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Recurrent nocturnal hypoglycemia in an insulin-dependent diabetic patient receiving a small daily dose of insulin
I Recurrent Nocturnal Hypoglycemia in an Insulin-Dependent Diabetic Patient Receiving a Small Daily Dose of Insulin JAMES D. WALKER, B.Sc., M.R.C,P., GIANCARLO VlBERTI, M.D., M.R.C.P., London, UnitedKingdom
ypoglycemia is a frequent and feared consequence of insulin treatment, yet usually the H causes of such events are apparent. Rarely are unusual causes of hypoglycemia encountered in diabetic patients, and these have usually been ascribed to either spontaneous or peripartum pan-pituitary necrosis [13]. Panhypopituitarism following acute encephalopathy and isolated growth hormone deficiency following cerebral edema complicating diabetic ketoacidosis have been described in young diabetic patients [4,5], but in the latter case it was suggested that the deficiency was secondary to hypothalamic dysfunction. We describe herein an insulin-dependent patient in whom recurrent, incapacitating hypoglycemic episodes occurred with a small daily dose of insulin. CASE REPORT
A 41-year-old nurse with a 33-year history of insulin-dependent diabetes mellitus presented in 1986 with a 6-year history of frequent, nocturnal, hypoglycemic episodes. In 1978, dipstick-positive proteinuria was discovered, and in 1980 proliferative retinopathy necessitated laser therapy. She became pregnant in 1980, and at 30 weeks' gestation, she developed a preeclamptic syndrome with arterial hypertension, edema, and a marked increase in proteinuria. At 32 weeks, she required an emergency lower-section cesarian section. She had no lactation after the birth and required no insulin for some days. Her insulin requirements had been around 10 U/day during childhood and had increased to around 20 U/day in 1960 and remained stable until 1980. Hypoglycemia had never been a problem until that time. During the months subsequent to her pregnancy, her insulin requirements declined to 6 U/day, and, due to severe hypoglycemic episodes, continuous subcutaneous insulin infusions were started in an attempt to stabilize her diabetes. This was unsuccessful, and the hypoglycemic episodes, usually nocturnal, continued despite an insulin infusion rate during the night of 0.1 U/hour. She received no medication except insulin. No weight loss had been noted, nor had libido or menstrual patterns changed. Examination was unremarkable, with a supine blood pressure of 152/70 mm Hg with no postural drop. Visual fields were full to confrontation, and retinal examination showed bilateral laser scars and widespread blot hemorrhages but no new vessels in both eyes.
From the Unit for Metabolic Medicine, UMDS (Guy's Campus), Guy's Hospital, London, United Kingdom. Dr. Walker is a Juvenile Diabetes Foundation International fellow. Requests for reprints should be addressed to GianCarlo Viberti, M.D., M.R.C.P., Unit for Metabolic Medicine, UMDS (Guy's Campus), Guy's Hospital, London SE] 9RT, United Kingdom. Manuscript submitted June 8, 1989, and accepted in revised form November 2, 1989.
