Glucose metabolism and β receptor function in atopic asthmatics

Biomed& Pharmacother(1990)44,41-52 0 Elsevier, Paris

47

B receptor functio

iucose

tics

AM Kamik 1*9KA Gumaa 2, RT Guindi ‘, FF Fenech 2 ’ Department of Medicine, Kuwait University; 2 Department of Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait (Received 20 June 1989; accepted 19 October 1989)

Summary - Severe asthma and diabetes have been reported not to co-exist in the same patient. Various studies have attributed this to the possible association of asthma with hyperinsulinism, increased responsiveness to insulin or to betablockade. Previous studies have not addressed all these possible mechanisms in the samepatient.In this prospective study. 7 atopic asthmatics and 7 age and sex-matched healthy controls underwent glucose, insulin and glucagon tolerance tests. The results showed no evidence of hyperinsulinism or increased responsiveness to insulin. Jntravenouz administration of glucagon. however, showed a lesser increase of glucose and insulin in asthmatics. Since glucagon has a p-agonist effect on the liver and activates glycogenolysis and gluconeogenesis via p-receptor stimulation and stimulates insulin secretion by activating adenylate cyclase of pancreatic B-cells through e-receptors, the results of glucagon tolerance test in our study may therefore suggest the presence of partial beta-blockade in atopic asthmatics. asthma / beta-receptors / glucose metabolism R&urn4 - MBtabolisme glucosique et la fooction de beta-rkepteur dans I’asthme atopique. II a dt?jk&t! signal6 qu’on

ne pouvait trouver d la fois un asthme se’vPre et un diabate chez le m&e malade. Diverses ktudes ont artrib& ce ph6nomSne b une possible association de l’asthme avec un hyperinsulinisme. d une riponse accrue d l’insuline et b un blocage b&a. Les Ctudes d6jd metties n’ont cependant pas & consacrkes h ces diffirents mkanismes possibles chez le mi?me malade. Dans le p&sent travail prospectif. sept malades atteints d’asthme atopique et sept tPmoins bien portants, comparables pour la Gpartition des ciges et des sexes, ont subi des tests de tolkance au glucose, B l’insuline et au glucagon. Les rt%ultats n’ont pas mis en Pvidence d’hyperinsulinisme ou d’accroissement de la riponse i l’insuline. L’ariministration intra-veineuse de glucagon a montrk nt!anmoins une tSarion du glucose et de l’insuline moins nette cher les asthmatiques. Compte-tenu du fait que le glucagon exerce un effet agoniste b&a sur le foie. qu’il active la glycogholyse et la gluconJogetu?se par l’intermidiaire de la stimulation des rkepteurs b&a. afn qu’il stimule la &t&ion d’insuline en activant l’adhyl cyclase des cellules b&a du pan&as via les r&epteurs b&a. Les rbultats des test de tolhance dons la prksente itude pourraient suggher la presence d’un blocage b&a partiel chez les malades atteints d’un asthme atopique.

asthme 1 b&a rkcepteur I metabolisme glucosique

Introduction Severe asthma not to co-exist

and diabetes have been reported in the same patient [l, 71. This

was attributed to possible association of asthma with hyperinsulinism [l], or that asthmatics possibly make more economical use of insulin and have increased responsiveness to its hypoglyl

Correspondence and reprints

cemic action [26]. In 1967 the “beta-adrenergic blockade theory” of bronchial asthma was proposed 1271. This theory hypothesized that the fundamental abnormality common to all asthmatics may be an inherited or an acquired deficiency of adenylate cyclase, thereby producing a state of partial beta-blockade. While further studies [2, 11, 16, 241 supported this hypothesis, others [13, 18,

48

A M Karnik ef 01 .

