Chlorpropamide-alcohol flushing, malar thermal circulation index, and baseline malar temperature

Chlorpropamide-Alcohol Flushing, Malar Thermal Circulation and Baseline Malar Temperature Jonathan

Index,

K. Wilkin

Chlorpropamide-alcohol flushing (CPAF) has been advanced and challenged as a specific marker for familial noninsulin dependent diabetes mellitus. The previous studies assay flushing reactions employing arbitrarily defined critical threshold values of rise and rate of rise in facial temperature. Since these methods ignore the curvilinear relationship between skin temperature and cutaneous blood flow, errors of analysis obtain. Further, the role of baseline facial temperature is obfuscated. The method of malar thermal circulation index derived from the relationship between skin temperature and cutaneous blood flow provides a more accurate assay method and permits the characterization of the role of baseline facial temperature. Baseline facial temperature is less in subjects with CPAF and noninsulin dependent diabetes than in normal subjects. The lower baseline facial temperature alone may account for the reported differences in the parameters of the CPAF test.

I

N 1978 Pyke’s group at King’s College Hospital reported exciting results from a simple test, the provocation of flushing by a combination of chlorpropamide and alcohol. They concluded that chlorpropamide-alcohol flushing (CPAF) is a dominantly inherited trait, that CPAF is associated with noninsulin-dependent diabetes (5 1%) but not insulin-dependent diabetes (only lo%), and that non-insulin dependent diabetics who are CPAF-positive are less likely to develop retinopathy and macroangiopathy.‘-4 Since the pure opiate antagonist naloxone blocked CPAF, and CPAF is mimicked by an enkephalin analogue with opiate-like activity, they suggested that CPAF results from an increased sensitivity to endogenous opiates.’ Since enkephalin and other opioids affect carbohydrate metabolism and insulin release, Pyke suggested that these endogenous opiates act as neurotransmittors causing non-insulin-dependent diabetes by a sympathetically mediated effect on the liver and pancreas.sV6 Keen’s group at Guy’s Hospital concluded that the site of enkephalin activity in CPAF is central rather than peripheral.’ Additionally, they found that CPAF could be blocked by aspirin, and they proposed a prostaglandin-dependent step, probably central.* Others have suggested that the prostaglandin dependent step operates peripherally.g Since indomethacin blocked CPAF in patients with non-insulin-dependent diabetes who were free of vascular complications but not in those with such complications, Pyke’s group suggested a role for prostaglandins in the etiology of From the Departmeni of Dermatology, The University of Texas Medical School at Houston, P.O. Box 20708. Houston, Texas. Received for publication Supported in part by a Dermatology Foundation Research Gram. Address reprint requests to Jonathan K. Wilkin, M.D., Department of Dermatology. The University of Texas Medical School at Houston, P.O. Box 20708, Houston, Texas 77030. 0 1982 by Grune & Stratton, Inc. 0026~495/82/3109~016%01.00/0

948

both retinopathy

and macroangiopathy associated with diabetes.” Jerntorp’s group found that plasma acetaldehyde concentration was higher in CPAFpositive subjects than CPAF-negative subjects,” and that serum chlorpropamide level may be a critical factor in CPAF.” In the CPAF theory both genetic and physiologic elements of diabetes mellitus are attractively interwoven. In 1980 discordant reports appeared. Kobberling’s group at Gottingen argued that the studies by Pyke’s group on flushing induced by the enkephalin analogue did not justify the conclusion that endogenous opioids play a role in mediating CPAF. They pointed out that the difference between the CPAF-positive and CPAFnegative groups is solely due to the difference in baseline malar temperature (Tmb).13 Other workers found that the prevalence of CPAF in patients with non-insulin-dependent diabetes mellitus was only 20%. unlike the 51% reported by Pyke’s group,’ and was actually less common in those with a family history.14 Also, unlike Pyke’s group, Radder’s group at Leiden found no clear-cut threshold for rise in malar skin temperature (ATm) for CPAF in subjects with noninsulin-dependent diabetes mellitus.” This experience has obtained in other studies.‘4,‘6 Observing a prevalence of CPAF of 17% in both non-jnsulin-dependent diabetics and controls, Kobberling’s group concluded that CPAF is not specific for non-insulin-dependent diabetes.” DeSilva, Tunbridge and Alberti at Newcastle found a similarly low prevalence of 24% of CPAF among 50 non-insulin-dependent diabetics.18 Since many had a subjective flush when placebo was given instead of chlorpropamide, desilva, Tunbridge and Alberti regarded the “true prevalence” of CPAF as only 4%, i.e., the “prevalence” of CPAF minus the prevalence of flushing when placebo was given instead of chlorpropamide equals the “true prevalence” of CPAF. CPAF, however, is widely defined as a flush from 40 ml of sherry after pretreatment 12 hr earlier with 250 mg of chlorpropamide. Since CPAF is

