Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations have been identified in the insulin-receptor gene in insulin-resistant patients. We studied two patients with acanthosis nigricans and insulin resistance caused by a decrease in the number of cell surface insulin receptors. Patient 1 was an 11-yr-old boy with a fasting insulin level of 2130 pM; patient 2 was a 14-yr-old girl with hyperandrogenism and a fasting insulin level of 580-740 pM. Based on Southern-blotting studies, the structure of both alleles of the insulin-receptor gene in both patients appeared to be grossly normal. There was no evidence of insertions, deletions, or major rearrangements. Moreover, the nucleotide sequences of all 22 exons of the gene were normal in both patients. Thus, the predicted amino acid sequences of both patients' insulin receptors were normal. In Epstein-Barr virus-transformed lymphoblasts from patient 1, insulin-receptor mRNA levels were so low they could not be detected with an RNase A protection assay, whereas mRNA levels from patient 2 were in the lower half of the normal range. By use of a more sensitive assay based on the polymerase chain reaction, insulin-receptor mRNA could be detected in Epstein-Barr virus-transformed lymphoblasts from both patients. Moreover, because of the existence of silent polymorphisms in the nucleotide sequences, it was possible to differentiate the two alleles of the insulin-receptor gene in both patients. In patient 2, the two alleles were expressed asymmetrically, with 90% of the mRNA molecules having been transcribed from one allele but only 10% transcribed from the second allele. This suggests that there is an unidentified mutation in the underexpressed allele that acts in a cis-dominant fashion to decrease insulin-receptor mRNA levels. However, in patient 1, both alleles were expressed symmetrically in similarly low levels. Although not proven, it seems likely that the mutations that decrease insulin-receptor mRNA levels in patient 1 also map to the insulin-receptor locus.
Diabetes 1991 May
PMID:Two patients with insulin resistance due to decreased levels of insulin-receptor mRNA. 167 62

Diabetes mellitus and late onset congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency were observed in two female siblings aged 51 and 60 years. Not only coincidence but also causality (hyperinsulinism, glucose intolerance due to hyperandrogenism) should be considered when explaining the association of diabetes mellitus with late onset congenital adrenal hyperplasia.
 ...
PMID:Diabetes mellitus associated with late onset congenital adrenal hyperplasia: coincidence or causality? 183 May 36

1. The clinical association between glucose intolerance, hyperinsulinaemia, insulin resistance and hyperandrogenism is well recognized in premenopausal women with polycystic ovarian disease. We examined the hypothesis that fasting plasma glucose levels might be related to endogenous androgen levels in postmenopausal women in the absence of overt clinical disease. 2. In a Southern Californian cohort of 848 nondiabetic postmenopausal women aged 50-79 years, fasting plasma glucose levels positively correlated with levels of the endogenous androgens dehydroepiandrosterone sulphate and free testosterone and negatively with sex-hormone-binding globulin across the whole range of glucose and hormone levels. Mean dihydroepiandrosterone sulphate and free testosterone levels were 16% and 46% higher, respectively, and mean sex-hormone-binding globulin levels 27% lower in the top compared with the bottom quartile of fasting plasma glucose levels. This relationship was independent of age, body mass index, cigarette smoking habit and exogenous oestrogen use. 3. These findings raise questions about the possible physiological role of androgens in the regulation of glucose metabolism and insulin resistance and, possibly, in the mediation of the some of the cardiovascular consequences of diabetes in women.
 ...
PMID:Fasting plasma glucose levels and endogenous androgens in non-diabetic postmenopausal women. 185 Jun 78

Sulfotransferases controlling the intrahepatic ratio of active androgens to estrogens represent key determinants of whether an obesity mutation will be diabetogenic in C57BL/KsJ female mice. Three unlinked genes (diabetes [db], obese [ob], and fat [fat]) all produced comparable obesity in C57BL/KsJ females, but only the fat mutation was not diabetogenic. The fat gene was incapable of eliciting virilizing changes in hepatic sulfotransferase activity, whereas both db and ob accelerated estrogen and suppressed androgen sulfation. Northern-blot analysis confirmed anomalous suppression of hepatic androgen sulfotransferase transcription in db and ob but not fat females. These findings suggest the utility of obesity genes in analyzing the interaction between hyperandrogenism, hyperinsulinemia, and diabetes.
Diabetes 1991 Oct
PMID:Synergism of obesity genes with hepatic steroid sulfotransferases to mediate diabetes in mice. 193 98

