UMLS:C0011854 - FACTA Search

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Query: UMLS:C0011854 (type 1 diabetes)
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We have reviewed the role of insulin in ovarian physiology. Clinical observations and experimental data strongly support the hypothesis that insulin possesses gonadotropic activity, when acting alone or with FSH or LH. This idea is further supported by the recent discovery of insulin in follicular fluid. The idea that insulin has gonadotropic function can explain a variety of clinical observations, which otherwise are difficult to understand. For example, manifestations of ovarian hypofunction (primary amenorrhea, late menarche, anovulation, low pregnancy rate, and early menopause) in IDDM can be understood if it is accepted that insulin is necessary for the ovary to reach its full steroidogenic potential. The idea that insulin affects ovarian steroidogenesis also helps to understand the observation that hyperandrogenism frequently accompanies each of the various insulin-resistant states, regardless of the latter's etiology (e.g. genetic deficiency in the number of insulin receptors, antiinsulin receptor antibodies, obesity, etc.). The explanation for this association is based on the idea that hyperinsulinemia intensifies ovarian steroidogenesis, which manifests clinically as hyperandrogenism. Continuous stimulation of the ovary by insulin over a long period of time possibly produces morphological ovarian changes, such as hyperthecosis or polycystic changes; these changes commonly are observed among women with insulin resistance. The effects of insulin on ovarian cells are mediated possibly through binding of the peptide to its own receptor or to the IGF-1 receptor (the specificity spillover phenomenon). The latter could be an important mechanism in cases of insulin resistance. Potential mechanisms underlying the gonadotropic activity of insulin include direct effects on steroidogenic enzymes, modulation of FSH or LH receptor number, synergism with FSH or LH, or nonspecific enhancement of cell viability. The gonadotropic function of insulin adds yet another note to what has been termed a symphony of insulin action. Further investigation into this new area may yield greater insights not only into normal ovarian physiology, but also into the pathogeneses of such diverse entities as PCO, obesity, diabetes mellitus, and the syndromes of insulin resistance and acanthosis nigricans.
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PMID:The gonadotropic function of insulin. 330 17

A single base change has been found in the promoter region of CYP17, the gene encoding P450c17 alpha, which appears to be a significant factor in the expression of hyperandrogenism in PCO but which can be excluded as the primary genetic defect. These findings are consistent with the biochemical data from the studies of patients with PCOS reported above, in which the production of ovarian 17 hydroxyprogesterone and androstenedione were observed to be greatly increased but the generation of progesterone was also exaggerated in PCO theca. Thus, genetic factors may well be involved in the observed dysregulation of 17 hydroxylase/17,20 lyase, but this does not appear to be the whole story. It remains a tenable hypothesis that a single-gene effect is the major cause of PCOS and that a gene involved in the expression of androgen production will be implicated. On the other hand, increased androgen production may be a reflection of an 'upstream' abnormality in the ovary, perhaps involving the fundamental processes of proliferation, differentiation and atresia in ovarian follicles. It is also possible that PCOS is truly polygenic and that CYP17 is one of several genes-including those related to insulin secretion and action-that contribute to the PCOS phenotype. Further candidate genes will need to be investigated using well-characterized, large families, but if several predisposing genes are involved, other approaches may be applicable, for example analysis of shared alleles by affected sibling pairs, which has proved valuable in understanding the genetics of type 1 diabetes (Davies et al, 1994). In conclusion, PCOS--one of the most common endocrinopathies--remains an enigmatic condition but one which may prove to be an important model for understanding the interaction of genetic and environmental factors in the aetiology of endocrine disorders.
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PMID:Hypersecretion of androgens by polycystic ovaries: the role of genetic factors in the regulation of cytochrome P450c17 alpha. 877 44