Metabolism,Vol. 3 1,

No. 9 6eptember). 1982

CHLORPROPAMIDE-ALCOHOL

FLUSHING

it is incumbent upon the operationally defined, Newcastle group to establish that the mechanism of flushing after placebo and sherry is qualitatively and/ or quantitatively different from CPAF, before the construct of “true prevalence” can be accepted. It is entirely possible that the tendency to flush after sherry is related in part to the tendency to CPAF. The possible association of CPAF with familial non-insulin-dependent diabetes mellitus, and the implications for prognosis and new therapeutic strategies, cannot be considered trivial issues. The potential importance of CPAF demands a second look before accepting the death knell by Kobberling’s group and deSilva, Tunbridge, and Alberti. Although Kobberling’s group claims that “no plausible explanation can be provided for the differences between the results by Leslie and Pyke and their study,” at least some apparent discrepancies may be attributed to methodologic problems. In the report that follows I will consider the heuristic methods employed in the above studies, consider a more accurate method, and suggest that Tmb may be quite significant.

THE “CRITICAL

THRESHOLD”

ERROR

Without exception all of the studies cited above employ arbitrarily selected values of the change in malar temperature (ATm) in the interpretation of results of flushing monitored in the clinical laboratory. Pyke’s group considered a ATm of 1. I “C or more as a positive reaction,’ while Kobberling’s group, apparently in an attempt at greater specificity, regarded a ATm of I .2”C or more as a positive reaction.” Additionally, Pyke’s group arbitrarily defined blocking as a reduction of the expected ATm by more than 0.5°C.‘o Since flushing, a transient erythema of the face, results from an increased facial cutaneous blood flow, it would be logical to employ, as a measure of flushing intensity, a linear index of facial cutaneous blood flow. The method of interpretation based on arbitrarily selected threshold values suffers from several errors. The arbitrary selection of critical threshold values of ATm is implicitly based on the false assumption that skin temperature relates linearly to cutaneous blood flow. While skin temperatures lower than 30°C may appear to correlate linearly with cutaneous blood fto~,‘~ the relationship is actually curvilinear in the absence of modifying factors.*’ Assuming little or no metabolic heat production occurs in the skin and an ambient temperature lower than core temperature. then skin temperature should never exceed core temperature. Moreover, as cutaneous blood flow approaches infinity, the temperature of the skin will approach core temperature asymptotically (Fig. 1).

11111111111

1234567I

9 10 11 12 13 14 15 16 17 16 19 CutaneousBloodFlowIndex,MTCI

Fig. 1. Relationship of maiar temperature mal circuktion index of cutaneous blood flow.

to the melar ther-

The nature of the measurement scale determines which mathematical operations and statistics are permissible.2’ Since a ATm of 2.0°C from a Tmb of 3O.O”C indicates less of a flush than a ATm of l.O”C from a Tmb of 34.5V, it follows that the raw ATm cannot be interpreted in the absence of the Tmb (Fig. I). As a result, it is impossible to determine (1) the equality of intervals or differences, (2) greater or less, and (3) equality with ATm alone. Accordingly, comparison of mean ATm’s between two groups, order correlation statistics, and enumeration of cases in any groups defined by ATm alone are not permissible.2’ Thus, the method of interpretation based on arbitrarily selected threshold values suffers from several errors. On the other hand, these errors may be eliminated by considering the change in malar thermal circulation index (AMTC1).22.23 Briefly, this index is based on the law of heat flow (H):