201 considered the partial eta-bl~kade to be an acquired phenomenon and not a basic defect. Additionally, the @-adrenergic hyporesponsiveness has been attributed either to decreased number of p-receptors [4, 5, 6, 211, or to p-receptor antibodies [28, 291. Glycogenolysis and lipolysis are two areas of catccholamine activity in which the mediating role of 3’, 5”-CAMP has been studied in detail [2S]. Various authors have studied the metabolic response of asthmatics to epinephrine and have shown that asthmatics responded less to the effects of epineph~e than did non-asthma~c individuals [lo, 15, 193. The altered carbohy~ate metabolism in asthmatics may, in addition, be due to the rapid utilization of glucose, a possibility which has not been previously investigated. In the present study an attempt was made to assess all the 3 proposed mechanisms ie, the rapid utilization of glucose, hyperinsulinism and increased sensitivity to insulin and B-blockade in the same patient. Seven atopic asthmatics and sex and agematched controls underwent glucose, insulin and glucagon tolerance tests to evaluate their utilization of glucose, the dynamics of insulin metabolism and the p-receptor response respectively.

Patients and Methsds Selection of patients and controls Seven non-obese, non-diabetic, atopic male asthmatic patients (with a history of other atopic diseases, and/or raised IgE levels) were selected for the study. AI1 of them had mild stable asthma and none was in acute attack at the time of the tests. The duration of asthma ranged from l-7 yr except for one patient who had had occasional asthmatic attacks since childhood. Two patients were using s~~tamol inhaler as and when requited, 3 were using satbutamol and beclomethasone inhalers on a regular basis, and 2 were using disodium cromoglycate by spinhalers regularly. None were on xanthine preparations regularly and had not received oral corticosteroids within the last 6 months. The dose of salbutamol used was 0.1 to 0.2 mg/inhalation. Only 20% of the inhaled dose is absorbed [14] and we felt that this small amount would not produce any systemic effects. The average age of the patients was 29 f 3.6 yr, weight 60.4 + 7.5 kg and height 168 f 5.9 cm. Seven age-matched, non-obese, non~ia~tic males acted as controls. All were hospital staff and volunteered for the tests. None had a history of asthma, chronic chest problems, atopic diseases or other systemic illness at the time of the tests or in the past. Physicat examination of these subiects was normal; they had

normal blood sugar and normal liver and renal profiles. Their average age was 28.1 + 2.6 yr, weight 56.1 f 4.7 kg and height 161 f 4 cm. The asthma patients as well as the healthy volunteers gave informed consent for the tests. Approval of the Ethics Committee of Kuwait University had been obtained before beginning the study. Protocol performed after an overnight fast. Pulse and blood pressure were checked and an intravenous can&a was inserted in an antecubital vein and heparinized and the subject was allowed to rest for half and hour. Ten and 5 min before the injection, blood was collected for the estimation of glucose and insulin. The first 1 ml of blood, contaminated with heparin, was discarded. Subsequently, Zml aliquots of blood were collected and sent to the laboratory for analysis. The dose of the 3 drugs administered and the time-intervals at which the blood was sampled, are given below.

The tests were

Glucose test. Fifty ml of 25% glucose was given intravenously. Blood sampling was performed at IO-min intervals for 60 min and an additional sample was collected at 90 min after the injection. rusuljn test. Soluble insulin was administered intravenously at a dose of 0.1 unit/kg bw. Blood was sampled at 5-min intervals during the first 20 min after the injection; thereafter, 3 samples were collected at 15 min intervals and a final sample was collected at 90 min. Glucagon test. Glucagon was administered intravenously at a dose of 7 pg/kg bw. Blood was sampled as for the glucose test. During the insulin and glucagon tests, blood glucose changes were monitored at the bedside by a Reflomat (Boehringer Mannheim, Gmb, Mannheim, FRG) to diagnose dangerous hypoglycemia. None of the subjects developed hypoglycemia severe enough to necessitate te~ination of the test. Methods Blood glucose was determined by the glucose oxidase method using “Glucose Enzymatique FAP” reagents from BioMBrieux(Marcy I’Etoile, France). Insulin was determinedby radioimmunoassayusing Pharmacia100 Insulin RIA kits (PharmaciaDiagnostics AB, Uppsala, Sweden). Glucose disappearance from the circulation was calculated from the. slope of the change in the blood glucose concentration (expressed as the logarithm) with time, starting 20 min after the challenge. Results were expressed as the mean f SD of 7 observations performed in duplicate in each group. Statistical analysis of the data was performedusing the two-tailed Student’s r-test.The level of statisticaldifference was 53P 0.05.

