Insulin sensitivity and PCOS -
PCOS is a heterogeneous disease , meaning that it can have multiple causes. We need more research to understand these better, but we know that high levels of androgens and insulin resistance can play a role in both causing and exacerbating PCOS.
Women's Health. Jessica Migala. Insulin is a hormone produced by the pancreas that helps keep glucose in check. When we eat carbohydrates, they convert into a type of sugar called glucose, a primary fuel source along with fat for all of the cells in our body.
That glucose enters our bloodstream so it can be distributed throughout the body. Insulin makes it possible for glucose to enter cells to be used for energy or storage if all our current energy needs are met.
If we consume high amounts of carbohydrates including sugar , the level of glucose in our blood can rise faster than insulin can deal with it.
This is known as a glucose—or blood sugar—spike. Other things besides diet can also cause a spike in glucose, such as intense exercise and acute stress. A blood sugar spike causes our body to release even more insulin.
This produces more insulin to compensate , which only exacerbates the cycle. Insulin resistance refers to cells no longer effectively listening to the cue to bring in glucose.
Over time, as increased insulin resistance leads to chronically high blood sugar, it can result in prediabetes and, ultimately, Type 2 diabetes. Insulin resistance can also increase the risk of many other cardiometabolic and reproductive conditions , as well as contribute to or exacerbate PCOS.
Androgens include testosterone, androstenedione, dihydrotestosterone DHT , and dehydroepiandrosterone DHEA.
Females also produce androgens and have higher androgen levels than estrogen most of the time. Healthy androgen levels are critical for reproductive function, libido, cardiometabolic health, and building healthy bones and muscles.
However, when androgens are too high, it is called hyperandrogenism —one of the three core factors that can lead to a PCOS diagnosis. Hyperandrogenism is responsible for many unwanted PCOS symptoms, such as acne, excess body hair, or hair thinning on the head. It also can play a critical role in infertility.
Finally, high androgen levels link insulin resistance — and its associated cardiometabolic health risks — to PCOS. Excess insulin can stimulate specific cells in the ovary, called theca cells, into producing more androgens than normal. The ovaries remain sensitive to insulin , even when other body parts—such as muscles, fat, or the liver—become insulin resistant.
As your body makes more insulin, the ovaries continue to respond to insulin production, causing androgen levels to climb higher and higher. Elevated insulin levels can also decrease levels of sex hormone-binding globulin SHBG.
As its name suggests, SHBG is a protein that binds to androgens, controlling the number of these hormones circulating in the body and keeping levels in a healthy range. When there is not enough SHBG, androgen levels remain higher than they should be.
Higher levels of androgens can also make insulin resistance worse. Excess androgens in women can cause fat to accumulate around the abdomen. Excess androgens can also worsen insulin resistance by reducing insulin sensitivity in skeletal muscle.
These two types of hormones continue to instigate each other in a vicious cycle, ultimately worsening both PCOS and insulin resistance. This can lead to increased PCOS symptoms, both those caused by high androgens acne, excess hair growth on the face and body and insulin resistance increased belly fat, trouble losing weight.
Not only are the symptoms of PCOS linked to androgens and insulin, but these two hormones also drive the more severe risks of PCOS in most cases. These include reproductive risks like infertility and pregnancy complications, issues with weight and obesity, and other metabolic conditions ranging from heart disease and diabetes to sleep apnea.
For more on the risks associated with PCOS, click here. Diagnosing PCOS is a notoriously fuzzy process. Hyperandrogenism and anovulation are challenging to measure objectively and lack clear clinical standards. Moreover, there are no separate criteria for adolescence or menopause , despite global agreement that hormonal changes during these stages of life can influence the diagnostic markers for PCOS.
Diagnosing PCOS amidst the hormonal fluctuations of shifting life phases is difficult, but the resulting ambiguity can lead people to be overdiagnosed, underdiagnosed , or misdiagnosed. As mentioned above, to have a PCOS diagnosis according to the Rotterdam criteria, two of the following symptoms are needed: high androgens, irregular cycles, and cysts on the ovaries.