H

=$(t,-

t2)

where h is the thermal conductivity, a parameter expressing the ease with which heat flows in the substance, a is the surface area, L is the effective thickness of the intervening substance. and t, ~ t2 is the temperature difference between each side of the substance. The derivation of AMTCI, which is based on two thermal gradients, and a consideration of some limitations of this method are more fully discussed elsewhere.23 The change in malar thermal circulation

JONATHAN K. WILKIN

950

index (AMTCI)

can be expressed Tmp AMTCI

as - Tap

= Tcp - Tmp Tmb - Tab Tcb - Tmb

where Tmb is the baseline malar temperature, Tab and Tcb are the ambient and core temperatures, respectively, during the baseline period, Tmp is the maximum malar temperature, and Tap and Tcp are the ambient and core temperatures, respectively, at the time of the maximum malar temperature. It is clear from this model that Tmb depends on ambient room temperature, an observation reported previously,

18.24

In a study of 162 challenges with flush-provocative agents employing the AMTCI method there were 71 positive flushing reacti0ns.l’ The sensitivity, specificity, and predictive value of a positive result for AMTCI 2 1.5 was 90.1, 95.6, and 94. I, respectively. The critical values of ATm selected by Kobberling (rl.2”C) and Leslie and Pyke (2 1. I “C) provide sensitivities of 54.9 and 63.4, respectively. At an ambient temperature of 23°C and a core temperature of 37°C for AMTCI 2 1.5, then ATm 2 [0.5(Tmb)’ + 30(Tmb) 425.5]/ [0.5(Tmb) + 2.51 (Fig. 2).23 Employing this new criterion for ATm based on Tmb and the curvilinear relationship between skin temperature and cutaneous blood flow, we may reconsider the data presented in the early studies. For example, Pyke’s group found that all 9 CPAF-positive

subjects flushed during the intravenous infusion of an enkephalin analogue, while all 8 CPAF-negative subjects did not exceed the critical threshold of I. I “C. Since the room temperature was always 23”-24OC, if one assumes a core temperature of 37”C, then the new value for ATm based on AMTCI ~1.5 would indicate that three of the 8 CPAF-negative subjects had a flush (Table 1). It is noted in the text that “only three CPAF-negative subjects reported facial symptoms and they had only a very slight flush.“‘ False negative flushes based on arbitrary critical thresholds are also identified in a recent study by Kobberling’s group in which 24 flushing challenges are described (Table 4 in ref. 17). Fifteen challenges led to flushing reactions in which ATm was greater than or equal to their arbitrarily established critical threshold of 1.2”C. In four apparently positive flushing reactions the ATm was less than 1.2%. In the five challenges in which flushing did not occur the ATm was also below I .2”C. The calculated sensitivity of this test employing Kobberling’s critical threshold value of ATm ~l.2”C is 78.9. If one assumes an ambient temperature of 23OC and a core temperature of 37V, then these data may be interpreted utilizing the ATm based on AMTCI 2 I .5 (Fig. 3). Employing this latter method all apparent flushes save one are greater than the critical threshold based on the curviiinear relationship between skin temperature and cutaneous blood flow (Fig. 3). Clearly, with the AMTCI method the sensitivity is 94.7 without any loss in specificity or predictive value of a positive result. That the arbitrary critical threshold method becomes increasingly inacTable 1. Interpretation of Date from Pyke’s Group on Flushing

1.6-

Provoked by an Enkephalin Analogue (Table in ref. 5). Three

1.5-

CPAF-negative Subjects are Identified as Flushing* by the AMTCI

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Fig. 2. Critical threshold values of Pyke,* Kobberling,” and Wilkin= based on change in malar temperature and baseline malar temperature.

