PRELIMINARY REPORT

Carbohydrate Intolerance in Gout

By GUSTAVE DENIS AND MARC P. LAUNAY

A three-hour oral glucose tolerance test (OGTT) was carried out in thirty consecu- tive cases of gouty arthritis. All subjects were male members of the Canadian Armed Forces. According to the most widely used criteria, the OGTT curve was “borderline” in two-thirds of the subjects, and strongly suggestive of diabetes in one- third to one-half. Depending on the cri- teria used for diagnosis, from 7 to 55 per cent of the subjects were “established” diabetics. In none of the 30 subjects had diabetes been previously suspected. It is apparent that the variability of currently

accepted criteria for the interpretation of the OGTT, especialy in the range where a distinction is established between those individuals with a diabetic tendency and those without, greatly affects the signif- icance of studies such as this one. It is difficult, however, not to conclude that in the present group, carbohydrate intoler- ance of the type found in diabetes mel- iitus was much more frequent than could be explained by chance alone. (Metabo- lism 18: No. 9, September, 770-775, 1969)

F EW PRACTITIONERS have had occasion to observe both gout and diabetes mellitus in the same individual. The rare occurrence of this

combination is not a mere clinical impression and has been confirmed in a number of studies. Mikkelsen’s recent and exhaustive review refers to no less than eighteen publications on the gout-diabetes association: older investigators found gout in S-9% of diabetics, whereas in two large series published in the past decade, it was observed in only 1.8 and 0.8 per cent, respectively, of subjects with diabetes.’ The evidence on the prevalence of hyperuricemia in diabetes is conflicting, as two separate groups of investigators recently re- ported increased serum uric acid levels in 2.4 and 24.8 per cent of their cases, respective1y.l The frequency of diabetes in gouty subjects has been variously reported as being between 3 and 8 per cent,l but Weiss et al.” and Herman3 observed a decrease in carbohydrate tolerance in approximately one-fourth of their patients with gout.

There appears to be some relationship between gout and diabetes mellitus by which these two widespread metabolic errors are associated more often than can be ascribed to chance alone. In spite of a century of scientific observation,” little is known of the epidemiological, clinical and, above all, the pathophysio- logical aspects of this relationship. The authors have undertaken long-term in- vestigations designed to explore the latter, and present herein preliminary results on the tolerance to carbohydrate of 30 individuals with gout.

-____ __.~ From the Department of Physiology, University of Montreal, Montreal, Canada. Received for publicution February 20, 1969. Supported by Grant MA 1839 from the Medical Research Council of Carlada. Presented in part at the Ninth Annual Clinical Conference of the Canadiarz Forces

Medical Service, kkgstorl, Onturio, April 1968 GUSTAVE DENIS, M.D.: Assistant Professor, Department of Physiology, Urliversiry of

Montreal, Montreal, Canada. MARC P. LAUNAY, M.D., M.Sc.: Consultant in Endocrirfology, Verdun General Hospitul, Montreal, Canada.

770 METABOLISM, VOL. 18, No. 9 (SEPTEMBER). 1969

CARBOHYDRATE INTOLERANCE 771

Table l.-Criteria for Interpretation of Oral Glucose Tolerance Test ___.. __- -___

Values Essential - Type of OGTT Curve Source 0

Venou; Bloo; Sugar 3 Hours for Positiveness

Borderline

Probable Diabetes

Chemical Diabetes

Wildberger & Rickettsr 90 150 90 105 170 105

Joslin Clinics 130 150

Wilkerson et a1.Q 100 1.50 110 115 170 125

1 % % Wildberger & RickettsP 110 170 120

125 195 140 Joslin Clinics 110 1.50 120

125 170 140 Wilkerson et al.9 110 170 120

125 195 140 1 1% %

Mosenthal & Barry10 150? 100 170 120

Fajans & ConnIl 160 120 180 140

British Diabetic Ass.12 160t 110 180 125

90 105 *

Any one

100 Two points or more 115 or one point from

1 point diabetic values 110 Any three 125 110 Any one 125 110 Two points or more 125

1 point Both

Both

Both

* Figures in italics are values obtained with Folin-Wu methods. Others are values ob- tained with “true glucose” methods.

i Maximal value, not necessarily after one hour.

MATERIALS AND METHODS

All 30 subjects were members of the Canadian Armed Forces who had been referred to the Internal Medicine Clinic at the Saint-Hubert air base for management of gout.. From the cases thus gathered in the past two years, the only ones excluded from the experimental series were those in which the original diagnosis could be questioned on clinical or other grounds. Appropriate investigation had shown that in every case the gout was of the primary type.

All subjects were males, with an age range of 27 to 52. Six had a body weight more than 20 per cent over the standard obtained from the Build and Blood Pressure Study (Society of Actuaries, 1959). Diabetes had never been suspected in any of the subjects.