METHODS
Six 24-hour blood glucose profiles showed consistently nocturnal hypoglycemia at around 2 A.M. The insulin infusion rates, via the insulin infusor, were remarkably low with no preprandial boosts, resulting in a total insulin dose of 5.6 U/day. Free insulin levels, measured on the occasion of one of the blood glucose profiles, were at the lower level of detection for our assay (6 mU/L). A 24-hour human growth hormone (hGH) profile was flat, with values ranging between 0.55 and 2.0 mU/L (Figure 1). A combined pituitary function test showed no growth hormone response to hypoglycemia. The responses of thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin were normal. Cortisol was elevated at the beginning of the test, probably due to stress, and no further rise was seen; a cortisol diurnal profile was normal. A growth hormone-releasing factor test confirmed a deficiency of pituitary growth hormone production and excluded a hypothalamic defect (Figure 2). Insulin-induced hypoglycemia produced a blunted rise in the plasma adrenaline level and no elevation of noradrenaline or glucagon levels (Table I). Fasting Cpeptide was less than 60 pmol/L (which is the lower limit of detection of our assay) and failed to rise in response to either a meal or intravenous glucagon. Pro-insulin levels similarly showed no response to the same stimuli. Computed tomographic scan of the pituitary fossa yielded normal findings. The results of gastrointestinal examinations, including barium meal, were normal, which excluded the presence of abdominal and pelvic abnormalities. Treatment with biosynthetic human growth hormone (Norditropin, a gift from Dr. L.H. Rasmussen, Nordisk, Gentofte A/S, Denmark) 2 IU subcutaneously at 10 P.M. was started. This produced a rise in growth hormone into the high physiologic range during the night; the total daily insulin requirement increased to around 14 units. Free insulin levels rose, and the nocturnal hypoglycemic episodes were abolished (Figure 3). Maintained on this regimen, the patient has developed a more stable glycemic profile on a daily insulin dose of 15 units, with only occasional mild episodes of hypoglycemia and has been able to return to full-time employment. COMMENTS
We describe a patient with repetitive incapacitating hypoglycemic episodes while taking a small daily insulin dosage following a toxemic episode. A combination of counter-regulatory hormone deficiencies was found. Blunted glucagon and catecholamine responses to insulin-induced hypoglycemia have been previously described in long-term diabetic patients but, although May 1990 The AmericanJournalof Medicine Volume88
537
NOCTURNAL INSULIN HYPOGLYCEMIA / WALKER AND VIBERTI
1
TABLE I
1
Responses to Insulin-Induced Hypoglycemia (0,15 units/kg of soluble insulin intravenously) in a Hypoglycemic-Prone Insulin. Dependent Diabetic Patient*
"
-
-
Blood Plasma Time Glucose Glucagon (minutes) (mmol/L) (pmol/L)
2
0 90
0
8.1 2.0
Plasma Adrenaline (nmol/L)
Plasma Noradrenaline (nmol/L)
10(10-20) 0.11(0.01-0.5) 1.03(0.6-3.55) 10(>25) 0.44(>4.0) 0.97(>3.55)
Normalrangesareshownin parentheses. 14
o =~
10 t
ff
o
-
4
_
12
~
e 6
%
4
e
~.
o
-
2 o
2U
1U
2U
"E 8
10 12 14 16 18 20 22 24
2
4
6
8
C~ock Time (hours)
Figure 1. Twenty-four-hour profiles of plasma glucose (collected on six occasions, mean ± SEM), insulin infusion rates, plasma-free insulin, and serum growth hormone (hGH) levels in a hypoglycemic-prone insulin-dependent diabetic patient.
oJ
35
1()
30 25 20
E
15 10
oJ
5 0
D I
0
8 . . . .
I
20
. . . .
I
. . . .
40
I
60
. . . .
I
80
. . . .
I
. . . .
100
I
'
•
120
10 12 14 16 t8 20 22 24 2
4
6
8
Clock Time (hours)
TIME (MIn) Figure 2. Growth hormone levels after injection of 100 #g of growth hormone-releasing factor intravenously at time zero. Open squares show our patient and closed squares show the normal response in diabetic patients. Data are mean ± SEM. Reproduced with permission from [14].
Figure 3. Twenty-four-hour profiles of plasma glucose (collected on four occasions, mean ± SEM), insulin infusion rates, plasmafree insulin levels, and serum growth hormone levels after the subcutaneous injection of 2 IU of human growth hormone (hGH) at 10 P.M. daily (open arrow). Solid arrows indicate preprandial insulin boluses. The patient had received hGH at 10 P.M. for two days before this profile.