Insulin resistance is an important feature in the pathogenesis of non-insulin-dependent diabetes mellitus. Some rare patients have syndromes associated with a severe form of insulin resistance, usually involving acanthosis nigricans and, in premenopausal females, hyperandrogenism. This review discusses two of the causes of insulin resistance: mutations in the insulin receptor gene and autoantibodies directed against the insulin receptor.
 ...
PMID:Unusual forms of insulin resistance. 203 82

Women with the polycystic ovary syndrome (PCO) have significant insulin resistance and are at risk to develop noninsulin-dependent diabetes mellitus. It remains controversial, however, whether hyperandrogenism directly decreases insulin action. Hence, we performed 2-h euglycemic glucose (approximately 772 pmol/L steady state insulin levels) clamps in nine PCO women with insulin resistance basally and after the 12th week of therapy with a superagonist GnRH analog (40 micrograms every 8 h, sc). Diet, activity, and weight were kept constant. Despite significant decreases in plasma testosterone and androstenedione levels (both P less than 0.05), there was no significant change in insulin-mediated glucose disposal, plasma insulin levels, or hepatic glucose production. The sample size was adequate to detect a clinically significant change in insulin-stimulated glucose disposal (i.e. approximately 3.3 mumol/kg.min; P less than or equal to 0.05). We conclude that suppressing androgen levels into the normal range did not result in significant changes in insulin resistance in PCO. Thus, controlling hyperandrogenemia is not a clinically effective modality to improve insulin action and thereby decrease the risk of noninsulin-dependent diabetes in PCO.
 ...
PMID:Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. 210 27

Resistance to insulin consists in a decrease in insulin's biologic action and is manifested mainly by hyperinsulinism. Clinical investigation of insulin resistance states relies on specialized tests, performed both in vitro and in vivo. The hyperinsulinemic-euglycemic clamp is the reference method for quantifying insulin resistance and can differentiate decreased insulin sensitivity and decreased maximal capacity for glucose uptake. Glucose flux measurements, using glucose labelled with stable isotopes, distinguish hepatic and peripheral factors involved in insulin resistance. In vitro studies include investigations for antibodies against insulin and insulin receptors, studies of insulin receptors and their tyrosine kinase activity, and studies of postreceptor cell metabolism. These investigations are especially useful in genetic syndromes of extreme insulin resistance, whose pathophysiology is largely unelucidated, including: insulin resistance syndromes with acanthosis nigricans, obesity-acanthosis nigricans-hyperandrogenism syndrome, lipoatrophic diabetes, leprechaunism, and other syndromes. But insulin resistance also plays a major role in non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus, and various pathological or even physiological endocrine alterations.
 ...
PMID:[Hyperinsulinism syndromes caused by insulin resistance]. 219 May 20

This review has characterized the current state of knowledge of four clinical situations in which an interrelationship of gynecology, endocrinology and carbohydrate metabolism is recognized. The literature contains conflicting descriptions of changes in glucose homeostasis during the menstrual cycle and while using birth control pills. Physiologic changes in receptor number have been demonstrated in each of these situations, so failure to observe differences using glucose tolerance testing may reflect an in vivo homeostatic response to changes in these hormone levels. Thus, in vivo identification of alterations in carbohydrate metabolism induced by endogenous or exogenous steroids may require utilization of models that prevent these homeostatic mechanisms. The association between hyperandrogenism and hyperinsulinism has been better characterized, but the relationship is complicated by the frequent coexistence of obesity. The association may be due to insulin-stimulated ovarian androgen production, and insulin insensitivity may reflect a postreceptor defect. Insulin and its metabolic effects have also been implicated in ovulatory dysfunction in women with diabetes mellitus and identified as a factor affecting all levels of the hypothalamic-pituitary-ovarian axis. A clearer understanding of these relationships and their application to clinical management await further study.
 ...
PMID:Alterations in carbohydrate metabolism as they apply to reproductive endocrinology. 304 41

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.
 ...
PMID:The gonadotropic function of insulin. 330 17

We report a young woman with systemic lupus erythematosis (SLE) who developed diabetes secondary to extreme insulin resistance, associated with severe hyperandrogenism and acanthosis nigricans. Her insulin resistance was found to be associated with high titers of insulin receptor antibodies. The hyperandrogenism has been favourably influenced by cyclical treatment with cyproterone acetate and ethinyl oestradiol, but the insulin resistance and acanthosis nigricans have remained unmodified after 15 months of follow up.
 ...
PMID:Hyperandrogenism, insulin resistance, acanthosis nigricans, and systemic lupus erythematosis associated with insulin receptor antibodies. 338 33


1 2 3 4 5 6 7 8 9 10 Next >>