Brief Communications

nfluence of Smoking on Insulin Requirement

and Metabolic Status in Diabetes Mellitus

S. MADSBAD, P. McNAIR, M. S. CHR1STENSEN, C. CHRISTIANSEN, O. K. FABER, C. BINDER, AND I. TRANSB0L

This study was performed in order to examine the influence of tobacco smoking on carbohydrate and
lipid metabolism and microangiopathy in diabetic patients with normal serum creatinine. Among 163
adult insulin-treated patients 114 smoked daily (smokers). Compared with nonsmokers, smokers had
on the average a 15-20% higher insulin requirement (P < 0.001) and serum triglyceride concentration
(P < 0.05), increasing to a 30% rise in heavy smokers (P < 0.01). The degree of retinopathy was
equal in the two groups, as was the average creatinine clearance [99 2 (mean 1 SEM) versus
101 it 4 ml/min in smokers compared with nonsmokers]. Smokers and nonsmokers were comparable
regarding sex ratio, age at diabetic onset, duration of diabetes, residual beta-cell function, fasting
hyperglycemia, and glycosuria. Evidently, tobacco smoking represents a strain on both carbohydrate
and lipid metabolism in insulin-treated diabetes mellitus. DIABETES CARE 3.- 41-43, JANUARY-FEBRUARY 1980.

ecent reports indicated associations between smoking and the frequency of both diabetic nephropathy1'2 and retinopathy,2'3 although others have
challenged these observations.4 A comparison
between metabolic indices was not performed in any of these
investigations. We therefore studied the influence of smoking
on endogenous insulin secretion, insulin dosage, and carbohydrate and lipid metabolism in a large group of adult insulintreated diabetic patients. Furthermore, ophthalmoscopy and
creatinine clearance were compared in smoking and nonsmoking patients.
PATIENTS

The investigation was performed as a cross-sectional study

of 163 insulin-treated diabetic outpatients aged 21-70 yr,
with normal serum creatinine levels (<115 /nmol/L). None
of the patients had known endocrine diseases other than
diabetes mellitus or were treated with oral antidiabetic agents,
diuretics, anticonvulsants, lithium, neuroleptics, or betablocking agents. Detailed information on the exclusion criteria has been presented previously.5 Patients who smoked
daily at the time of the study were classified as smokers (N
= 114) and the remainder as nonsmokers (N = 49) (Table
1). The duration of diabetes varied between 0 and 29 yr,

and the frequency distribution in the following three classes,

0-9, 10-19, and >20 yr, was 77, 57, and 29 patients,
respectively.
METHODS

The quantitation of smoking was estimated, by personal

interview, as the daily number of cigarettes smoked during
the last month before the study. One cigar equaled 1^2
cigarettes, but less than 5% of the smokers used cigars. The
insulin requirement was calculated for each patient as the
dose of insulin given at the time of investigation (IU/kg/day).
Blood samples were obtained after an overnight fast and
tobacco abstinence, before the administration of insulin.
Endogenous insulin secretion was measured by the serum
concentration of immunoreactive C-peptide 6 min after i.v.
injection of 1 mg glucagon: A C-peptide level exceeding
0.05 nmol/L signifies residual beta-cell function.6 Glucose,
creatinine, cholesterol, and triglyceride levels were measured
by methods routinely used in our laboratory. The ophthalmoscopic findings of a routine examination performed by an
eye specialist were graded as follows: Grade 0: normal fundi;
Grade I: minor changes (microaneurysms and/or exudates
smaller than microaneurysms); Grade II: microaneurysms plus
larger hemorrhages; and Grade III: exudates and proliferative

DIABETES CARE, VOL. 3 NO. 1, JANUARY-FEBRUARY 1980

41

Smokers
No. of patients
Sex ratio (F/M)
Age (yr)
Duration of diabetes (yr)
Weight (kg)

114
0.30
41.5 1.4
11.5 1.3
64.6 0.8

Nonsmokers

Significance
of difference

49
0.31
44.6 2.0
11.3 1.9
66.9 1.9

NS
NS
NS
NS

0.6-

en

bUUN1 DOSEJ

TABLE 1
Clinical data in 163 insulin-treated adult diabetic patients grouped according
to smoking habits (values given as mean 1 SEM)

/day

INFLUENCE OF SMOKING ON INSULIN REQUIREMENT/S. MADSBAD AND ASSOCIATES

0.5-

0.4-

NS, not significant (P > 0.05).