these h o r m o n e s are central in the counter-regulatory response to hypoglycemia, such disturbances are not usually associated with a clinical s y n d r o m e such as the one described here [6-9]. In our patient, complete deficiency of growth hormone secretion, an i m p o r t a n t insulin-action antagonist, was present, and the time course of clinical events suggests t h a t the toxemia of pregnancy was responsible for it [10]. P e r i p a r t u m pituitary failure has been
previously described b u t normally involves multiple hormones [2,3,11]. Isolated pituitary growth h o r m o n e deficiency has recently been described in a diabetic patient after an episode of severe ketoacidosis and was associated with a 30% reduction in insulin dosage [5]. T h e absent growth h o r m o n e response in our patient was unlikely to be due to other reasons such as the level of preceding blood glucose control, presence of diabetes, or age [12-15].
538
May 1990
The American Journal of Medicine Volume 88
NOCTURNAL INSULIN HYPOGLYCEMIA / WALKERAND VIBERTI
Our patient was truly insulinopenic as evidenced by the negative C-peptide level. This and the virtually absent levels of pro-insulin excluded the possibility of an insulinoma. Moreover, the documented low levels of free insulin rule out factitious hypoglycemia. The temporal regularity of the hypoglycemic episodes at night, when under physiologic circumstances growth hormone is maximally secreted, combined with the correction of the episodes by the administration of exogenous growth hormone, strongly implicates deficiency of this hormone as a prime culprit in the genesis of the hypoglycemic manifestations [16,17]. Impaired glucagon and catecholamine responses to hypoglycemia may have played a contributory role to the full manifestation of this syndrome. Elevated growth hormone levels in insulin-dependent diabetic patients with poor metabolic control have been implicated in the pathogenesis of microvascular complications, especially retinopathy [18-20]. In this case, we have replaced physiologic levels of growth hormone, and 8 months of treatment with growth hormone have caused no change in the retinal status of our patient as assessed by fundus photography. A potential risk, however, cannot be entirely excluded, and regular follow-up of retinal and renal function is required. Despite complete insulinopenia, this patient did not require, even before the pregnancy and after many years of diabetes, more than 20 units of insulin a day. This, although not associated with hypoglycemia, is rather a low dose of insulin and suggests an exquisite baseline sensitivity to insulin.
ACKNOWLEDGMENT We are grateful to Ms. Andrea Collins for the insulin assays, Professor Vincent Marks for the glucagon, C-peptide, proinsulin and IGF1assays, Dr. N. Dalton for the adrenaline assays, Dr. de Nobel for continued management of the patient, Dr. J.S. Christiansen for useful suggestions and advice, and to Ms. M.V. Nelson for secretarial assistance.
REFERENCES 1. Frey HM: Spontaneous pituitary destruction in diabetes mellitus. J Clin Endocrinol Metab 1959; 19: 1642-1650. 2. Schalch DS, Burday SZ: Antepartum pituitary insufficiency in diabetes mellitus. Ann Intern Med 1971; 74: 357-360. 3. Flynn MD, Cundy TF, Watkins PJ: Antepartum pituitary necrosis in diabetes mellitus. Diabetic Med 1988; 5: 295-297. 4. Lufkin EG, Reagan TJ, Duan DJ, Yanagihari T: Acute cerebral dysfunction in diabetic ketoacidosis: survival followed by panhypopituitarism. Metabolism 1977; 26: 363-369. 5. Keller RJ, Wolfsdorf Jl: Isolated growth hormone deficiency after cerebral edema complicating diabetic ketoacidosis. N Engl J Med 1987; 316: 857-859. 6. Cryer PE, Gerich JE: Glucose counter-regulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus. N Engl J Med 1985; 313: 232-241. 7. Bolli GB, Dimitriadis GD, Pehling GB, et al: Abnormal glucose counter-regulation after subcutaneous insulin in insulin-dependent diabetes mellitus. N Engl J Med 1984; 310: 1706-1711. 8. Gerich JE, Langlois M, Noacco C, Karam JH, Forsham PH: Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alphacell defect. Science 1973; 182: 171-173. 