Action of Sex Hormones on Experimental Diabetes

Houssay, B. A.

doi:10.1136/bmj.2.4730.505

Cited by 55 publications

(24 citation statements)

References 5 publications

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“…This difference is related to the opposite effects of androgens and estrogens on the insulin sensitivity of cells: androgens lower insulin sensitivity, whereas estrogens increase it (Kava et al, 1989;Leiter, 1988Leiter, , 1989. Accordingly, partial pancreatectomy-induced diabetes in normal rodents is more frequent in males than in females, and its effect is reversed in each sex by castration (Houssay, 1951). The administration of exogenous androgens is likely to prevent the effects of castration on glucose homeostasis because in the multiple-dose streptozotocin diabetes model it has been shown that testosterone administered to control females or orchidectomized males resulted in an increase in glucose response to levels comparable to those in control males (Rossini et al, 1978).…”

Section: Discussionmentioning

confidence: 93%

Sex Steroids Influence Pancreatic Islet Hypertrophy and Subsequent Autoimmune Infiltration in Nonobese Diabetic (NOD) and NODscid Mice

Rosmalen

Pigmans

Kersseboom

et al. 2001

Laboratory Investigation

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SUMMARY:Female nonobese diabetic (NOD) mice more frequently develop autoimmune diabetes than NOD males.Orchidectomy of the latter aggravates insulitis and diabetes. Because clear differences in immune function have not been observed between prediabetic females and males, before or after castration, we hypothesized that sex-related differences in diabetes incidence are related to target organ-specific actions of sex steroids. Previously, we showed that prediabetic NOD females develop hyperinsulinemia and subsequently mega-islets. Infiltration of the first inflammatory leukocytes is predominantly associated with these mega-islets. Here, we determined the relationship between sex hormones, mega-islet formation, and infiltrating cells in NOD and nonobese diabetic/severe combined immune-deficient (NODscid) mice. Mega-islet formation was reduced in NOD males compared with NOD females, and orchidectomy increased it, indicating a relationship between androgen levels and mega-islet formation. Moreover, enhanced mega-islet formation in castrated NOD males was associated with increased numbers of infiltrating leukocytes. Castrated NODscid males also exhibited increased mega-islet formation and dendritic cell infiltration, indicating that lymphocytes are not required for castration-induced effects. In conclusion, we show that androgens influence pancreatic islets and autoimmune infiltration in NOD and NODscid mice. This suggests that the gender difference in diabetes incidence in NOD mice is related to target organ-specific androgen effects. (Lab Invest 2001, 81:231-239).

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Section: Discussionmentioning

confidence: 93%

Sex Steroids Influence Pancreatic Islet Hypertrophy and Subsequent Autoimmune Infiltration in Nonobese Diabetic (NOD) and NODscid Mice

Rosmalen

Pigmans

Kersseboom

et al. 2001

Laboratory Investigation

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“…It is also of interest that plasma free cortisol is elevated in pregnant women and in normal subjects during estrogen treatment (22). The relevance of possible estrogen and cortisol effects alone or estrogen-cortisol interactions to diabetes in pregnancy remains to be determined, since other studies suggest that estrogens may actually protect against the development of diabetes mellitus (17,23). Perhaps the type of estrogen, duration of exposure and clinical setting are critical factors that determine the ultimate metabolic effects of this steroid.…”

Section: Discussionmentioning

confidence: 94%

Progesterone, Pregnancy and the Augmented Plasma Insulin Response¹

Kalkhoff

Jacobson

Lemper

1970

The Journal of Clinical Endocrinology & Metabolism

125

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Intramuscular progesterone, 300-400 mg, was given daily to 5 normal men and to 2 hysterectomized women for 6 days to assess the role of this steroid in the development of hyperinsulinemia observed during pregnancy. Twentyfour hr urinary pregnanediol excretion increased to levels that were within the range of late gestation. On days 5 and 6 plasma glucose concentrations during oral glucose and intravenous tolbutamide tolerance tests were unchanged, but plasma insulin responses including fasting levels were significantly increased above control values.Patterns of insulin response were similar to those measured during studies of 10 normal women in late pregnancy. Progesterone effects were independent of any changes in fasting plasma glucose, free fatty acids, serum cortisol or immunoreactive growth hormone. These results suggest that progesterone, like pregnancy, evokes an enhanced plasma insulin response to insulinogenic stimuli as pancreatic islet adjustment to peripheral insulin antagonism evolves during gestation. (J Clin Endocr 31: 24,1970) P ROGRESSIVE biologic resistance to endogenous insulin is a uniformly observed consequence of advancing pregnancy (1-4). Normal women compensate by increasing plasma levels with little change in carbohydrate tolerance. Subclinical and overtly diabetic subjects frequently demonstrate marked deterioration of carbohydrate tolerance during late gestation despite higher levels of circulating insulin (3).Since the milieu of metabolic and hormonal alterations that accompany pregnancy is very complex, efforts to delineate factors responsible for the diabetogenic stress and associated hyperinsulinemia in this condition have been difficult. The findings of the present study suggest that the placental steroid, progesterone, may contribute to altered plasma insulin responses observed in the gravid state. Materials and MethodsPatient selection. Two women and 5 men volunteered for progesterone studies. Their mean age was 32 with a range of 23-46 yr. The 2 women, 31 and 36 yr old, had hysterectomies performed several months earlier for stress incontinence and a large uterine myoma, respectively. Ovaries were not removed. Women with an intact uterus were purposely excluded to avoid adverse effects that progesterone may have on menstruation. A second group of 10 women, who were studied in late pregnancy and after delivery, had an average age of 23 with a range of 17-32 yr.All patients in this study were in good health, within 17% of their ideal body weight (Metropolitan Life Insurance Tables, 1959), and had negative family histories of diabetes mellitus. None was receiving medications other than vitamin pills, and good nutrition was ascertained.Clinical studies. Standard 100 g oral glucose tolerance tests and 1 g intravenous tolbutamide tolerance tests were performed after overnight fasts on the 10 pregnant women late in the third trimester and were repeated 6-8 weeks after delivery. All procedures were done on an outpatient basis. Volunteers for progesterone studies were admitted to the ...

