate-mediated en-hanced beta-cell sensitivity to glucose.15

In the only human study in which no effect by salicylateson either blood glucose or insulin levels was recorded, Belletand associates gave 600 mg aspirin q.i.d. to a group of nondi-abetic subjects, then measured glucose and insulin levels fol-lowing an overnight fast.25 Curiously, in their subgroup ofwomen aged 20-30 yr, the mean fasting blood sugar wasslightly increased, as was the fasting insulin level.

In contrast to the salicylate studies on glucose-stimulatedinsulin release, there are relatively few reports on the effectsof salicylates on amino acid-mediated insulin secretion, andthese give contradictory results. Enhancement of arginine-induced insulin secretion by salicylates was reported in bothnormals23 and in type II diabetic subjects,26 but in anotherstudy this was not found in normals or in C-peptide positivediabetic subjects.15

More clinical studies are needed to clarify the effect of sali-cylates on the insulin response of various insulin secreta-gogues in well-defined groups of diabetic persons. Such stud-ies will determine if the effect of salicylates on insulin secre-tion is limited to glucose or is generalized to other secreta-gogues.

ANIMAL STUDIES ON THE EFFECT OF SALICYLATES ON GLYCEM1AAND INSULIN SECRETION

In contrast to the clinical studies, animal data give con-fusing results that are difficult to interpret, probablybecause of protocol and species differences. For exam-ple, hypoglycemia,27 hyperglycemia,28"31 and no glu-

cose change28'32"34 have been reported following the parent-eral administration of salicylate in the normal rat, while inthe partially depancreatized35"37 and in the alloxan-diabeticrat31"33'38 diminished glycosuria and decreased blood glucosehave been observed. Consistent with the salicylate-inducedhypoglycemic reports is the study of Mortimer and Lepow,39

who observed in normal rats that a 4-day fast during whichsalicylate was given resulted in both lower blood sugar and adiminished glucose response to epinephrine. In a glucose tol-erance study in rats, Smith found that salicylates diminishedoral glucose tolerance, but had no effect on i.v. glucose tol-erance.29 In the dog, improvement in intravenous glucosetolerance was noted at relatively high serum salicylate levels(mean, 21.5 mg/dl), but not at low levels (mean, 5.3mg/dl).40 In another canine study, hyperglycemia was notedfollowing salicylate administration,41 but no glucose changewas noted in two other studies.42'43 In rabbits, no change inblood glucose occurred following 3 days of i.v. salicylate.44

Observations in animals on the effect of salicylates on in-sulin secretion have yielded variable results. Almost 20 years

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SAL1CYLATES AS HYPOGLYCEMIC AGENTS/STEVEN H. BARON

ago, Seltzer found no elevation of canine pancreaticoduo-denal vein insulin following the systemic administration ofsalicylate.45 However, as pointed out by others,12 Seltzerused a relatively insensitive bioassay technique to measureinsulin. In contrast, Vik-Mo and his associates found de-creased levels of plasma insulin following salicylate adminis-tration to anesthetized dogs,43 while Baron and Foa found nochange in insulin secretion following intravenous glucose toaspirin-treated dogs.40 Using rabbit pancreatic pieces, Cooreand Randle found a salicylate-induced inhibition of insulinsecretion,46 as did others with intact rabbits.44 In the per-fused rat pancreas,47 no effect by salicylates on insulin secre-tion was observed, while both no effect48 and an inhibitionof insulin secretion49 have been reported in incubated ratislets. In another study in rats, Arnold and Feinstrom dem-onstrated that salicylates decreased both serum glucose levelsand insulin secretion after an oral glucose load, and that thediminished glucose levels could not fully account for the di-minished insulin.50 In the hamster, islets derived from aspi-rin-treated animals,51 as well as islets incubated51 and peri-fused52 with aspirin, showed no change in insulin secretion.

From the above, it is apparent that the effects of salic-ylates on glucose metabolism and insulin secretion arecomplex, and vary depending on species and experimentalconditions.