1.2-

retinopathy. Student's t test and chi-square test were used

for statistical evaluation of the differences between averages
and frequencies.
LU
U

RESULTS

1.0-

cc

The smokers and nonsmokers were comparable in all essential clinical data (Table 1). Metabolic data are given
in Table 2. Both the insulin requirement and the mean
serum triglyceride level were about 20% higher in the smoker
group. The mean levels of blood glucose, serum cholesterol,
and glycosuria were similar in the two groups. An insignificantly higher percentage of the nonsmokers had some endogenous insulin secretion preserved. However, also in patients
without residual beta-cell function, the mean insulin requirement was significantly higher (16%) in smokers than in nonsmokers (P < 0.001).
The insulin dosage and serum triglyceride concentration
in relation to the amount of smoking are presented in Figure
1. In patients smoking less than six cigarettes daily, the
insulin requirement and serum triglyceride level were comparable to those found in the nonsmokers. Patients smoking
more than five cigarettes daily have, on the average, 30%

FIG. I. Insulin dose and serum triglyceride concentration in 49 insulintreated diabetic nonsmokers (O) and in 114 smokers ( ) subdivided
according to daily tobacco consumption. Each point represents

TABLE 2
Metabolic data in 163 insulin-treated adult diabetic patients grouped
according to smoking habits (values given as mean 1 SEM)

DISCUSSION

Insulin dosage (IU/kg/day)

Percent with B-cell function
Blood glucose (g/L)
Glycosuria (g/24 h)
S-Triglyceride (g/L)
S-Cholesterol (g/L)

Smokers

Nonsmokers

0.54 0.02
31
2.15 0.08
60 6
0.97 0.06
2.16 0.04

0.44 0.02

NS, Not significant (P > 0.05).

42

43
2.20
62
0.81
2.11

0.12
9
0.04
0.06

Significance
of difference
P < 0.001
NS
NS
NS
P < 0.05
NS

5:
LU

NUMBER OF CIGARETTES

if)

0
Patients:

~5

I49II 19 I 28

10

15

I 31 I

20

1T~

36

mean 1 SEM.

higher insulin dosage and serum triglyceride concentration

(P < 0.001 and P < 0.01, respectively).
The frequency and severity of retinopathy were comparable
in smokers and nonsmokers (Table 3). The mean creatinine clearance was 99 2 (1 SEM) versus 101 4 ml/min
in the smokers and nonsmokers, respectively.

he present study clearly demonstrates that smoking

is a strain on carbohydrate metabolism in diabetic
patients. Smoking patients, comparable to nonsmokers respecting sex ratio, age, duration of
disease, body weight, and beta-cell function, required 20%
more insulin to maintain similar levels of fasting blood glucose
and 24-h glycosuria.
Smoking also interferes with lipid metabolism, as evidenced
by a 15% higher mean level of fasting triglycerides in smoking
patients. This was related to the amount of smoking: A 30%
increase in serum triglycerides was thus observed in patients

DIABETES CARE, VOL. 3 NO. 1, JANUARY-FEBRUARY 1980

INFLUENCE OF SMOKING ON INSULIN REQUIREMENT/S. MADSBAD AND ASSOCIATES

TABLE 3
Retinopathy grading of 163 insulin-treated adult diabetic patients grouped
according to smoking habits
Retinopathy
(grade)
0
1
11
III

Smokers (%)
(N = 114)

Nonsmokers (%)
(N = 49)

Significance
of difference

54

61
13
20
6

NS
NS
NS
NS

20

24
2

NS, not significant (P > 0.05).