After determination of serum uric acid level by a modified Caraway procedure,5 each subject was submitted to an oral glucose tolerance test (OGTT) in the following way: with no preparation other than overnight fast, blood sugar was determined before and I?, 1, 2, and 3 hours after oral administration of 100 Gm. of glucose. Sugar level in whole venous blood was measured by a modified Folin-Wu method,6 with all determina- tions being done by the same person, and the laboratory normal being 91.3 2 11 mg. per cent (mean t S.D.).

The results of the OGTT were then interpreted according to the most common criteria used to differentiate normal, borderline, prediabetic and diabetic curves (Table 1). To enable comparison with other data, Table 1 shows for each set of criteria whole blood sugar levels obtained by the widespread “true glucose” methods as well as by the method used in the present study.

RESULTS

The data collected in the 30 cases of gout appear in Table 2. Application

of the criteria described in Table 1 to the OGTT curves (Table 3) indicates

772 DENIS AND LAUNAY

Table Z.-Observations in 30 Males with Primary Gout __ ___ _ AS Obesity * Serum Uric Acid (mg. %)

0 ____.____~.

27 6.8 108 30 8.1 100 30 9.0 117 35 + 6.3 94 38 9.4 100 38 + 8.3 102 39 8.9 102 40 8.0 99 40 7.5 90 40 8.2 82 41 8.0 86 41 6.2 122 42 + 7.4 88 42 7.5 126 42 8.0 146 42 6.9 101 42 7.8 106 44 10.4 106 45 + 9.2 108 4.5 8.6 112 46 + 8.4 111 46 8.6 110 46 + 8.7 118 48 7.7 98 49 7.4 96 49 7.6 124

50 7.2 119 50 7.6 90 51 8.9 96 52 7.7 106

___~

Bloq/ Sugar Afte; Glucose lOO_ Gm. P.O. 2 L 3 Hours

140 128 100 130 110 90 166 158 138 176 134 66 140 180 118 217 223 160 160 124 93 200 184 122 130 104 90 152 186 172 145 114 75 172 160 112 116 112 99 252 300 238 232 220 138 169 180 134

142 140 124 142 124 96 244 224 152

216 246 158 192 210 151 148 142 90 210 252 208 198 216 170 168 138 140 172 202 130 145 158 112 138 106 52 178 210 165 138 188 160

68 85

112 -

64 84 80

102 80

108 61 62 92 98 72 95

106 60 80 80

101 86 84

158 44

124 98 68 86

102 - ._

* Considered obese subjects whose body weight was greater than standard weight for their age by more than 20 per cent.

Table 3.-Glucose Tolerance in 30 Cases of Primary Gout

Criteria of _____- Wildberger & Joslin Clinic* Willgnm Mosenthal &

Rickettsv 0 Barry’0 Fg;;l+ British Diabetic

Association” .._ ___-_ __~__ _____

Borderline 23 18 - - - -

Probable Diabetes - - 10 - - -

Chemical Diabetes 2 16 2 14 10 13 ____

that ( 1) in the majority of gouty subjects, the glucose load was not tolerated as well as by normal subjects; by the two appropriate sets of criteria, a border- line OGTT was observed in 23 (76% ) and 18 (60% ) cases, respectively; (2) glucose intolerance of a degree sufficient to strongly suggest the presence of diabetes was found in one-third of the subjects; and (3) the OGTT was diagnostic of established diabetes in 7 to 55 per cent of cases, according to the criteria used.

Statistical analysis of the data showed that there was no correlation between

CARBOHYDRATE INTOLERANCE 773

Table 4.-Prevalence of Positive Oral Glucose Tolerance Test ~____ ~___ ______ ---

Criteria of Unselected Population Present Population ---- _____-__ Wilkerson et al.9 3.5% (57)9 7% (30)#<

1.2% (176)ls Mosenthal and Barry19 8 % (5O)lO 47% Fajans and Corm11 5.6% (176)la 33% British Diabetic Association12 6.8% (176)13 43%

__- * Size of group appears in parentheses.

the serum level of uric acid and the blood sugar concentration, either in the fasting state or two hours after administration of glucose.

DISCUSSION

Apart from its specific purpose, this study illustrates how difficult it is to determine the true prevalence of diabetes in any given group. Observed pre- valence figures greatly vary with the critreia used to distinguish normal from abnormal blood glucose levels, before or after a glucose load, and the choice of criteria is itself influenced by the observer’s concept of the natural course of the disease. The lack of agreement on diagnostic criteria stems from the fact that the localization, along the spectrum “homozygote carrier state-ab- normal glucose reactor state-chemical diabetes,” of the point where the metabolic disturbance becomes truly pathological remains the subject of con- siderable controversy. This has striking effects on epidemiological studies, which can be divided into “high-prevalence” and “low-prevalence” according to the choice of either highly sensitive or highly specific diagnostic tests. O’Sullivan and Williams, for example, found that in a large unselected population the prevalence of diabetes varied from 1.2 to 21.8 per cent, according to the criteria used.13 The same type of discrepancy is present in our own data, and if it is not possible to ascertain from these observations the true proportion of diabetics among our gouty subjects, it remains that in one-third or more of them, glucose intolerance was diagnostic of chemical diabetes by four widely accepted sets of criteria.8J0-12 The usefulness of the present data is certainly diminished by the absence of a suitably matched control group, but this is partly compensated by existing data available in the literature (Table 4).