EFFECTS OF SALICYLATES ON GLUCAGON SECRETION

Few studies have been reported on the effects ofsalicylates on glucagon secretion. Following insulin-induced hypoglycemia in normals, Metz and his asso-ciates reported that sodium salicylate enhanced the

counterregulatory stimulation of glucagon secretion.53 Usingantisera specific for pancreatic glucagon, two groups haveshown that aspirin enhances fasting glucagon levels in bothnormal and diabetic patients.15'21 In the study of Prince andassociates, both C-peptide positive and negative diabetic sub-jects had enhanced fasting glucagon levels in response toaspirin, but statistical significance was achieved only in theC-peptide negative group.15 Despite higher aspirin-inducedbasal glucagon levels in normal and diabetic subjects, nochanges in glucagon levels following intravenous glucoseloading occurred.15 During an oral glucose load in aspirin-treated normals, glucagon levels were appropriately sup-pressed, but at higher levels compared with controls, whileduring similar testing in aspirin-treated type II diabetic sub-jects, glucagon levels paradoxically (as expected) increased,but also at higher levels compared with controls.21 In con-trast, other workers, using 30 K antiserum, found no differ-ence in basal glucagon levels before or after aspirin treat-ment in normal54 and insulin-dependent diabetic subjects,55

and in glucagon levels following tolbutamide stimulation innormal54 and arginine stimulation in diabetic subjects.55

In dogs, aspirin increased basal glucagon levels and gluca-gon levels during an intravenous glucose load.40 However,this observation may be explained in part by salicylate-in-duced damage to the canine stomach mucosa,56 which is

abundent with glucagon-containing cells,57 as well as by aspecific pharmacologic effect upon the alpha cell.

MECHANISM OF ACTION

Human studies indicate that the hypoglycemic effect of sali-cylates is mediated, at least in part, by enhanced insulin se-cretion. Since salicylates inhibit prostaglandin synthesis in avariety of tissues,58 it has been proposed that a similar actionoccurs in the pancreatic beta-cell, and that this inhibition isrelated to enhanced glucose-induced insulin secretion.59 Themost convincing evidence supporting this contention comesfrom a study using sodium salicylate in monolayer cultures ofneonatal rat pancreases. Using this model, Metz and co-workers demonstrated concomitant enhanced insulin secre-tion and diminished prostaglandin E synthesis.60 In man, theonly species in which salicylates have repeatedly been shownto be insulinogenic, there is indirect evidence supportingthis contention. In normal man, infusions of prostaglandinE2 and a methylated E2 analogue inhibit the acute insulin re-sponse to a glucose pulse,22'61"63 while, as noted, salicylatesenhance the acute insulin response in both normal and dia-betic subjects.20'22 In addition, the infusion of lysine acetyl-salicylate in normals reverses and also augments the glucose-induced acute insulin response blunted by furosemide, astimulator of endogenous PGE synthesis.64 On the otherhand, Spellacy and co-workers, studying nondiabetic third-trimester pregnant women and using substantially lowerdoses of PGE2 compared with those used by others,22'61 63

found no change in either glucose or insulin levels.65

The interrelationship between salicylates and insulin se-cretion has been further refined by Robertson and his col-leagues. In normals, they have demonstrated that the glu-cose-induced acute insulin response inhibited by an infusionof epinephrine is partially restored by the concomitant infu-sion of sodium salicylate, a finding consistent with the hy-pothesis that endogenous PGE synthesis mediates alpha-ad-renergic inhibition of insulin secretion.66"69

Observations in diabetic subjects in whom salicylateslower blood glucose with either a decrement or eliminationof the insulin dose,4"7 and in animals in which salicylateslower glucose without concomitant increases in insulin se-cretion,40'50 suggest that the hypoglycemic effect of salicy-lates may also be mediated by mechanisms other than en-hanced insulin secretion.

What might these mechanisms be? In the laboratory ani-mal and under appropriate conditions, salicylates have a gly-cogenolytic effect in liver28'31*32'34'70 and in muscle.71"73

These relatively transient effects are difficult to reconcilewith the long-term dimunition of blood glucose seen inman.6 Furthermore, in man, salicylates appear to have littleeffect on glycogen metabolism, as evidenced by a normal re-sponse to glucagon in aspirin-treated subjects.6 Recently,Woods and associates have demonstrated in the perfused ratliver that sodium salicylate inhibits gluconeogenesis fromtwo major glucose precursors, lactate and alanine,74 andhave suggested that this effect may be due to the uncouplingof oxidative phosphorylation75 and to the inhibition of the


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SALICYLATES AS HYPOGLYCEM1C AGENTS/STEVEN H. BARON

enzyme alanine aminotransferase. In addition, others havereported aspirin-induced inhibition of gluconeogenesis in in-cubated rat slices but enhanced gluconeogenesis in renal tis-

sue.'A salicylate-induced inhibition of intestinal glucose ab-

sorption appears unlikely because aspirin does not interferewith glucose absorption in man,4 although contradictoryfindings have been reported with animal preparations.77'78