15

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CHLORPROPAMIDE-ALCOHOLFLUSHING

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27.0 20.0 29.0 30.0 31.0 32.0 339 34.0 35.0 36.0 0trsllnr Mlr Tes0eshtra (Tmb).1: Interpretation of data of Kobberling’s group (Table 4 in Fig. 3. ref. 17) comparing their method with the AMTCI method.

curate the greater the Tmb, a concern stated earlier (I 8). is also evident by comparison with the AMTCl method (Fig. 2). In sum, not only is the theoretical basis for the AMTCI method secure, but, indeed, it works better than the arbitrary critical thresholds in analyzing the data presented in the earlier works. THE

“RATE

OF TEMPERATURE

RISE”

ERROR

DeSilva, Tunbridge and Alberti observed that, while ATm was an inadequate method, the rate of rise in malar temperature could discriminate.‘* Further, they suggested that “the rise in maiar temperature 20 minutes after the sherry may be a satisfactory discriminator.” Again, the error is the comparison of raw skin temperatures as indices of the flushing reaction (their

Fig. 3 in ref. 18 gives all Tmb’s at a common origin). Describing flushes with different Tmb’s from a common origin obscures the true relationship between skin temperature and intensity of flush (Fig. 4). Further, the different Tmb’s should lead to greater differences between maiar temperatures earlier in the course of the flushes. One may arbitrarily select a flush from a low Tmb and a flush of equivalent intensity from a high Tmb. If the rates of increase in cutaneous blood Row are equal, the time at which half the ATm occurs will be earlier for the flush beginning at the lower Tmb than for the flush beginning at the higher Tmb. By inspection (Fig. I) a flush from 3O.O”C to 32.O“C will have the same intensity as a flush from 35.0°C to 35.8OC. Assuming an identical constant rate of increase in cutaneous blood flow for both flushes. the abscissa will also represent the time course of the flushes. Thus, the time at which half the ATm is achieved will be earlier for the flush with the low Tmb. This results solely from the asymptotic curvilinear relationship between skin temperature and cutaneous blood flow. in sum, not only will the differences in Tmb between groups account entirely for the differences 20 min after the sherry (ITm 20). but may also prove to be a better discriminator. BASELINE

MALAR

TEMPERATURE

(Tmb)

Not only is the AMTCI method more accurate in assaying flushing reactions, but it may also be employed, in a manner unavailable to the arbitrarily defined ATm critical threshold method, to assess the effect of Tmb on the flushing reaction. While Pyke’s group found Tmb lower in CPAF-positive subjects than in CPAF-negative subjects, they denied any correlation between the increases in skin temperature and Tmb.’ Kobberiing’s group held that in the study by Pyke’s group the difference between the two groups

A

Fig. 4. A plot of Tm versus time illustrates the dependency of ATm 20 on Tmb better than e plot of ATm versus time depicting different Tmb’s at a common origin. ATme is the difference in malar temperature at a point early in the course of the flush: ATmp is the difference in the peak temperatures. All flushes are of equal intensity.

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was solely due to the difference in Tmb.” Keen’s suggested that the significantly lower Tmb in CPAF-positive subjects than in CPAF-negative subjects might indicate a state of tonic local vasoconstriction temporarily released by the alcohol challenge, with a resulting vasodilatory “overshoot” and flush.’ Later, Pyke’s group reversed their posture in observing an inverse relation between the Tmb and ATm on CPAF testing.” In addition, Tmb was found to be a major determinant of ATm in flushing in diabetics after intravenous glucose challenge.24 There may be two reasons why ATm is inversely related to Tmb. First, this relationship is predicted by the method of estimating flushing intensity by comparative analysis of calculated thermal gradients, i.e., the AMTCI method. Briefly, as may be seen in Fig. 1, the relationship between malar temperature and cutaneous blood flow in the face is not linear. At higher malar temperatures a small ATm may lead to greater cutaneous blood flow (and intensity of the flush) than an even larger ATm at a lower Tmb. As seen in Fig. 2, assuming an ambient temperature of 23°C and a core temperature of 37% for a Tmb of 35.0% ATm must be greater than or equal to 0.6”C for a flush; whereas, for a Tmb of 3O.O”C ATm must be greater than or equal to 1.4% for a flush. Thus, ATm must be inversely related to Tmb, since the relationship between skin temperature and blood flow is curvilinear. That ATm must be inversely related to Tmb on the basis of the physical law of heat flow does not exclude an additional role for low Tmb potentiating the flushing reaction. While the distinction between these two factors, viz., the inverse relationship due to heat flow kinetics and the potentiation by low Tmb of flushing reactions, has not been addressed previously, it is

‘. ‘*.