Insulin resistance characterizes non-insulin dependent diabetes (NIDDM). Insulin resistance may coexist in clinical syndromes with hyperestrogenism and hyperandrogenism, suggesting that the ovary may be sensitive to effects of insulin. In addition, insulin-like growth factor-I receptors, which are capable of binding insulin, have been identified in ovarian cancer tissue and are proposed to regulate cell growth. We evaluated the association between a history of diabetes mellitus and ovarian cancer in a case-control study in seven counties in Washington and in Utah (United States) during the years 1975-87. Cases included women newly diagnosed with ovarian cancer over a five-year period who were identified through population-based cancer reporting. Controls similar to cases with regard to age and county of residence were identified via household surveys or random digit dialing. The study included 595 cases and 1,587 controls. Twenty-seven cases (4.5 percent) and 72 controls (4.5 percent) reported a history of diabetes. Logistic regression analysis of the association between diabetes and ovarian cancer controlling for age, body mass index, and race resulted in an odds ratio (OR) of 0.9 (95 percent confidence interval [CI] = 0.6-1.5). The OR was not changed with further controlling for prior oral contraceptive use or prior pregnancy. None of the 20 women with nonepithelial tumors (15 of which were stromal tumors) had a history of diabetes (upper CI = 4.0). These results, together with findings of two earlier cohort studies, do not support the hypothesis that diabetes is a risk factor for epithelial ovarian cancer.
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PMID:Is diabetes mellitus a risk factor for ovarian cancer? A case-control study in Utah and Washington (United States). 881 36

A 24 year old woman presented with a prolonged clinical history of fasting and exertional hypoglycaemia, and was subsequently diagnosed with an insulinoma. Concurrent symptoms of oligomenorrhoea and hyperandrogenism of similar duration were noted. Biochemically, hyperinsulinaemia was observed in association with a raised serum luteinizing hormone (LH), raised testosterone and androstendione concentrations. Surgical removal of the insulinoma resulted in resolution of the clinical and biochemical features of the polycystic ovarian syndrome (PCOS) but minimal change was observed in the ovarian ultrasound appearances. This case demonstrates the role of insulin in mediating the hypersecretion of both LH and androgens in women with polycystic ovaries. We suggest that hyperinsulinaemia converted occult 'polycystic ovaries' to become clinically manifest as 'polycystic ovary syndrome'. This paradigm has clear implications for women with insulin dependent diabetes mellitus who presumably have systemic hyperinsulinaemia.
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PMID:Clinical presentation of PCOS following development of an insulinoma: case report. 1061 Nov 94

The current recommendation for strict metabolic control of type 1 diabetes mellitus requires the administration of supraphysiological doses of insulin, which might result in insulin-mediated stimulation of androgen synthesis, as occurs in insulin-resistant states. At present, the prevalence of hyperandrogenic disorders in women with type 1 diabetes mellitus is unknown. Eighty-five women with type 1 diabetes mellitus were evaluated for symptoms and signs of hyperandrogenism. In 68 of the patients, several serum androgen and hormone concentrations were measured. The polycystic ovary syndrome (PCOS) was defined by the presence of menstrual dysfunction, together with clinical and/or biochemical evidence of hyperandrogenism, and exclusion of other etiologies. Eighteen healthy women, menstruating regularly, served as controls for the androgenic profiles. Thirty-three patients (38.8%) presented hyperandrogenic disorders (16 had PCOS, and 17 had hirsutism without menstrual dysfunction). Type 1 diabetic patients with PCOS presented increased serum total and free testosterone concentrations, and serum androstenedione levels, but had normal serum sex hormone-binding globulin and dehydroepiandrosterone-sulfate levels. Hirsute type 1 diabetic women without menstrual dysfunction presented normal serum androgen levels. There were no significant differences between hyperandrogenic and nonhyperandrogenic type 1 diabetes mellitus women in clinical variables such as the duration of diabetes, age at diagnosis of diabetes, conventional or intensive insulin therapy, mean daily insulin dosage, or metabolic control. In conclusion, women with type 1 diabetes mellitus have a high prevalence of hyperandrogenic disorders, including PCOS and hirsutism.
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PMID:High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus. 1109 51