Another possibility is that salicylates may stimulate basalmetabolic rate (BMR) and thus cause a lowering of bloodglucose. This hypothesis finds support in the observations ofReid et al.4 but not in those of other workers.8'42 Additionalevidence against this possibility has been found in studies inwhich the hypoglycemic effect of 2:4 dinitrophenol (DNP)and aspirin, both administered to diabetic subjects to pro-duce comparable increases in BMR, was compared.79 In thiscase, aspirin had a substantially greater hypoglycemic effectthan DNP, suggesting that enhanced BMR is not responsiblefor the fall in blood sugar.

It appears possible that the glucose lowering action of aspi-rin may be mediated by an enhanced peripheral glucose up-take independent of any insulinogenic effect. However, evi-dence from in vitro studies is confusing and contradictory,and from human studies lacks definitiveness.. Studies on iso-lated muscle tissue derived from normal rats have shown thatsalicylates enhanced,80 inhibited,71'73 or had no effect on theuptake of glucose.71>73>81 Despite assertions that differencesof media composition are responsible for these discrepan-cies,80'82 various investigators using the same media havefound different effects, for reasons that are obscure. With abicarbonate buffer, Manchester and his associates80 foundenhanced glucose uptake, whereas Segal and co-workers81

and Huggins and Smith73 found no effect. Using a phosphatebuffer, Smith and Jeffrey71 observed, depending on thelength of time of incubation, both no effect and inhibitionby salicylate on glucose uptake, while Huggins and Smith73

observed inhibition. In patients with mild diabetes, Stowersand co-workers83 found that salicylates given during glucoseloading enhanced glucose capillary-venous difference, a find-ing consistent with increased peripheral uptake. In addition,changes in other metabolic parameters, including serumpyruvate, lactate, potassium, and inorganic phosphate, wereconsistent with such an effect. However, insulin levels werenot measured in this study, leaving doubt regarding the pos-sible role of the hormone in the observed changes. Perhapsthe most convincing evidence suggesting a direct salicylate-induced stimulation of peripheral glucose uptake came fromLinbeck and his associates,84 who induced clinical hypogly-cemia, without augmentation of insulin levels, by the oraladministration of aspirin to an infant.

EFFECT OF SALICYLATES ON PLASMA LIPIDS

A decrease,55'85'86 increase,87 and no change12*25'88

in serum levels of free fatty acids have been re-ported following salicylate administration tonormal and diabetic subjects, while decreased

FFA were found in rats89'90 and in rabbits.44 The discrepan-

cies found in the human studies may be explained by the useof FFA analytical procedures, which may be interfered withby salicylates85 in the reports finding an increase or nochange in serum FFA.

The salicylate-induced decrement in FFA levels may bethe result of a direct effect of the drug upon adipose tissue.When rat epididymal fat bodies were incubated with andwithout sodium salicylate, FFA liberation was decreased inthe presence of salicylate.85 In tracer studies in diabeticman85 and dogs,43 the results have been consistent with sali-cylate inhibition of FFA release. In addition to salicylate-mediated inhibition of adipose tissue lipolysis, there also isevidence of salicylate-enhanced re-esterification of FFA inthe same tissue.91 Despite the attractiveness of attributingthe decreased FFA levels to salicylate-enhanced insulin se-cretion, no such correlation was found in a human study, 21

while in a dog study, FFA levels decreased despite diminu-tion in serum insulin.43 Similarly, in insulin-dependent pa-tients administered aspirin, decreased FFA levels were notedwithout concomitant changes in circulating C-peptide.55

Aspirin has been reported to decrease serum triglyceridesin rats92 and in type II diabetic subjects,21 but not in nondia-betic subjects.21 In a study using a purified preparation ofpara-aminosalicylic acid, Barter and co-workers noted amodest fall in triglycerides in patients with type II A and II Bhyperlipoproteinemia, and in those patients with serum tri-glycerides greater than 200 mg/dl, treatment with PAS led toan average 28% reduction.93 Since aspirin exerts effects simi-lar to clofibrate in the rat liver, i.e., proliferation of cytoplas-mic peroxisomes,94 enhanced peroxisomal fatty acyl-CoAoxidizing activity, and enhanced peroxisome associated poly-peptide content,92 it would appear that the hypotriglyceride-mic mechanism of these drugs is similar.