9. Bolli G, De Feo P, Compagnucci P, etal:Abnormal glucose counter-regulation in insulin-dependent diabetes mellitus: interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 1983; 32: 134-141. 10. De Feo P, Perriello G, Torlone E, et aL Demonstration of a role for growth hormone in glucose counter-regulation. Am J Physiol 1989; 256: E835. 11. Sheehan HL, Summers VK: The syndrome of hypopituitarism. Q J Med 1949; 18: 319. 12. Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin RS: Intensive insulin therapy reduces the counter-regulatory hormone responses to hypoglycemia in patients with type 1 diabetes. Ann Intern Med 1985; 103: 184-190. 13. Polonsky K, BergenstaI-R, Pons G, et al: Relation of counter-regulatory responses to hypoglycemia in type i diabetics. N Engl J Med 1982; 307:1106-1112. 14. Kopelman PG, Mason AC, Noonan K, Monson JP: Growth hormone response to growth hormone releasing factor in diabetic men. Clin Endocrinol (Oxf) 1988; 28: 33-38. 15. Shibasaki T, Shizume K, Nakahara M, et al: Age-related changes in plasma growth hormone response to growth hormone-releasing factor in man. J Clin Endocrinol Metab 1984; 58: 212-214. 16. Takahashi Y, Kipnis DM, Daughaday WH: Growth hormone secretion during sleep. J Clin Invest 1968; 47: 2079-2090. 17. Honda Y, Takahashi K, Takahashi S, et al: Growth hormone secretion during nocturnal sleep in normal subjects. J Clin Endocrinol Metab 1969; 29: 20-29. 18. Johansen K, Hansen AP: High 24-hour level of serum growth hormone in juvenile diabetics. Br Med J 1969; 2: 356-357. 19. Merimee TJ: A follow-up of vascular disease in growth hormone deficient dwarfs with diabetes. N Engl J Med 1978; 298: 1217-1222. 20. Kohner EM, Hamilton AM, Joplin GF, Fraser TR: Florid diabetic retinopathy and its response to treatment by photocoagulation or pituitary ablation. Diabetes 1976; 25: 104-110.
May 1990 The American Journal of Medicine Volume 88
539
ypoglycemia is a frequent and feared consequence of insulin treatment, yet usually the H causes of such events are apparent. Rarely are unusual causes of hypoglycemia encountered in diabetic patients, and these have usually been ascribed to either spontaneous or peripartum pan-pituitary necrosis [13]. Panhypopituitarism following acute encephalopathy and isolated growth hormone deficiency following cerebral edema complicating diabetic ketoacidosis have been described in young diabetic patients [4,5], but in the latter case it was suggested that the deficiency was secondary to hypothalamic dysfunction. We describe herein an insulin-dependent patient in whom recurrent, incapacitating hypoglycemic episodes occurred with a small daily dose of insulin. CASE REPORT
A 41-year-old nurse with a 33-year history of insulin-dependent diabetes mellitus presented in 1986 with a 6-year history of frequent, nocturnal, hypoglycemic episodes. In 1978, dipstick-positive proteinuria was discovered, and in 1980 proliferative retinopathy necessitated laser therapy. She became pregnant in 1980, and at 30 weeks' gestation, she developed a preeclamptic syndrome with arterial hypertension, edema, and a marked increase in proteinuria. At 32 weeks, she required an emergency lower-section cesarian section. She had no lactation after the birth and required no insulin for some days. Her insulin requirements had been around 10 U/day during childhood and had increased to around 20 U/day in 1960 and remained stable until 1980. Hypoglycemia had never been a problem until that time. During the months subsequent to her pregnancy, her insulin requirements declined to 6 U/day, and, due to severe hypoglycemic episodes, continuous subcutaneous insulin infusions were started in an attempt to stabilize her diabetes. This was unsuccessful, and the hypoglycemic episodes, usually nocturnal, continued despite an insulin infusion rate during the night of 0.1 U/hour. She received no medication except insulin. No weight loss had been noted, nor had libido or menstrual patterns changed. Examination was unremarkable, with a supine blood pressure of 152/70 mm Hg with no postural drop. Visual fields were full to confrontation, and retinal examination showed bilateral laser scars and widespread blot hemorrhages but no new vessels in both eyes.