These criteria are based on expert opinion rather than informed by epidemiological data. The Androgen Excess Society put forward criteria in that require hyperandrogenism. Meanwhile, some researchers have called for greater awareness of the link between metabolic conditions and PCOS, while others have said that screening for insulin resistance should be a part of the diagnostic procedure.
The argument for including those without hyperandrogenism within PCOS diagnostic criteria is to widen the scope of inclusion under the assumption that more people having a diagnosis would lessen the risks associated with PCOS for these people.
research demonstrates that women without dysregulated androgens or insulin do not have the same symptoms or risks. This aligns with the mechanistic understanding that the significant symptoms and risks for PCOS weight gain, acne, excess body hair, cardiometabolic risks stem from high androgens, insulin resistance, or both.
Moreover, the most common treatments for PCOS, such as hormonal contraception or metformin, specifically target lowering androgens or insulin resistance. The role of a diagnosis is to provide insight into risk assessment and treatment pathways. The current criteria for PCOS do not provide enough specificity to do this properly.
Instead, the broadness of the criteria hinders the ability of patients to get the proper treatment. A better, more comprehensive diagnostic criteria would consider the many hormonal factors and potential subtypes.
Until then, determining the impact of androgens, insulin, or both is a sound approach for targeted PCOS management. A clinician can diagnose androgen excess with bloodwork or by assessing symptoms, such as acne, hair growth on the body, or hair loss on the head. While there is no consensus on an upper cut-off, your doctor can tell you if your results are above a healthy range, particularly in the context of other symptoms.
The optimal ranges for metabolic testing are covered in this guide. However, this also gives one snapshot in time. Further testing may be beneficial to get a better sense of whether or not your body has more significant glucose spikes than expected, suggesting possible insulin resistance.
Larger studies, however, have found normal karyotypes Studies from the United Kingdom have phenotyped women on the basis of polycystic ovarian morphology detected by ultrasound The proportion of females affected in all sibships was However, not all women in each kindred were examined and, thus, an accurate ratio of affected to unaffected women could not be established for segregation analysis.
Further, the male phenotype was not sought. A more recent study prospectively examined the families of probands consecutively identified on the basis of polycystic ovarian morphology on ultrasound The first-degree relatives in 10 families were evaluated by history, measurement of physical indices, and hirsutism as well as serum levels of androgens, hydroxyprogesterone, gonadotropins, and PRL.
Transabdominal ultrasound was performed in female first-degree relatives. Glucose and insulin levels were assessed in obese but not lean probands. Twenty-two males were screened; eight had premature before age 30 yr fronto-parietal hair loss, 10 did not, and four were too young to assess. Female affected status was assigned on the basis of ultrasound evidence of polycystic ovaries.
If male affected status was considered to be premature balding, and a history of menstrual irregularity was used to assign postmenopausal affected status, the segregation ratio for affected families, excluding the proband, was Studies in monozygotic twins, however, have not found complete concordance of polycystic ovary morphology, arguing against this mode of inheritance The study contained only 19 pairs of monozygotic twins as well as a sample of 15 dizygotic twins.
This raises concern about the accuracy of the detection of polycystic ovaries. In several studies, PCOS affected status has been assigned on the basis of ovarian morphology rather than hormonal abnormalities.
Only one study has proposed a male phenotype on the basis of examination of male relatives, and this study was constrained by a small sample size Nevertheless, these studies strongly suggest that PCOS has a genetic component, most likely with an autosomal dominant mode of transmission , If this is true, are there other phenotypes in affected kindreds?
The studies cited above have suggested that premature male balding may be a male phenotype , This finding could be an artifact, since it is also possible that bald men choose to marry hirsute women. Recent studies in these families, however, suggesting linkage of this phenotype with a candidate gene in the steroidogenic enzyme pathway Ref.
Our studies have suggested that insulin resistance may be an additional male phenotype as well as a prepubertal and postmenopausal female phenotype , Table 4. This has been also reported recently in a series of Australian PCOS kindreds.
In the small number of families that we have studied , , when women of reproductive age are insulin resistant, they usually have possessed the other endocrine features of PCOS. The one insulin-resistant prepubertal girl was also hyperandrogenic and developed chronic anovulation after menarche consistent with the diagnosis of PCOS That insulin resistance and hyperandrogenism may be a prepubertal phenotype is supported by recent studies suggesting that PCOS develops in insulin-resistant girls with premature adrenarche 58 , , Table 4.