smoking more than 10 cigarettes per day. There was no

difference in mean serum cholesterol levels between smokers
and nonsmokers. The rise in fasting triglycerides was found
after at least 8 h abstinence from smoking, and therefore
seems to be a constant abnormality in smoking diabetic patients. Studies on long-term effects of smoking on serum
level of cholesterol and triglycerides in normal subjects are
conflicting, but increased serum levels of both cholesterol
and triglycerides were found in several studies on heavy smokers.7 We recently confirmed this in a large group of early
menopausal women (unpublished data).
Smoking is known to increase lipolysis and to release lactate
from muscles.8'9 Similar effects are known to be mediated
by catecholamines.10 Because smoking also stimulates the
secretion rate of catecholamines,8'9 the increased insulin
requirement and hypertriglyceridemia in diabetic smokers
may be secondary to raised catecholamine levels.
The possible influence of smoking on diabetic microangiopathy has recently been evaluated.1"4 Although no influence
can be demonstrated in adult-onset diabetes,4 certain groups
revealed associations between rather heavy smoking and proliferative retinopathy or chemically evident nephropathy.1"3
Our use of elevated levels of serum creatinine as a criterion
of exclusion prevents us from evaluating the entire range
of microangiopathic abnormalities. It is remarkable, however, that creatinine clearance and the degree of retinopathy
were identical in smokers and nonsmokers, who were also
strictly comparable regarding sex ratio and duration of diabetes. Obviously, more investigations are needed to clarify
if smoking is more deleterious in diabetic subjects than in
normal man.

ACKNOWLEDGMENTS: This work was supported by grants from

the Danish Hospital Foundation for Medical Research, Region

of Copenhagen, Faroe Islands, and Greenland; the Danish
Diabetic Association; the Danish Medical Research counsil;
Dr. Erik Garde and Elisabeth Garde's fund; and Nordisk
Insulinfoundation.
From the Department of Clinical Chemistry, Glostrup Hospital,
DK-2600 Glostrup; Hviddre Hospital, DK-2930 Klampenborg;
and Division of Endocrinology, Department of Internal Medicine,
Hvidovre Hospital, University Hospital of Copenhagen, DK-2650
Hvidovre, Denmark.
Address reprint requests to Sten Madsbad, M.D., Hvidtfre Hospital, DK-2930 Klampenborg, Denmark.

REFERENCES
1
Sandahl Christensen, J., and Nerup, J.: Smoking and diabetic
nephropathy. Lancet 1: 605, 1978.
2
Nielsen, M. M., and Hjtfllund, E.: Smoking and diabetic microangiopathy. Lancet 2: 5 3 3 - 3 4 , 1978.
3
Paetkau, M. E., Boyd, T. A. S., Winship, B., and Grace, M.:
Cigarette smoking and diabetic retinopathy. Diabetes 26: 4 6 - 4 9 ,
1977.
4
West, K. M., and Stober, J. A.: Smoking and diabetic retinopathy. Lancet 2: 4 9 - 5 0 , 1978.
5
McNair, P., Madsbad, S., Christiansen, C , Faber, O. K.,
Transbil, I., and Binder, C : Osteopenia in insulin treated diabetes
mellitus: its relation to age at onset, sex and duration of disease.
Diabetologia 15: 8 7 - 9 0 , 1978.
6
Hendriksen, C., Faber, O. K., Drejer, J., and Binder, C.:
Prevalence of residual B-cell function in insulin-treated diabetics
evaluated by the plasma C-peptide response to intravenous glucagon.
Diabetologia 13: 6 1 5 - 1 9 , 1977.
7
U. S. Department of Health, Education and Welfare: The
health consequences of smoking. A reference edition. Washington,
D. C , HEW Publication N o . (CDC) 78-8357, 1976.
8
Kershbaum, A . , Khorsandian, R., Caplan, R. F., Belief, S.,
and Feinberg, L. J.: The role of catecholamines in free fatty acid
response to cigarette smoking. Circulation 28: 52 57, 1963.
9
Cryer, P. E., Haymond, M. W., Santiago, J. V., and Shah,
S. D.: Norepinephrine and epinephrine release and adrenergic mediation of smoking associated hemodynamic and metabolic events.
N . Engl. J. Med. 295: 5 7 3 - 7 7 , 1976.
10
Kingsbury, K. J., and Jarrett, R. J.: Effects of adrenaline and
smoking in patients with peripheral atherosclerotic vascular disease.
Lancet 2: 2 2 - 2 3 , 1967.

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