From the Unit for Metabolic Medicine, UMDS (Guy's Campus), Guy's Hospital, London, United Kingdom. Dr. Walker is a Juvenile Diabetes Foundation International fellow. Requests for reprints should be addressed to GianCarlo Viberti, M.D., M.R.C.P., Unit for Metabolic Medicine, UMDS (Guy's Campus), Guy's Hospital, London SE] 9RT, United Kingdom. Manuscript submitted June 8, 1989, and accepted in revised form November 2, 1989.
METHODS
Six 24-hour blood glucose profiles showed consistently nocturnal hypoglycemia at around 2 A.M. The insulin infusion rates, via the insulin infusor, were remarkably low with no preprandial boosts, resulting in a total insulin dose of 5.6 U/day. Free insulin levels, measured on the occasion of one of the blood glucose profiles, were at the lower level of detection for our assay (6 mU/L). A 24-hour human growth hormone (hGH) profile was flat, with values ranging between 0.55 and 2.0 mU/L (Figure 1). A combined pituitary function test showed no growth hormone response to hypoglycemia. The responses of thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin were normal. Cortisol was elevated at the beginning of the test, probably due to stress, and no further rise was seen; a cortisol diurnal profile was normal. A growth hormone-releasing factor test confirmed a deficiency of pituitary growth hormone production and excluded a hypothalamic defect (Figure 2). Insulin-induced hypoglycemia produced a blunted rise in the plasma adrenaline level and no elevation of noradrenaline or glucagon levels (Table I). Fasting Cpeptide was less than 60 pmol/L (which is the lower limit of detection of our assay) and failed to rise in response to either a meal or intravenous glucagon. Pro-insulin levels similarly showed no response to the same stimuli. Computed tomographic scan of the pituitary fossa yielded normal findings. The results of gastrointestinal examinations, including barium meal, were normal, which excluded the presence of abdominal and pelvic abnormalities. Treatment with biosynthetic human growth hormone (Norditropin, a gift from Dr. L.H. Rasmussen, Nordisk, Gentofte A/S, Denmark) 2 IU subcutaneously at 10 P.M. was started. This produced a rise in growth hormone into the high physiologic range during the night; the total daily insulin requirement increased to around 14 units. Free insulin levels rose, and the nocturnal hypoglycemic episodes were abolished (Figure 3). Maintained on this regimen, the patient has developed a more stable glycemic profile on a daily insulin dose of 15 units, with only occasional mild episodes of hypoglycemia and has been able to return to full-time employment. COMMENTS
We describe a patient with repetitive incapacitating hypoglycemic episodes while taking a small daily insulin dosage following a toxemic episode. A combination of counter-regulatory hormone deficiencies was found. Blunted glucagon and catecholamine responses to insulin-induced hypoglycemia have been previously described in long-term diabetic patients but, although May 1990 The AmericanJournalof Medicine Volume88
537
NOCTURNAL INSULIN HYPOGLYCEMIA / WALKER AND VIBERTI
1
TABLE I
1
Responses to Insulin-Induced Hypoglycemia (0,15 units/kg of soluble insulin intravenously) in a Hypoglycemic-Prone Insulin. Dependent Diabetic Patient*
"
-
-
Blood Plasma Time Glucose Glucagon (minutes) (mmol/L) (pmol/L)
2
0 90
0
8.1 2.0
Plasma Adrenaline (nmol/L)
Plasma Noradrenaline (nmol/L)
10(10-20) 0.11(0.01-0.5) 1.03(0.6-3.55) 10(>25) 0.44(>4.0) 0.97(>3.55)
Normalrangesareshownin parentheses. 14
o =~
10 t
ff
o
-
4
_
12
~
e 6
%
4
e
~.