Our studies suggest that hyperandrogenism without insulin resistance is another phenotype in female PCOS kindred members of reproductive age Table 4.
Finally, we have found postmenopausal hyperandrogenic female family members with normal insulin sensitivity, which may represent an additional postmenopausal phenotype Table 4. This possibility is supported by the study of Dahlgren and colleagues 53 , which found that postmenopausal women with a history of PCOS had higher androgen levels than age-matched control women.
We have found that hyperandrogenism and insulin resistance can segregate independently in PCOS kindreds It is not yet possible to determine whether this reflects separate genetic traits or variable penetrance of a single defect. These studies also indicate that there is considerable phenotypic variation, even within kindreds.
Candidate genes for PCOS. The biochemical reproductive phenotype in PCOS is characterized by increased LH secretion and acyclic FSH release 2 , The ovaries in response to LH and, often, the adrenals secrete excessive androgens, and there is decreased ovarian aromatization of androgens to estrogens The circulating androgens feed back on the hypothalamic-pituitary axis directly or via their extragonadal aromatization to estrogen to increase LH relative to FSH release, producing a self-sustaining syndrome 34 — 37 , The defect that initiates these reproductive disturbances in PCOS is unknown, but it can be shown experimentally that factors that increase either androgen secretion or LH release can reproduce these disturbances 1 , 2 , 12 , 38 , Indeed, polycystic ovaries and hyperandrogenism were present in a girl with an aromatase gene mutation leading to an inactive enzyme Transgenic mice overexpressing the LH β-subunit gene in their gonadotropes develop polycystic ovary morphology, androgen elevations, and LH hypersecretion The insulin resistance in PCOS is secondary to a postbinding defect in insulin receptor signaling, as discussed above When this enzyme is identified, it will make an excellent candidate gene for insulin resistance in PCOS.
This enzyme may also be responsible for altering Pc17 activity that results in hyperandrogenism and the PCOS reproductive phenotype Polymorphisms in the Pc17 gene itself were found not to cosegregate with the polycystic ovary-premature balding phenotypes in the families reported by Carey et al.
However, the polymorphism did affect the promoter region of the gene, and the frequency of the polymorphism was significantly increased in PCOS, suggesting that it might play a role in modifying the phenotype Further candidate gene searches in these families suggest a linkage with the steroid synthesis gene CYP11a, and an association study indicated a significant increase in a CYP11a polymorphism in hirsute PCOS women The polymorphism was also significantly associated with elevated testosterone levels.
These investigators have recently reported that an insulin gene VNTR-regulatory polymorphism was significantly associated with PCO in the same families Case-control studies suggested that the polymorphism was associated with anovulation and higher insulin levels , women who would be considered to have the endocrine syndrome.
This observation suggests that there may be a genetic basis for the finding of insulin resistance only in anovulatory women with hyperandrogenism or the PCO morphology.
This insulin gene VNTR has been associated with decreased levels of islet cell insulin RNA and may thus result in decreased insulin secretion. The mechanism by which this might cause hyperinsulinemia and insulin resistance is unknown.
Polymorphisms in the dopamine and androgen receptors have not been significantly associated with PCOS , , There have been no mutations in the coding portions of the insulin receptor gene detected in PCOS 69 , , Extreme caution must be exercised, however, in the interpretation of both linkage and association studies.
Case-control association studies can give false-positive results because of subtle genetic differences between the populations This appears to have occurred in the association studies of the polymorphism in the Pc17 gene promoter with PCO Subsequent larger studies by these investigators failed to confirm the finding a.
Linkage studies of many candidate genes in the same families must have the level of significance for positive results adjusted for multiple tests. Thus log of odds scores greater than the traditional threshold of 3 must be used to prove linkage Such log of odds scores have not been achieved in the reported studies in PCOS , Does insulin resistance produce PCOS in women with PCO?
The polycystic ovary morphology detected by ultrasonography has been reported to be inherited as an autosomal dominant, if premature balding is used as the male phenotype see above. We have found that Caribbean Hispanic women have twice the prevalence of PCOS compared with other ethnic groups Brothers, as well as sisters, of PCOS women can be insulin resistant , The insulin-resistant sisters usually also have PCOS All of these observations support the hypothesis that there is a genetic component to PCOS and the insulin resistance associated with it.