Even small increases in the frequency of thrombotic disease in users of OCs have general health impact because of their widespread use, which is currently expanding to potential risk groups. The present investigations were launched to study the effects of OCs containing 20-40 micrograms of EE combined with the latest developed gonane progestogens on biochemical risk markers within metabolic systems involved in the development of arterial thrombotic disease. The studies included evaluation of carbohydrate and lipid metabolism as well as the haemostatic system and were performed in non-diabetic women and in women with IDDM, who are prone to the development of arterial thrombosis. In the evaluation of the carbohydrate metabolism in non-diabetic women, we found no effect on fasting glucose or insulin and no effect on the insulin response to oral glucose in women using monophasic OCs containing EE combined with DSG or GST. This contrasts the evaluation of triphasic OCs containing EE combined with GST or NGT, which increased fasting insulin and reduced insulin sensitivity without affecting the glucose-effectiveness or the beta-cell function. Impaired glucose tolerance developed in 10% of the women after 6 months. These finding suggest that OCs are able to induce a state of insulin resistance, which should be considered in the prescription for women with potential disturbed insulin sensitivity or reduced beta-cell secretory capacity e.g. women with ovarian hyperandrogenism, obesity, previous GDM or perimenopausal women. We found no change in glycaemic control in 22 women with well-regulated IDDM treated with a monophasic combination of EE and GST for one year and none of the women developed microalbuminuria during treatment. In the women with diabetes we observed an increase in fasting levels of triglycerides, a decrease in LDL-cholesterol, and unchanged concentrations of total cholesterol and HDL-cholesterol during treatment. In non-diabetic women treated with the same compound or an OC containing EE and DSG we found similar changes in triglycerides and total cholesterol, but increased levels of HDL-cholesterol and unchanged LDL-cholesterol concentrations. In the women with IDDM there was a negative correlation between daily insulin requirement and HDL-cholesterol before and during treatment, but no other statistically significant correlation between estimates of glycaemic control and lipids and lipoproteins were observed. In the non-diabetic women, changes in the haemostatic system included an increase in the procoagulant factors fibrinogen and Factor VIIc; the concentration of active t-PA increased, mainly because of decreased inhibition by PAI-1. The ratio between molecular markers of the activity of the coagulation system and the efficacy of fibrinolysis was unchanged. This was also found in the women with IDDM, who showed evidence of increased fibrin formation and an attenuated fibrinolytic response during treatment. The regulation of the t-PA/PAI system was studied in non-diabetic women in order to elucidate if the effects of OCs are caused by a direct effect on synthesis or clearance of these variables or if they are secondary to changed insulin sensitivity, as described in individuals with atherosclerosis. We found no indications that insulin resistance is involved in the regulation of t-PA and PAI-1 antigen levels, neither before nor during intake of OCs. We showed, however, that the decreased t-PA antigen concentration observed in OC users is caused by reduced synthesis outside the splanchnic circulation. The studies indicate that low-dose OCs containing newer gonane progestogens are able to induce insulin resistance and to impair glucose tolerance. Lipoproteins were not adversely influenced by the OCs neither in the diabetic nor the non-diabetic women; on the contrary, there was a tendency towards increased plasma levels of HDL-cholesterol and decreased LDL-cholesterol which are associated with a decreased risk of atherosclerosis. The changes observed within the haemostatic system were in accordance with a maintained balance between coagulation and fibrinolysis although the rate of fibrin formation may be increased in the women with IDDM. Irrespective of OC use, the interrelationships between metabolic systems in young non-diabetic women are different from those reported in individuals with atherosclerosis or insulin resistance. The effects of OCs on the t-PA/PAI system seem to be mediated by a direct effect on the vessel wall and not by changes in the hepatic clearance. The present findings were obtained in diabetic women without vascular complications, so the conclusion that women with IDDM can use OCs without metabolic alterations of known clinical significance is therefore restricted to those without evidence of diseased vessels. When evaluating the results obtained in the non-diabetic women, it should be remembered that women with recognised risk factors were excluded. The results may therefore be of limited value when evaluating the risk of arterial thrombosis in predisposed populations. In healthy individuals, the present integrated evaluation of biochemical markers does not indicate an increased risk of arterial thrombosis during use of low-dose OCs containing newer gonane progestogens; thus, the findings are in accordance with the recent epidemiological studies on these compounds. The application of relevant biochemical markers facilitate the understanding of the non-reproductive effects of sex steroids which have increasing importance because of their expanding use, not only as contraceptives, but also in the treatment of benign gynaecological disorders, as hormone replacement therapy and as prophylactic agents against specific degenerative conditions. Moreover, they may prove to be helpful in the future identification of women, who have increased susceptibility to the metabolic effects of sex steroids due to genetic predisposition.
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PMID:Pharmacodynamic effects of oral contraceptive steroids on biochemical markers for arterial thrombosis. Studies in non-diabetic women and in women with insulin-dependent diabetes mellitus. 1189 23

