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Inhibitory Effect of Circulating Insulin on Glucagon Secretion During Hypogjycemia in Type T Diabetic Patients DATING LIU, MD ULF C.K. ADAMSON, MD, PHD PER-ERIC S. LINS, MD, PHD MAGNUS E. KOLLIND, MD, PHD ERIK A.R. MOBERG, MD KARIN ANDREASSON, BSC

OBJECTIVE— To clarify whether the circulating insulin level influences hormonal responses, glucagon secretion in particular, during hypoglycemia in patients with insulin-dependent (type I) diabetes. RESEARCH DESIGN AND METHODS— Nine type I diabetic patients were studied. During two separate experiments, hypoglycemia was induced by low-dose (244 pmol • kg" 1 • h" 1 ) and high-dose (1034 pmol • kg" 1 • h" 1 ) intravenous insulin infusion, for 180 min in each case. The arterial blood glucose level was directly monitored every 1.5 min, and glucose was infused in the high-dose test to clamp the arterial blood glucose level to be identical as in the low-dose test. RESULTS— Despite the fact that the plasma insulin level was four times higher in the high-dose than in the low-dose test (740 ± 50 vs. 180 ± 14 pM), a close to identical arterial hypoglycemia of —3.3 mM was obtained in the two experiments. During hypoglycemia, a significant rise of the plasma glucagon level was found only in the low-dose test (188 ± 29 vs. 237 ± 37 ng/L, P < 0.05), and the incremental area under the glucagon curve was significantly greater in the low-dose than in the high-dose test (140 ± 19 vs. -22.7 ± 34 ng/L • h" 1 , P < 0.005). The responses of plasma epinephrine, norepinephrine, growth hormone, pancreatic polypeptide, and somatostatin were similar in both tests and, consequently, were not significantly modified by the circulating insulin level. CONCLUSIONS— This study demonstrates that, in type I diabetic patients, the glucagon response to hypoglycemia is suppressed by a high level of circulating insulin within the physiological range. Our findings may help to explain the impairment of glucagon secretion during hypoglycemia frequently seen in these patients.

FROM THE KAROLINSKA INSTITUTE, DEPARTMENTS OF MEDICINE AND CLINICAL CHEMISTRY, DANDERYD HOSPITAL, STOCKHOLM, SWEDEN. ADDRESS CORRESPONDENCE AND

REPRINT REQUESTS TO

DATING

LIU,

MD,

KAROLINSKA INSTITUTE,

DEPARTMENT OE MEDICINE, DANDERYD HOSPITAL, 1 8 2 8 8 DANDERYD, STOCKHOLM, SWEDEN. RECEIVED FOR PUBLICATION 30 MARCH 1991

DIABETES CARE, VOLUME 15,

AND ACCEPTED IN REVISED FORM 28 AUGUST

NUMBER 1, JANUARY

1992

1991.

S

eventeen years have passed since the deficient glucagon response to insulin-induced hypoglycemia was first described by Gerich et al. (1) in insulin-dependent (type I) diabetic patients. Since then, this defect has been recognized as almost universally present in type I diabetic patients after a few years of the disease, and when it coexists with a defective epinephrine response to hypoglycemia, the diabetic patient will be prone to develop severe hypoglycemia (2-8). Despite many efforts to discover the cause of the deficient function of the A-cell during hypoglycemia, the underlying mechanism of this defect is not fully understood, although some factors (e.g., chronic hyperglycemia and autonomic neuropathy) have been ruled out (7-22). Among the factors regulating the function of the pancreatic A-cell, glucose and intraislet insulin are believed to be of major importance. Several animal studies have demonstrated that insulin in the islet exerts an inhibitory action on A-cell secretion (23-29), and circulating insulin has been shown to suppress the A-cell function during normoglycemia in man (30). We recently demonstrated in healthy humans that a high, yet physiological, level of insulin in the circulation exerts a specific inhibitory effect on the response of the pancreatic A-cell to hypoglycemia, whereas other counterregulatory hormones are not simultaneously suppressed (31). In another study of nondiabetic humans, however, a high concentration of circulating insulin was also found to suppress the secretion of other counterregulatory hormones (e.g., catecholamines and growth hormones; 32). In contrast, another group of investigators reported that insulin enhanced the catecholamine response during hypoglycemia in dogs (33). The injection of insulin into type I diabetic patients through the subcutaneous route gives rise to systemic hyperinsulinemia and, therefore, it seems essential to discover whether an inhibitory

59

Glucagon response to hypoglycemia in type I diabetes

Table 1—Characteristics of the insulin- dependent diabetic patients

PATIENTS

1 2 3 4 5 6 7 8 9 MEDIAN

BODY

DURATION

DAILY DOSE

INSULIN BINDING

AGE

MASS

OF DIABETES

OF INSULIN

TO ANTIBODIES

HBA1C

SEX

(YR)

INDEX

(YR)

(U)

(%)

(%)*

M M M M M M M M F

20 20 21 25 27 30 32 37 44 27

22.9 19.0 20.3 22.3 21.1 22.6 20.3 23.3 19.0 21.1

11 9 4 10 11 15 13 10 6 10

80 55 24 32 48 50 60 40 26 48

0 9.0 4.0 1.0 1.0 2.0 1.0 0 6.0 1.0

6.5 7.6 7.4 6.7 7.2 7.3 6.9 8.1 7.4 7.3

''Normal range was

Inhibitory effect of circulating insulin on glucagon secretion during hypoglycemia in type I diabetic patients.

To clarify whether the circulating insulin level influences hormonal responses, glucagon secretion in particular, during hypoglycemia in patients with...
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