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THE EFFECT OF CRUDE SECRETIN IN MATURITY-ONSET DIABETES MELLITUS
445 Carolina Memorial Hospital on Oct. 20, 1965, with a referring diagnosis of schizophrenia. Bizarre behaviour became apparent to her husband in August, 1965, 6 days after she had started c-quens, 80 tg. mestranol, daily for menorrhagia. She became irritable and argumentative and withdrew from her customary social activities. She accused her husband of various immoral acts and became paranoid. In September she was sleeping poorly and threatened to injure her son; her husband left her to live with his mother. She lost 10 lb. (5 kg.) in weight. At this hospital she was noted to be agitated, suspicious, with loosening of associations and was quite paranoid, the delusions involving her husband and his giving her drugs to make her an immoral woman. She had visual and auditory hallucinations. She performed well on tests of intellectual function and she was well orientated. This patient also had a poor early history but her adjustment was good until her first psychosis after delivery of her son in 1957. (She was treated with electroconvulsant therapy.) In hospital she responded well to chlorpromazine 600 mg. daily with supportive therapy and was discharged on trifluoperazine. At the time of discharge on Nov. 18, 1965, she had a firm grasp of reality and some insight into her marital situation. She has progressed satisfactorily since her discharge.
taking
We have described two cases showing close temporal association between psychotic disturbance and the use of sequential oral contraceptives. The first patient had three episodes associated with the use of the oestrogen-progestogen mixture only and she seemed to tolerate oestrogen therapy quite well. It would seem that the progestogen (chlormadinone) was the important variable in her illness, while in the second patient exogenous oestrogen therapy seemed closely associated with the onset of psychotic behaviour. These patients and one previously reported (Keeler, Kane, and Daly 1964) have had serious postpartum disturbance in the past. There seem to be several possible explanations for these
findings. Emotional Variability Related to Changes of Female Sex Hormone Benedek and Rubenstein (1942) reported active objectdirected heterosexual tendencies and a sense of well-being and alertness during the oestrogen phase followed by increased preoccupation with the body and its welfare in the second half of the cycle. There were premenstrual mood changes with activation of conflicts, especially of dependency. Gottschalk et al. (1962) using more reliable methodology substantiated their findings. The combination oral contraceptive agents give patients a continuous cycle and may contribute to the emotional disturbances reported. Regarding our second case, the description by Lingjaerde and Bredland (1954) of a woman with cyclic psychosis attributable to hyperoestrogenism is of interest.
Biological Effects of Steroid Sex Hormones Parenteral administration of these hormones has been
reported to produce anaesthesia (at high doses) (Merryman 1954) and electroencephalographic (Matsumoto et al.
1966), central-nervous-system vascular (Bickerstaff and Holmes 1967), and other neurological effects. It may be important, in the light of Grant’s (1965) findings, that the first case had " migraine ". Alteration in Metabolism of Adrenal Steroids The presence of excess oestrogens usually increases total and bound plasma-hydrocortisone, with unbound hydrocortisone remaining unchanged (Plager et al. 1964). Our previous data raised the possibility that, in some patients,
binding might
not
be
"
steroid diabetes ". Glucocorticoids have been shown to cause emotional disturbance and frank psychosis with the
premorbid personality
as a
contributor
(Glaser 1953).
REFERENCES B. (1942) The Sexual Cycle in Women. Washington, D.C. Bickerstaff, E. R., Holmes, J. MacD. (1967) Br. med. J. i, 726. Glaser, G. H. (1953) Psychosom. Med. 15, 280. Gottschalk, L., Kaplan, S., Winget, C. (1962) ibid. 24, 300. Grant, E. C. G. (1965) Lancet, i, 1143. Kane, F. J., Jr, Daly, R. J., Ewing, J. A., Keeler, M. H., Flowers, C. E. (1967) Br. J. Psychiat. 113, 265. Keeler, M. H., Kane, F. J., Jr, Daly, R. J. (1964) Am. J. Psychiat. 120, 11. Lingjaerde, P., Bredland, R. (1954) Acta psychiat. neurol. Scand. 29, 355. Matsumoto, S., Sato, I., Ito, T., Matsuoka, A. (1966) Int. J. Fertil. 11, 195. Merryman, W. (1954) J. clin. Endocr. 14, 1567. Plager, J. E., Schmidt, K. G., Stanbitz, W. J. (1964) J. clin. Invest. 43, 1066. Scott, J. W., Brass, P. (1966) Am. J. Obstet. Gynœc. 95, 1166. Wynn, V., Doar, J. W. H. (1966) Lancet, ii, 715.