Over the last 50 years the prognosis for growth and pubertal development in children with type 1 diabetes mellitus (T1DM) has improved considerably. The early reports of Mauriac's syndrome were related not only to relative deficiency of insulin but also reduced caloric intake. Improved insulin delivery and liberalisation of caloric intake has resulted in improved growth, but subtle abnormalities persist. The frequently reported increased height at diagnosis may relate to prior hyperinsulinaemia and genetic background with respect to lDDM2 the insulin gene VNTR. Subsequent growth faltering is thought to be related to impairment of the GH/IGF-1 axis but children with T1DM are also more at risk of hypothyroidism and coeliac disease. At puberty, persisting abnormalities of the GH/IGF-1 axis and our inability to reverse these totally, even with intensified insulin therapy, contribute to the blunted pubertal growth in the girls but abnormal sex steroid concentrations may also be important. Intensification of insulin therapy may result in leptin resistance and excessive gains in fat mass, particularly in girls. Although it is likely that most children with T1DM will have normal final heights, this excessive weight gain in girls may lead to problems with compliance. Furthermore, hyperinsulinaemia in these subjects may also lead to ovarian hyperandrogenism, increased early risk of microvascular complications and long-term risk of cardiovascular disease.
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PMID:Growth and body composition in type 1 diabetes mellitus. 1237 17

The polycystic ovary syndrome (PCOS) and hyperandrogenism are some of the most common endocrine disorders in women of fertile age. Insulin resistance is present in a significant proportion of hyperandrogenic patients, yet also, impaired beta-cell function, even in absence of clinically evident glucose intolerance, is a frequent finding, especially in patients with familial history of type 2 diabetes mellitus. Therefore, it is not surprising that hyperandrogenism, PCOS, and disorders of carbohydrate metabolism are associated frequently. This association was first reported 75 years ago and, although the mechanisms responsible are not precisely understood, insulin resistance plays an important role in the development of both disorders. PCOS patients develop type 2 diabetes mellitus more frequently than non-hyperandrogenic women and, conversely, women with type 2 diabetes have a greater risk of having PCOS compared with the normal population. Although type 1 diabetes mellitus is a disease characterized by complete abolition of endogenous insulin secretion, a certain degree of hyperinsulinism may exist, resulting from the relatively excessive insulin doses needed to maintain a strict metabolic control. This exogenous hyperinsulinism may increase ovarian androgen secretion, and it has been reported that there is an increased prevalence of hyperandrogenic disorders in type 1 diabetic women. Considering that insulin resistance, hyperinsulinemia and androgen excess may collaborate in increasing the risk for CVD in these women, the identification of hyperandrogenic symptoms in diabetic women, and the identification of disorders of glucose tolerance in hyperandrogenic patients, may have important consequences for the correct management of these women.
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PMID:Hyperandrogenism, insulin resistance and hyperinsulinemia as cardiovascular risk factors in diabetes mellitus. 1822 Jun 16

Insulin is well known for its effects on carbohydrate metabolism, but this hormone also plays an important role in regulating ovarian function. Granulosa, theca and stromal ovarian cells may be affected by insulin deficiency or excess, which may be present in women with type 1 diabetes mellitus (T1D). Recent publications have shown that in spite of intensive insulin therapy, some delay in the age of thelarche, pubarche and menarche is still observed in girls with T1D. In addition, ovarian hyperandrogenism may be observed during late adolescence and an increased prevalence of hirsutism and polycystic ovarian syndrome (PCOS) has been described in adult women with T1D. These endocrine abnormalities may be related to nonphysiologic insulin replacement therapy and to hyperglycemia. This paper reviews the pubertal development and the clinical reproductive abnormalities observed in girls with type 1 diabetes mellitus, and shows that several significant clinical problems, such as pubertal delay, menstrual disturbances and hyperandrogenism which may ultimately lead to the development of PCOS in adulthood, may be observed in some of these patients.
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PMID:Puberty and ovarian function in girls with type 1 diabetes mellitus. 1903 32

The purpose of this report is to present the case of a patient with type 1 diabetes with acne and chronic renal failure on dialysis admitted to the hospital with high total total and free testosterone (612 ng/dL, normal < 90 ng/dL; 255 pMol/L, normal: 20-45 pMol/L). On clinical evaluation, she presented facial acne, and no other signs of hyperandrogenism. As this result was confirmed, she underwent adrenal and ovary morphological assessment (adrenal CT and pelvic ultrasound), which yielded normal results. Due to divergence between clinical and laboratory findings, we considered other possibilities that could explain the elevation of testosterone, including the presence of comorbidities (diabetes and chronic renal failure) and failure of the testosterone assay. Testosterone levels were determined again by high performance liquid chromatography, as a preparative method, and tandem mass spectrometry, yielding normal results (21 ng/dL), which were compatible with a falsely elevated total testosterone level caused by the presence of factors that intereferred with the assay.
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PMID:[Falsely elevated testosterone in a type 1 diabetes patients with acne and chronic renal failure on dialysis]. 2291 Dec 85

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