Reports of the effects of aspirin on serum cholesterol inhumans are contradictory. Aspirin, at the dose of 1.5 gdaily, has been reported to lower serum cholesterol in hyper-cholesterolemic patients,95 while others have noted an effectonly at toxic doses of 5 g or higher.96"99 On the other hand,Micossi et al. found no change in cholesterol levels in eithernondiabetic or diabetic subjects following 10 g of aspirin ad-ministered over 4 days.21 Interestingly, MacDougall andAlexander have observed that subjects with cholesterolvalues greater than 280 mg/dl respond best,99 and the lack ofsubjects with cholesterol levels greater than this in the studyof Micossi et al. may account for their negative findings.

In contrast to aspirin, para-aminosalicylate has been dem-onstrated in multiple studies to have a cholesterol loweringeffect in both normocholesterolemic100 and hypercholestero-lemic patients.101"104 However, use of this drug has been cur-tailed because of its unpalatability and gastrointestinal ad-verse effects. A purified preparation of PAS, which is welltolerated, has been shown to have a substantial cholesterollowering effect in both type II A and II B patients for up to1 yr.93

PERSPECTIVE

In type II diabetic persons, diet and weight control are themainstays of treatment. However, dietary compliance is only


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sporadically achieved, necessitating other modes of therapy,i.e., sulfonylureas or insulin, whose precise roles in the treat-ment of type II diabetes remain controversial. In patients inwhom oral agents are indicated, it is conceivable that salicy-lates may play a therapeutic role. This was suggested overtwenty years ago,105 but it has been heretofore unappre-ciated.

The characteristics of diabetic patients who might benefitfrom salicylates remain to be determined, although there islimited evidence suggesting that such patients tend to bemoderately to severely hyperglycemic.6"8 Considering thehigh primary and secondary failure rate of the sulfonyl-ureas,106 an alternative agent, particularly one that is inex-pensive, in which massive pharmacologic data are available,and whose adverse effects are familiar to all physicians,would be a welcome therapeutic addition. However, clinicalstudies are needed to define those diabetic patients whoseglycemia responds best, the doses needed to effect a hypogly-cemic response, and the potential synergism of action of sali-cylates and sulfonylureas.83 With regard to the latter, there isevidence that aspirin enhances the hypoglycemic effect ofthe second generation oral agent glipizide107 and the insulinresponse to intravenous tolbutamide.54

The same considerations regarding the hypoglycemic ac-tion of salicylates apply to their hypolipidemic effects. Spe-cifically, the characteristics of hyperlipidemic patients, bothdiabetic and nondiabetic, in whom salicylates might be effi-cacious, the dosage needed to effect a hypolipidemic re-sponse, and the potential synergism with other establishedhypolipidemic agents need to be determined.

Despite these exciting therapeutic possibilities for salicy-lates, their propensity to cause adverse effects, particularlyon the gastrointestinal tract, would appear to limit their po-tential widespread use at the moderate to high doses thatwould probably be needed to exert their hypoglycemic andhypolipidemic effects. Nonetheless, imaginative pharmaco-logic manipulations, such as inserting aspirin in place of afatty acid residue of the triglyceride molecule,108 may obviatesuch difficulties.

Still to be determined is the interaction that salicylateshave on the function of the platelet and endothelial prosta-glandin systems. Although diabetic individuals have hy-peraggretable platelets,109'110 and inhibition of this hyperag-gregative state may be beneficial to prevent vascularcomplications,110 the doses of salicylates needed for a meta-bolic effect may concomitantly inhibit endothelial throm-boxane production, leading to unwanted and potentially ad-verse vasoconstriction and thrombosis.111

It is apparent that salicylates have a multiplicity of poorlyunderstood effects on carbohydrate and lipid metabolism.Whether they shall remain as pharmacologic probes for met-abolic investigation, or find a new role as hypoglycemicand/or hypolipidemic agents, remains to be determined.

ACKNOWLEDGMENTS: The secretarial assistance of PamelaJoyce is gratefully acknowledged. This work was supported inpart by National Institutes of Health grant AMO5469.

From the Division of Endocrinology, Department of Medicine,Veterans Administration Medical Center (HIE), 16111 PlummerStreet, Sepulveda, California 91343.

Address reprint requests to Steven H. Baron at the above ad-dress.

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