Studies similar to this one have been done in the past. Weiss et al. quote the 1940 report of an Italian investigator who found abnormal blood glucose levels in eight out of ten cases of gout, while they themselves observed some increased blood glucose levels, either in the fasting state or after a glucose load, in 28 per cent of 143 cases of gout and in only 15 per cent of a similar number of nongouty nondiabetic subjects.2 Application of their criteria, once corrected by a factor of 0.14 to allow for differences in methods of blood sugar determination, shows that similarly abnormal blood glucose levels were present in 19, or 63 per cent, of our 30 cases. Herman reported finding an elevated fasting blood sugar in 37 per cent of 82 gouty individuals,3 and it can be estimated from his data that the OGTT was abnormal in 38 per cent of those in whom it was performed. Mikkelsen investigated 17 gouty subjects and found in four of them a “typically diabetic” OGTT and in seven others

774 DENIS AND LAUNAY

a postprandial blood sugar level strongly suggestive of chemical diabetes1 Maclachlan performed an OGTT in 29 cases of gout and found an abnormal ( > 120 mg. per cent at two hours, “true glucose” method) result in 25 of these subjects but in only 40 per cent of the contro1s.l”

A diabetic state, or at least a state of impaired carbohydrate tolerance, thus appears to exist in a proportion of individuals with gout. Even though it cannot be defined with precision, this proportion is nevertheless impressive. The physiopathologic basis for this relationship between gout and diabetes is en- tirely unknown. Genetic linkage has been suggested because of the simultaneous presence of both diseases in more than one generation of a number of families,3,4.‘5 but this interesting hypothesis has yet to be systematically verified. The appearance in gouty individuals of a purine metabolite with alloxane-like properties is purely speculative. lS Of more immediate importance is the ques- tion of the natural course of the diabetes developed by subjects with gout. Older author? have suggested that in such cases the diabetes is exceptionally mild, and more recent data1 confirm this impression, If this is truly the case, the relationship between the two diseases would appear unique in that gout, after having unmasked another metabolic disturbance, would eventually curtail its development.

Further studies designed to explore the nature of the biochemical links between gout and diabetes and the reciprocal influence of the two are presently under way. From what is known now, one can draw the practical conclusion that an OGTT should be included in the initial work-up and repeated period- ically thereafter in every case of hyperuricemia. This will lead to the early discovery of a good number of diabetics and may materially affect the prognosis in a few of them.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the technical assistance of Sgt. Z. Courteau and the cooperation of members of the Canadian Armed Forces who were the willing subjects of this study.

REFERENCES

1. Mikkelsen, W. M.: The possible as- 6. Folin, O., and Wu, H.: A system of sociation of hyperuricemia and/or gout with blood analysis-A simplified and improved diabetes mellitus. Arthritis Rheum. 8:853, method for determination of sugar. J. Biol. 1965. Chem. 41:367, 1920.

2. Weiss, T. E., Segaloff, A., and Moore, 7. Wildberger, H. L.. and Ricketts, H. T.: C.: Gout and diabetes. Metabolism 6: 103, Prediabetes. Med. Clin. N. Amer. 47:61, 1957. 1963.

3. Herman, J. B.: Gout and diabetes. 8. Krall, L. P.: When is diabetes? Med. Metabolism 7:703, 1958. Clin. N. Amer. 49:893, 1965.

4. Charcot, J.-M.: Lecons cliniques sur 9. Wilkerson. H. L. C.. Hyman. H., Kauf- les maladies des vieillards et les maladies man, M., McCuistion, A. C., and Francis, chroniques (Clinical lectures on diseases J. O’S: Diagnostic evaluation of oral glu- of old age and chronic diseases). Paris, case tolerance tests in nondiabetic subjects Delahaye, 1874. after various levels of carbohydrate intake.

5. Caraway, W. T.: Determination of New Eng. J. Med. 262:1047, 1960. uric acid in serum by a carbonate method. 10. Mosenthal, H. O., and Barry, E.: Cri- Amer. J. Clin. Path. 25:840, 1955. teria for and interpretation of normal glu-

CARBOHYDRATE INTOLERANCE 775

case tolerance test. Ann. Int. Med. 33: 117.5, 1950.

1 I. Fajans, S. S., and Corm, I. W.: Early recognition of diabetes mellitus. Ann. N. Y. Acad. Sci. 82:208, 1959.

12. FitzGerald, M. G., and Keen, H.: Diagnostic classification of diabetes. Brit. Med. J. 1:1568, 1964.

13. O’Sullivan, J. B., and Williams, R. F.:

Early diabetes mellitus in perspective: A population study in Sudbury, Massachusetts. JAMA 198:579, 1966.

14. Maclachlan: Discussion of Reference 1. Arthr. Rheum. 8:860, 1965.

1.5. Bartels, E. C., Balodimos, M. C., and Corn, L. R.: The association of gout and diabetes mellitus. Med. Clin. N. Amer. 44: 433, 1960.