Glucose

metabolism and p receptor function in atopic asthmatics

Rem1 ts The fasting levels generally lower in subjects (table I). of asthmatics was controls (t = 5.06,

The response of asthmatics to the IV-GTT was similar to that of controls except for the consistently lower blood glucose and higher insulin levels (table II). This was reflected in the smaller area under the glucose curve, and the larger area under the insulin curve for asthmatics. Nevertheless, none of these changes attained statistical significance. The calculated rates of change per min in blood glucose following the IV-GTT were almost identical for asthmatics and controls (fig 1). In contrast with the responses to the IV-G’IT’, the responses of blood glucose and insulin to glucagon administration (fig 2) were consistently lower in asthmatics. This decrease was more apparent for insulin which was statistically significant 10 min after the challenge (t = 2.962, P< 0.02). However, the areas under the curves in asthmatics and controls for blood glucose (47.8 4 6.4 and 52.4 + 6.4 units) and for insulin (168 f 69 and 234 f 110 units), although lower in

of glucose and insulin were asthmatics than in the control Only the lower blood glucose statistically different from the PC 0.001).

Table I. Fasting blood glucose and insulin in asthmatics and controls. Results are the mean f SD of 7 subjects in each group. The values for glucose and insulin were from 6 determinations per subject on different days. Group

Asthmatics Controls

Glucose

Insulin

(mmoill)

(~Uhll)

4.47 _+0.65 5.06 f0.38

49

11.5 zk7.0 13.9 k7.7

Table II. Changesin blood glucose and insulin in asthmatics and controls durhig the intravenous glucose tolerance test (IV-GIT) and the insulin tolerance test (ITT). Results represent the mean f SD of 7 subjects in each group. Area denotes the area under the glucose or insulin curves determined as Z[glucose] or Z[insulin] respectively. Glucose (mmolll)

Time (min)

IV-GTT 0 10 20 30 40 50 60 90 Area ITT 0 5 10 15 20 25 30 35 45 60 90 Area

Asthma

4.5 kO.7 12.5 zk2.0 11.2 * I.0 9.8 f 1.1 8.4 + 1.2 7.4 11.6 6.7 zk1.4 5.2 f0.7 68.8 f 8.9