o
-
2 o
2U
1U
2U
"E 8
10 12 14 16 18 20 22 24
2
4
6
8
C~ock Time (hours)
Figure 1. Twenty-four-hour profiles of plasma glucose (collected on six occasions, mean ± SEM), insulin infusion rates, plasma-free insulin, and serum growth hormone (hGH) levels in a hypoglycemic-prone insulin-dependent diabetic patient.
oJ
35
1()
30 25 20
E
15 10
oJ
5 0
D I
0
8 . . . .
I
20
. . . .
I
. . . .
40
I
60
. . . .
I
80
. . . .
I
. . . .
100
I
'
•
120
10 12 14 16 t8 20 22 24 2
4
6
8
Clock Time (hours)
TIME (MIn) Figure 2. Growth hormone levels after injection of 100 #g of growth hormone-releasing factor intravenously at time zero. Open squares show our patient and closed squares show the normal response in diabetic patients. Data are mean ± SEM. Reproduced with permission from [14].
Figure 3. Twenty-four-hour profiles of plasma glucose (collected on four occasions, mean ± SEM), insulin infusion rates, plasmafree insulin levels, and serum growth hormone levels after the subcutaneous injection of 2 IU of human growth hormone (hGH) at 10 P.M. daily (open arrow). Solid arrows indicate preprandial insulin boluses. The patient had received hGH at 10 P.M. for two days before this profile.
these h o r m o n e s are central in the counter-regulatory response to hypoglycemia, such disturbances are not usually associated with a clinical s y n d r o m e such as the one described here [6-9]. In our patient, complete deficiency of growth hormone secretion, an i m p o r t a n t insulin-action antagonist, was present, and the time course of clinical events suggests t h a t the toxemia of pregnancy was responsible for it [10]. P e r i p a r t u m pituitary failure has been
previously described b u t normally involves multiple hormones [2,3,11]. Isolated pituitary growth h o r m o n e deficiency has recently been described in a diabetic patient after an episode of severe ketoacidosis and was associated with a 30% reduction in insulin dosage [5]. T h e absent growth h o r m o n e response in our patient was unlikely to be due to other reasons such as the level of preceding blood glucose control, presence of diabetes, or age [12-15].
538
May 1990
The American Journal of Medicine Volume 88
NOCTURNAL INSULIN HYPOGLYCEMIA / WALKERAND VIBERTI
Our patient was truly insulinopenic as evidenced by the negative C-peptide level. This and the virtually absent levels of pro-insulin excluded the possibility of an insulinoma. Moreover, the documented low levels of free insulin rule out factitious hypoglycemia. The temporal regularity of the hypoglycemic episodes at night, when under physiologic circumstances growth hormone is maximally secreted, combined with the correction of the episodes by the administration of exogenous growth hormone, strongly implicates deficiency of this hormone as a prime culprit in the genesis of the hypoglycemic manifestations [16,17]. Impaired glucagon and catecholamine responses to hypoglycemia may have played a contributory role to the full manifestation of this syndrome. Elevated growth hormone levels in insulin-dependent diabetic patients with poor metabolic control have been implicated in the pathogenesis of microvascular complications, especially retinopathy [18-20]. In this case, we have replaced physiologic levels of growth hormone, and 8 months of treatment with growth hormone have caused no change in the retinal status of our patient as assessed by fundus photography. A potential risk, however, cannot be entirely excluded, and regular follow-up of retinal and renal function is required. Despite complete insulinopenia, this patient did not require, even before the pregnancy and after many years of diabetes, more than 20 units of insulin a day. This, although not associated with hypoglycemia, is rather a low dose of insulin and suggests an exquisite baseline sensitivity to insulin.