Benedek, T., Rubenstein,
THE EFFECT OF CRUDE SECRETIN IN
Discussion
transcortin
However, Wynn and Doar (1966) interpreted their data as showing that women on oral contraceptives may show effects due to an excess of glucocorticoid action, i.e.
as
effective
as
usual.
MATURITY-ONSET DIABETES MELLITUS I. PERSSON Copenhagen
M.D.
F. JUHL M.D.
Copenhagen D. SVENDSEN M.D. Copenhagen
From Medical
Department E, Frederiksberg Hospital, Copenhagen, Denmark
After intravenous
injection of crude secrestatistically highly significant fall in the blood-sugar level was found in maturity-onset diabetes, but not in juvenile diabetes or in predisposed patients Summary tin
a
and controls. Introduction
Moore et al. (1906) published the results of investigations which indicated that extracts of duodenal mucosa might play a part in glucose metabolism. In animal experiments, however, the effect of duodenal extracts on the blood-sugar varied, perhaps because the extracts were not sufficiently pure so far as secretin was concerned. Scow and Cornfield (1954) showed that, in the rat, glucose disappeared more rapidly when given by mouth than when administered intravenously. Dupre (1964) showed that, in man, a glucose-load given by mouth was accompanied by a quicker fall in the blood-sugar level than after intravenous glucose loading. In our investigations we tried to use as simple a method as possible so that only the effect of the crude secretin came into play. Patients and Materials
experiments were conducted in the morning (after an overnight fast of 12 hours). The diabetics received insulin and tablets not later than 7 P.M. on the day before the investigation. We injected an ampoule intravenously of 100 units of crude secretin (Boots) made up in 2 ml. of physiological saline solution (without side-effects in any patient). Blood-sugar was estimated with an Auto Analyzer, according to the method of Hoffman (1937) The patients fell into various groups. 27 patients (group I) had maturity-onset diabetes mellitus. The diagnosis was estabAll
lished by oral glucose-tolerance
tests
giving
a
blood-sugar
446 concentration above 130 mg. per 100 ml. 2 hours after the administration of glucose. The age-range of the patients was 46-83 years (average 66 years). The duration of the diabetes ranged from 6 months to 18 years (average 7 years). 8 of the patients were obese; 14 were being treated with tablets, 7 with insulin, and the rest with diet only. 5 of the patients (group II) had juvenile diabetes (average age 30 years, average duration 20 years) and all were receiving insulin. 13 patients were obese and hypertensive (group III) and were thus predisposed to diabetes mellitus. 9 patients with neurosis and arthritis had no disposition to diabetes (group IV). The crude secretin contained small amnunrs
nf insulin and aiiiencrnn- A
Fig. 2-S.S.D.y values.
cnn-
trol group of 6 patients (group V) with maturity-onset diabetes, therefore received an intravenous injection of insulin, 0.1 l.u. and glucagon (400 mfJ.g) (stabilised with albumin) in the same amounts as were present in an ampoule of secretin.