WnW WC TW

group

‘.

Fig. 5. A plot of AMTCI versusTmb may distinguish the relationship between flushing intensity and Tmb better then a plot of ATm versusTmb.

(Tmb)

doubtful that the existing method of an arbitrarily defined critical threshold for ATm could have separated these two roles. On the other hand, the AMTCI method may permit an enhanced discrimination between these two factors. Thus, plots of Tmb versus ATm might be quite similar whether intensity is unrelated to Tmb or intensity is inversely related to Tmb

.

3.0 2.4 2.3

.

2.2 2.1 2.0

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1.9 p

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1.6

5

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Fig. 6. Interpretation of data of Pyke’s group (Table in ref. 5) comparing their method with the AMTCI method.

CHLORPROPAMIDE-ALCOHOL

953

FLUSHING

(Fig. 5). If the intensity is indeed unrelated to Tmb then a plot of Tmb versus AMTCI should be flat. If the intensity is inversely related to Tmb then a plot of Tmb versus AMTCI should display a negative slope (Fig. 5). In a study of 162 flushing challenges AMTCI appeared to be unrelated to Tmb (slope = 0.082).23 If a low Tmb does not potentiate the intensity of the flushing reaction, then the AMTCI method may be used without modification in comparing two groups with different values of Tmb. Further, while one may attribute a larger ATm to a low Tmb. a low Tmb will not predispose to a greater AMTCI or intensity of fush. Thus, employing the AMTCI method in a reevaluation of the data from Pyke’s group,5 we still find a significant difference in enkephalin analogue provoked flushing between the CPAF-positive subjects, all of whom flushed, and the CPAF-negative subjects, only three of whom flushed. Therefore, the contention by Kobberling’s group that this difference can be attributed to only the difference in Tmb between the two groups” is unfounded (Fig. 6). The difference in Tmb between the CPAF-positive and CPAF-negative subjects is, however, not without considerable interest. A comparison between the Tmb of subjects with non-insulin-dependent diabetes mellitus and the Tmb of normals in Table 2 of the study by Kobberling’s group” shows a significant difference (Fig. 7). While Kobberling’s group pointed out the lower Tmb in CPAF-positive subjects in the study by Pyke’s group, it is curious that they did not comment on this same finding in their own study. The lower Tmb in diabetics may be due to a diabetic autonomic neuropathy, viz., the loss of innervation to the facial cutaneous blood vessels.2’ Moreover, the innervation to the cutaneous vasculature of the blush area is composed predominantly of vasodilator fibers,z6 the loss of which would lead to a relative vasoconstriction and lower Tmb. Perhaps a lower Tmb is a more specific marker for dominantly inherited non-insulin-dependent diabetes. If this is the situation then it is possible to understand why non-insulin-dependent diabetics should have a greater ATm during a flushing reaction (again, due to

N#lMh n=lO

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001 n=21 l

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Fig. 7. The values for Tmb between subjects with noninsulin-dependent diabetes and normal subjects are significantly different in the study by Kobberling’s group (Table 2 in ref. 171.

the curvilinear relationship between skin temperature and cutaneous blood flow) even if the “prevalence” of CPAF is not different between diabetics and controls. Thus, even if both groups had an equal prevalence of CPAF, given the lower Tmb of the diabetics, one should expect a greater ATm than would obtain with normals. It is possible that the occurrence of the flush may not be specific, but the parameters that characterize it may still specify a population predisposed to dominantly inherited non-insulin-dependent diabetes. The potential implications for CPAF are too important to consider the issue closed.

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large-vessel disease in non-insulin-dependent diabetes. Br Med J 2:261-262, 1980 5. Leslie RDG, Pyke DA, Stubbs WA: Sensitivity to enkephalin as a cuase of non-insulin dependent diabetes. Lancet I :34l-343. 1979 6. Pyke DA: Diabetes: The genetic connections. Diabetologia 17:333-343.1979 7. Jefferys DB. Strakosch CR, Keen H: Facial flushing in diabetes. Lancet 2: I 195. 1979

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JR: Diabetic

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vasomotor J Physiol