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“…The results of several studies have suggested that genetic background is of considerable importance in determining the proliferative response of beta cells to diabetogenic factors [17,18]. Moreover, studies in normal and experimentally diabetic rats have shown that ovarian hormones possess the ability to increase beta-cell proliferation [19]. In fact, beta-cell hypertrophy accounted for much of the increased betacell mass, but an increase in the mitotic activity of beta cells early after surgery is not trivial and certainly is a significant component, since it would determine the function of latter remnant pancreas [9,20].…”

Section: Discussionmentioning

confidence: 99%

Ovarian hormone-induced beta-cell hypertrophy contributes to the homeostatic control of beta-cell mass in OLETF female rat, a model of Type II diabetes

et al. 1998

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Type II (non-insulin-dependent) diabetes mellitus model rats, namely the Otsuka Long-Evans Tokushima Fatty (OLETF) show sexual dimorphism with respect to the incidence of diabetes mellitus, with the cumulative incidences of diabetes in male and female OLETF rats being 86 % and 0 %, at ages over 23 weeks [1]. However, the females are also potentially diabetic because approximately 40 % of offspring hybrid F1 male rats (OLETF ,x LETO <, Long-Evans-Tokushima-Otsuka, a counterpart strain of diabetes-resistance rats) also develop diabetes [2]. In this case, an early ovariectomy (Ox) of some led to the development of diabetes [3], suggesting a hormonal role in this sexual dimorphism. Ovarian hormones have been shown to affect beta-cell function and glucose homeostasis by increasing insulin pro- Diabetologia (1998) Ovarian hormone-induced beta-cell hypertrophy contributes to the homeostatic control of beta-cell mass in OLETF female rat, a model of Type II diabetes Summary A sexual dimorphism regarding the incidence of diabetes mellitus in OLETF rat, a model of Type II diabetes, has been reported. As a result, the effects of ovarian hormones on beta cells per se was examined by comparing the capacity of beta-cell proliferation and changes in blood glucose and plasma insulin concentrations after a 70 % pancreatectomy. All female animals were randomly assigned to two protocols. The rats involved in protocol I received either a 70 % pancreatectomy (Px) or a sham pancreatectomy (sham) at 6 weeks of age, along with their diabetes-resistant counterparts, female LETO rats, which served as normal controls. The rats belonging to protocol II were given an ovariectomy (Ox) at 5 weeks of age, and one week later, they were subjected to either Px or the sham operation, with/without hormone (estradiol, 50 mg/kg; testosterone, 1 mg/kg) replacement. The findings indicate that the capacity for compensatory growth of beta cells after Px was affected by both sex hormonal and genetic components, since a 70 % Px resulted in sustained hyperglycaemia within the first week after surgery, but was ameliorated by an increase in beta-cell mass thereafter in the non-Ox Px OLETF rats. The Ox also caused a decline in beta-cell mass which could be improved by replacement with ovarian hormones. Not only endogenous but also replacement ovarian hormones, led to a beneficial effect on beta cells per se in OLETF female rats. This was reflected by an increased beta-cell mass accompanied by a parallel increase in plasma immunoreactive insulin concentration. The effects of ovarian hormones, however, contributed to the beta-cell hypertrophy rather than expansion of the beta-cell population to achieve glucose homeostasis, as evidenced by an increased area of individual beta-cell after Px rather than an increased BrdU-labelling index for the beta cells. The present study suggests that ovarian hormone-induced beta-cell hypertrophy may typically occur, to compensate for changes in functional demand as the results of a 70 % Px in female OLETF rats. [Diabetologia (...

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Action of Sex Hormones on Experimental Diabetes

Cited by 55 publications

References 5 publications

Sex Steroids Influence Pancreatic Islet Hypertrophy and Subsequent Autoimmune Infiltration in Nonobese Diabetic (NOD) and NODscid Mice

Sex Steroids Influence Pancreatic Islet Hypertrophy and Subsequent Autoimmune Infiltration in Nonobese Diabetic (NOD) and NODscid Mice

Progesterone, Pregnancy and the Augmented Plasma Insulin Response¹

Ovarian hormone-induced beta-cell hypertrophy contributes to the homeostatic control of beta-cell mass in OLETF female rat, a model of Type II diabetes

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Action of Sex Hormones on Experimental Diabetes

Cited by 55 publications

References 5 publications

Sex Steroids Influence Pancreatic Islet Hypertrophy and Subsequent Autoimmune Infiltration in Nonobese Diabetic (NOD) and NODscid Mice

Sex Steroids Influence Pancreatic Islet Hypertrophy and Subsequent Autoimmune Infiltration in Nonobese Diabetic (NOD) and NODscid Mice

Progesterone, Pregnancy and the Augmented Plasma Insulin Response1

Ovarian hormone-induced beta-cell hypertrophy contributes to the homeostatic control of beta-cell mass in OLETF female rat, a model of Type II diabetes

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Progesterone, Pregnancy and the Augmented Plasma Insulin Response¹