Results
The
patients were regrouped into: Group A (previously groups I and V), 33 patients with maturity-onset diabetes (in 9 patients the investigation was
expression the sum of square deviations (s.s.D.y) was calculated (F. Abildgard Jorgensen, consulting statistician) for the degree of variations for each patient. Fig. 2 shows these values for each group. Group I is clearly different from all others with a relatively great variation in the blood-sugar concentrations throughout the period of observation. The differences in reaction between the patients in group A are evaluated by dividing them into three subgroups : s.s.D.y ranging from 0 to 175, 18 patients; S.S.D.y 175-350, 9 patients; and s.s.D.y>350, 6 patients. In these three sub-groups and in the group C patients, the bloodsugar concentration shows a strikingly uniform course. The great values of s.s.D.y over 175 are expressions for a significant fall in the blood-sugar concentration. By contrast, the patients with maturity-onset .diabetes (group A) show constant blood-sugar values after intravenous injections of insulin and glucagon in the same strength as was present in the ampoule of secretin. In groups A and B
an
Discussion
An insulinotropic effect of secretin was postulated by Unger et al. (1966) and Dupre et al. (1966) from their investigations in man and dog. Evidence has also been presented that secretin stimulates the release of insulin from in-vitro preparations of animal pancreas (Pfeiffer et al. 1965) Boyns. et al. (1967), however, suggested that
insulin release was elicited with of the hormone, a conclusion unphysiological based on their failure to influence the plasma-insulin level by infusing acid into the duodenum. In previous investigations, however, the results have been difficult to interpret, since as a rule at least two active substances came into play-glucose and secretin. In our experiments, in which only one (i.e., crude secretin) was used, the fall in the blood-sugar level observed in maturity-onset diabetes but not in the other groups could have been due only to the secretin or to another substance in the duodenal extract. The control experiments showed that the effect was not due to insulin or glucagon.
this effect of secretin
on
amounts
Fig. 1-Blood-sugar concentrations before and after injection.
repeated); Group B (previously group II), 5 patients with juvenile diabetes; and Group C (previously groups III and IV), 22 patients without diabetes (13 with obesity and arterial hypertension and 9 controls). Fig. 1 shows the blood-sugar concentration before the injections and 20, 30, 60, and 90 minutes after. The three groups are clearly separable into three different levels. Group A shows a fall in the blood-sugar during the period of investigation, B group a rise, and C group a 20-minute fall after which the blood-sugar reverted to the initial values. The striking rise in the blood-sugar level in the B group was produced by one patient; another had a minor rise; and three patients had nearly constant values.
Requests
for
reprints should
be addressed to 1. P.
REFERENCES
Boyns, D., Jarrett, R., Keen, H. (1967) Br. med. J. i, 676. Dupré, J. (1964) J. Physiol. Lond. 178, 58. Rojas, L., White, J., Unger, R., Beck, J. (1966) Lancet, ii, 26. Hoffman, W. (1937) J. biol. Chem. 120, 51. Moore, B., Edie, E., Abram, J. (1906) Biochem. J. 1, 28. Pfeiffer, E., Telib, M., Ammon, J., Melani, F., Ditschuneit, H. (1965) Diabetologia, 1, 131. Scow, R., Cornfield, J. (1954) Am. J. Physiol. 179, 435. Unger, R., Ketterer, H., Eisentraut, A., Dupré, J. (1966) Lancet, ii, 24. —
taking
We have described two cases showing close temporal association between psychotic disturbance and the use of sequential oral contraceptives. The first patient had three episodes associated with the use of the oestrogen-progestogen mixture only and she seemed to tolerate oestrogen therapy quite well. It would seem that the progestogen (chlormadinone) was the important variable in her illness, while in the second patient exogenous oestrogen therapy seemed closely associated with the onset of psychotic behaviour. These patients and one previously reported (Keeler, Kane, and Daly 1964) have had serious postpartum disturbance in the past. There seem to be several possible explanations for these
findings. Emotional Variability Related to Changes of Female Sex Hormone Benedek and Rubenstein (1942) reported active objectdirected heterosexual tendencies and a sense of well-being and alertness during the oestrogen phase followed by increased preoccupation with the body and its welfare in the second half of the cycle. There were premenstrual mood changes with activation of conflicts, especially of dependency. Gottschalk et al. (1962) using more reliable methodology substantiated their findings. The combination oral contraceptive agents give patients a continuous cycle and may contribute to the emotional disturbances reported. Regarding our second case, the description by Lingjaerde and Bredland (1954) of a woman with cyclic psychosis attributable to hyperoestrogenism is of interest.
Biological Effects of Steroid Sex Hormones Parenteral administration of these hormones has been
reported to produce anaesthesia (at high doses) (Merryman 1954) and electroencephalographic (Matsumoto et al.