4.5 4.3 3.6 3.1 2.6 2.4 2.2 2.2 2.6 3.2 3.7 36.6

50.7 fO.l f0.2 zko.2 f0.3 +0.3 f0.4 f0.2 kO.3 kO.4 kO.6 f 2.5

Insulin (~Uiml) Control

Asthma

Control

5.1 15.5 13.2 11.1 9.5 8.4 7.1 5.8 76.7

+ 0.4 zk 1.9 f I.4 * 1.3 f 1.0 zk 1.3 +I 1.3 EL 0.5 f 11.2

11.5 54.8 44.9 39.9 38.0 34.1 31.2 20.8 280

f 7.0 f 11.1 f 11.2 f 19.4 f 17.3 f 20.9 f 23.4 z!z 19.6 fll0

13.9 43.1 37.6 36.9 35.3 29.0 29.5 19.4 239

zk 7.7 f. 20.3 f 11.4 f 8.1 f 13.6 f 7.8 f 12.3 + II.5 +64

5.1 4.7 3.4 2.7 2.4 I.8 2.2 2.2 2.9 3.4 4.0 38.8

kO.4 f0.4 kO.7 f0.7 kO.7 kO.7 f0.4 kO.5 kO.4 kO.4 kO.5 f3.0

11.5 441 303 189 II3 58.9 51.4 35.2 23.8 17.2 12.7 1164

f 7.0 I? I91 f114 + 55 f 31 + 24.4 + 24.8 zk 9.0 zk 9.5 f 6.2 + 8.0 +374

13.9 526 347 226 156 125 69.0 39.4 31.2 34.5 22.6 1549

* 7.7 f169 * 94 zk106 f 68 f 30 f 27.4 +- 4.4 f 8.0 zk 33.1 + 8.4 z!z435

50

A M

Karnik

et ai

asthmatics than in controls, did not attain statistical significance. Again, the rates of change per minute for glucose were almost identical for both groups and decreased linearly with time 30 min after the glucagon challenge (fig 1). The administration of insulin resulted in very similar changes in blood glucose and insulin levels in both asthmatics and controls (table II). The areas under the corresponding curves, though generally lower in asthmatics, were not statistically different from control values. The rates of change per min for glucose showed a linear increase with time 30 min after the insulin challenge {fig I).

iscussion Oh ,

I

I

1

I

40

20

Time

60

imint

Fig 1. Rates of chrnge in blood glucose foIlowing the in-

travenous ~dminisIr~Iion 7 JQ ~iuca~~kg b.w. ( tion of 0.1 IU insulin/kg spectively. Filled symbols represent asthmatics and open symbols represent controls respectively.

The significantly lower faiting blood glucose level found in asthmatics cannot be attributed to hyperinsulinism since their plasma insulin levels were lower than in control subjects, and the insulin to glucose ratio was identical for both groups. This lower blood glucose could be the result of decreased rates of glucose production by glycogenolysis and/or gluconeogenesis. Both of these processes are activated by p-receptor stimulation [S]. Glucagon has a p-agonist effect on the

0 I

0

-

I

I

I,,

30

Time

Fig 2. point

,

ii0

,

,

SO

1 II

’

n

I

‘

30

0

(a&)

lime

I

60

I

I,

50

(min)

Changes in {a) blood glucose and (b) plasma insulin following the administration of glucagon (7 pg/kg bw. IV). Each

represents the mean + SEM of 7 observations determined in duplicate. * Denotes

PC

0.02.

Glucose

metabolism

and p receptor function in atopic asthmatics

liver and activates both of these processes, resulting in hyperglycemia [S]; and in the pharmacologic doses used in this study may increase the secretion of growth hormone and catecholamines. The latter two are known to be hyperglycemic. Blockade of &receptors would thus be expected to result in decreased glycemic response to a challenge with glucagon. This was indeed the case in the present study. Moreover, glucagon administration could not elicit as much an insulin secretory response in asthmatics as it did in controls (fig 2). This is consistent with the view that glucagon could stimulate insulin secretion fl2, 231 by activating the adenylate cyclase of pancreatic pcells through @eceptors. We did not observe differences between asthmatics and controls in their hypoglycemic responses to exogenous insulin. Jt is therefore unlikely that there were differences in insulin receptors or in the glucose metabolic pathways in these two groups. The response to exogenously administered glucose was similar in asthmatics and in controls. In contrast to glucagon which stimulates insulin secretion through P-receptors, glucose stimulates insulin secretion through as yet undete~i~ed receptors, probably by activating phospholipase C [17] which results in increased turnover of phosphoinositides and secondarily in the influx of calcium [3, 91. Asthmatics secrete more insulin in response to a glucose load than do controls, but the difference was not statistically significant perhaps because of the small group size. Neverthel.ess, this increase above control levels may explain why asthmatics maintained a lower blood glucose level throughout the IV-GTT, and hence a smaller area under the glucose curve than did the controls. It may therefore be concluded that asthmatics may be partially protected against diabetes mellitus by virtue of the state of partial P-blockade and possibly by the greater sensitivity of their pancreatic P-cells to stimulation by glucose. We found no evidence of more rapid utilization of glucose in asthmatics compared to controls. There is also no evidence of hyperinsulinism or increased responsiveness to insulin in asthmatic patients. The present study does not exclude the possibility of genetic factors protecting asthmatics against diabetes, such as the presence of HLADR2 [22-j

51

We wish to thank the research assistants Dr Sawsan Abdul Aziz Madi, and Mrs AA Karnik for their help in conducting the various tolerance tests. The skilled technical assistance of Mrs V Sidhan is greatly appreciated. This work was supported by Kuwait Unive~i~ Research Grant No MM o/o.

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