ACKNOWLEDGMENT We are grateful to Ms. Andrea Collins for the insulin assays, Professor Vincent Marks for the glucagon, C-peptide, proinsulin and IGF1assays, Dr. N. Dalton for the adrenaline assays, Dr. de Nobel for continued management of the patient, Dr. J.S. Christiansen for useful suggestions and advice, and to Ms. M.V. Nelson for secretarial assistance.
REFERENCES 1. Frey HM: Spontaneous pituitary destruction in diabetes mellitus. J Clin Endocrinol Metab 1959; 19: 1642-1650. 2. Schalch DS, Burday SZ: Antepartum pituitary insufficiency in diabetes mellitus. Ann Intern Med 1971; 74: 357-360. 3. Flynn MD, Cundy TF, Watkins PJ: Antepartum pituitary necrosis in diabetes mellitus. Diabetic Med 1988; 5: 295-297. 4. Lufkin EG, Reagan TJ, Duan DJ, Yanagihari T: Acute cerebral dysfunction in diabetic ketoacidosis: survival followed by panhypopituitarism. Metabolism 1977; 26: 363-369. 5. Keller RJ, Wolfsdorf Jl: Isolated growth hormone deficiency after cerebral edema complicating diabetic ketoacidosis. N Engl J Med 1987; 316: 857-859. 6. Cryer PE, Gerich JE: Glucose counter-regulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus. N Engl J Med 1985; 313: 232-241. 7. Bolli GB, Dimitriadis GD, Pehling GB, et al: Abnormal glucose counter-regulation after subcutaneous insulin in insulin-dependent diabetes mellitus. N Engl J Med 1984; 310: 1706-1711. 8. Gerich JE, Langlois M, Noacco C, Karam JH, Forsham PH: Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alphacell defect. Science 1973; 182: 171-173. 9. Bolli G, De Feo P, Compagnucci P, etal:Abnormal glucose counter-regulation in insulin-dependent diabetes mellitus: interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 1983; 32: 134-141. 10. De Feo P, Perriello G, Torlone E, et aL Demonstration of a role for growth hormone in glucose counter-regulation. Am J Physiol 1989; 256: E835. 11. Sheehan HL, Summers VK: The syndrome of hypopituitarism. Q J Med 1949; 18: 319. 12. Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin RS: Intensive insulin therapy reduces the counter-regulatory hormone responses to hypoglycemia in patients with type 1 diabetes. Ann Intern Med 1985; 103: 184-190. 13. Polonsky K, BergenstaI-R, Pons G, et al: Relation of counter-regulatory responses to hypoglycemia in type i diabetics. N Engl J Med 1982; 307:1106-1112. 14. Kopelman PG, Mason AC, Noonan K, Monson JP: Growth hormone response to growth hormone releasing factor in diabetic men. Clin Endocrinol (Oxf) 1988; 28: 33-38. 15. Shibasaki T, Shizume K, Nakahara M, et al: Age-related changes in plasma growth hormone response to growth hormone-releasing factor in man. J Clin Endocrinol Metab 1984; 58: 212-214. 16. Takahashi Y, Kipnis DM, Daughaday WH: Growth hormone secretion during sleep. J Clin Invest 1968; 47: 2079-2090. 17. Honda Y, Takahashi K, Takahashi S, et al: Growth hormone secretion during nocturnal sleep in normal subjects. J Clin Endocrinol Metab 1969; 29: 20-29. 18. Johansen K, Hansen AP: High 24-hour level of serum growth hormone in juvenile diabetics. Br Med J 1969; 2: 356-357. 19. Merimee TJ: A follow-up of vascular disease in growth hormone deficient dwarfs with diabetes. N Engl J Med 1978; 298: 1217-1222. 20. Kohner EM, Hamilton AM, Joplin GF, Fraser TR: Florid diabetic retinopathy and its response to treatment by photocoagulation or pituitary ablation. Diabetes 1976; 25: 104-110.
May 1990 The American Journal of Medicine Volume 88
539