1966), central-nervous-system vascular (Bickerstaff and Holmes 1967), and other neurological effects. It may be important, in the light of Grant’s (1965) findings, that the first case had " migraine ". Alteration in Metabolism of Adrenal Steroids The presence of excess oestrogens usually increases total and bound plasma-hydrocortisone, with unbound hydrocortisone remaining unchanged (Plager et al. 1964). Our previous data raised the possibility that, in some patients,
binding might
not
be
"
steroid diabetes ". Glucocorticoids have been shown to cause emotional disturbance and frank psychosis with the
premorbid personality
as a
contributor
(Glaser 1953).
REFERENCES B. (1942) The Sexual Cycle in Women. Washington, D.C. Bickerstaff, E. R., Holmes, J. MacD. (1967) Br. med. J. i, 726. Glaser, G. H. (1953) Psychosom. Med. 15, 280. Gottschalk, L., Kaplan, S., Winget, C. (1962) ibid. 24, 300. Grant, E. C. G. (1965) Lancet, i, 1143. Kane, F. J., Jr, Daly, R. J., Ewing, J. A., Keeler, M. H., Flowers, C. E. (1967) Br. J. Psychiat. 113, 265. Keeler, M. H., Kane, F. J., Jr, Daly, R. J. (1964) Am. J. Psychiat. 120, 11. Lingjaerde, P., Bredland, R. (1954) Acta psychiat. neurol. Scand. 29, 355. Matsumoto, S., Sato, I., Ito, T., Matsuoka, A. (1966) Int. J. Fertil. 11, 195. Merryman, W. (1954) J. clin. Endocr. 14, 1567. Plager, J. E., Schmidt, K. G., Stanbitz, W. J. (1964) J. clin. Invest. 43, 1066. Scott, J. W., Brass, P. (1966) Am. J. Obstet. Gynœc. 95, 1166. Wynn, V., Doar, J. W. H. (1966) Lancet, ii, 715.
Benedek, T., Rubenstein,
THE EFFECT OF CRUDE SECRETIN IN
Discussion
transcortin
However, Wynn and Doar (1966) interpreted their data as showing that women on oral contraceptives may show effects due to an excess of glucocorticoid action, i.e.
as
effective
as
usual.
MATURITY-ONSET DIABETES MELLITUS I. PERSSON Copenhagen
M.D.
F. JUHL M.D.
Copenhagen D. SVENDSEN M.D. Copenhagen
From Medical
Department E, Frederiksberg Hospital, Copenhagen, Denmark
After intravenous
injection of crude secrestatistically highly significant fall in the blood-sugar level was found in maturity-onset diabetes, but not in juvenile diabetes or in predisposed patients Summary tin
a
and controls. Introduction
Moore et al. (1906) published the results of investigations which indicated that extracts of duodenal mucosa might play a part in glucose metabolism. In animal experiments, however, the effect of duodenal extracts on the blood-sugar varied, perhaps because the extracts were not sufficiently pure so far as secretin was concerned. Scow and Cornfield (1954) showed that, in the rat, glucose disappeared more rapidly when given by mouth than when administered intravenously. Dupre (1964) showed that, in man, a glucose-load given by mouth was accompanied by a quicker fall in the blood-sugar level than after intravenous glucose loading. In our investigations we tried to use as simple a method as possible so that only the effect of the crude secretin came into play. Patients and Materials
experiments were conducted in the morning (after an overnight fast of 12 hours). The diabetics received insulin and tablets not later than 7 P.M. on the day before the investigation. We injected an ampoule intravenously of 100 units of crude secretin (Boots) made up in 2 ml. of physiological saline solution (without side-effects in any patient). Blood-sugar was estimated with an Auto Analyzer, according to the method of Hoffman (1937) The patients fell into various groups. 27 patients (group I) had maturity-onset diabetes mellitus. The diagnosis was estabAll
lished by oral glucose-tolerance
tests
giving
a
blood-sugar
446 concentration above 130 mg. per 100 ml. 2 hours after the administration of glucose. The age-range of the patients was 46-83 years (average 66 years). The duration of the diabetes ranged from 6 months to 18 years (average 7 years). 8 of the patients were obese; 14 were being treated with tablets, 7 with insulin, and the rest with diet only. 5 of the patients (group II) had juvenile diabetes (average age 30 years, average duration 20 years) and all were receiving insulin. 13 patients were obese and hypertensive (group III) and were thus predisposed to diabetes mellitus. 9 patients with neurosis and arthritis had no disposition to diabetes (group IV). The crude secretin contained small amnunrs
nf insulin and aiiiencrnn- A
Fig. 2-S.S.D.y values.
cnn-
trol group of 6 patients (group V) with maturity-onset diabetes, therefore received an intravenous injection of insulin, 0.1 l.u. and glucagon (400 mfJ.g) (stabilised with albumin) in the same amounts as were present in an ampoule of secretin.
Results
The
patients were regrouped into: Group A (previously groups I and V), 33 patients with maturity-onset diabetes (in 9 patients the investigation was
expression the sum of square deviations (s.s.D.y) was calculated (F. Abildgard Jorgensen, consulting statistician) for the degree of variations for each patient. Fig. 2 shows these values for each group. Group I is clearly different from all others with a relatively great variation in the blood-sugar concentrations throughout the period of observation. The differences in reaction between the patients in group A are evaluated by dividing them into three subgroups : s.s.D.y ranging from 0 to 175, 18 patients; S.S.D.y 175-350, 9 patients; and s.s.D.y>350, 6 patients. In these three sub-groups and in the group C patients, the bloodsugar concentration shows a strikingly uniform course. The great values of s.s.D.y over 175 are expressions for a significant fall in the blood-sugar concentration. By contrast, the patients with maturity-onset .diabetes (group A) show constant blood-sugar values after intravenous injections of insulin and glucagon in the same strength as was present in the ampoule of secretin. In groups A and B
an
Discussion
An insulinotropic effect of secretin was postulated by Unger et al. (1966) and Dupre et al. (1966) from their investigations in man and dog. Evidence has also been presented that secretin stimulates the release of insulin from in-vitro preparations of animal pancreas (Pfeiffer et al. 1965) Boyns. et al. (1967), however, suggested that
insulin release was elicited with of the hormone, a conclusion unphysiological based on their failure to influence the plasma-insulin level by infusing acid into the duodenum. In previous investigations, however, the results have been difficult to interpret, since as a rule at least two active substances came into play-glucose and secretin. In our experiments, in which only one (i.e., crude secretin) was used, the fall in the blood-sugar level observed in maturity-onset diabetes but not in the other groups could have been due only to the secretin or to another substance in the duodenal extract. The control experiments showed that the effect was not due to insulin or glucagon.
this effect of secretin
on
amounts
Fig. 1-Blood-sugar concentrations before and after injection.
repeated); Group B (previously group II), 5 patients with juvenile diabetes; and Group C (previously groups III and IV), 22 patients without diabetes (13 with obesity and arterial hypertension and 9 controls). Fig. 1 shows the blood-sugar concentration before the injections and 20, 30, 60, and 90 minutes after. The three groups are clearly separable into three different levels. Group A shows a fall in the blood-sugar during the period of investigation, B group a rise, and C group a 20-minute fall after which the blood-sugar reverted to the initial values. The striking rise in the blood-sugar level in the B group was produced by one patient; another had a minor rise; and three patients had nearly constant values.
Requests
for
reprints should
be addressed to 1. P.
REFERENCES
Boyns, D., Jarrett, R., Keen, H. (1967) Br. med. J. i, 676. Dupré, J. (1964) J. Physiol. Lond. 178, 58. Rojas, L., White, J., Unger, R., Beck, J. (1966) Lancet, ii, 26. Hoffman, W. (1937) J. biol. Chem. 120, 51. Moore, B., Edie, E., Abram, J. (1906) Biochem. J. 1, 28. Pfeiffer, E., Telib, M., Ammon, J., Melani, F., Ditschuneit, H. (1965) Diabetologia, 1, 131. Scow, R., Cornfield, J. (1954) Am. J. Physiol. 179, 435. Unger, R., Ketterer, H., Eisentraut, A., Dupré, J. (1966) Lancet, ii, 24. —