Caribbean Hispanic women are also significantly more insulin resistant than non-Hispanic White women by euglycemic clamp determination of insulin-mediated glucose disposal PCOS independently further decreases insulin action. Non-Hispanic White PCOS women have similar degrees of insulin resistance to Caribbean Hispanic normal ovulatory women These findings suggest that the increased prevalence of PCOS in this ethnic group may be secondary to an increased prevalence of insulin resistance.
Hyperinsulinemia resulting from a spectrum of defects in insulin action, at least some of which are genetic, may play a permissive role in the development of PCOS in genetically susceptible women Fig. This hypothesis is supported by the finding of the full-blown polycystic ovary syndrome hyperandrogenism and anovulation primarily in women with polycystic ovaries who are also hyperinsulinemic , A proposed schema for the association of insulin resistance and PCOS.
A single factor that causes serine phosphorylation of the insulin receptor and serine phosphorylation of Pc17, the key regulatory enzyme controlling androgen biosynthesis, could produce both the insulin resistance and the hyperandrogenism characteristic of PCOS.
It is also possible that the insulin resistance and the reproductive abnormalities reflect separate genetic defects and that the insulin resistance unmasks the syndrome in genetically susceptible women. Recent studies suggest that insulin acting through its own receptor augments steroidogenesis and LH release.
Androgens amplify the associated insulin resistance. Could PCOS and insulin resistance result from a single defect? An exciting recent finding by Miller and colleagues is the observation that serine phosphorylation of human Pc17, the key regulatory enzyme of both ovarian and adrenal androgen biosynthesis, increases its 17,20 lyase activity.
This would result in increased androgen secretion A modulation of steroidogenic enzyme activity by serine phosphorylation has been reported for 17β-hydroxysteroid dehydrogenase If the same factor that serine-phosphorylates the insulin receptor causing insulin resistance also serine-phosphorylates Pc17 causing hyperandrogenism, this could explain the association of PCOS and insulin resistance by a single genetic defect Fig.
Making a diagnosis of insulin resistance in an individual is problematic. Second, clinically available measures of insulin action, such as fasting or glucose-stimulated insulin values , do not correlate well with more detailed measurements of insulin sensitivity in research settings In view of these constraints, it is prudent to consider all PCOS women at risk for insulin resistance and the associated metabolic abnormalities of the insulin resistance syndrome: dyslipidemia, coronary artery disease, and hypertension.
Lipid and lipoprotein levels should be obtained on all PCOS women, and obese PCOS women should also have fasting and 2-h post g glucose load glucose levels as a screen for glucose intolerance.
Individual values for fasting and 2-h post g oral glucose load insulin levels are shown in PCOS and in weight-matched control women. Although the means differ significantly, there is substantial overlap such that an individual value in a PCOS woman may not fall outside the normal range.
Dyslipidemia, dysfibrinolysis, and coronary artery disease. Women with PCOS would be predicted to be at high risk for dyslipidemia because they have elevated androgen levels and are frequently obese — Moreover, since they are also often hyperinsulinemic and insulin resistant, they would also be expected to be at increased risk for the dyslipidemia associated with insulin resistance Insulin, rather than androgen, levels correlate best with lipid abnormalities, and suppressing androgen levels does not alter lipid profiles in PCOS PCOS women also have impaired fibrinolytic activity with increased circulating levels of plasminogen activator inhibitor, PAI-1 , Elevated PAI-1 levels are associated with insulin resistance and are considered to be an independent cardiovascular risk factor by increasing the risk of intravascular thrombosis In PCOS, increased PAI-1 levels are also associated with insulin resistance, and these levels decrease with improvements in insulin sensitivity mediated by weight loss or insulin-sensitizing agents There are several intriguing cross-sectional studies that suggest that PCOS women may indeed be at increased risk for cardiovascular disease.
Women coming to cardiac catheterization who have a history of symptoms of hyperandrogenism have an increased prevalence of coronary artery disease Postmenopausal women with a history of ovarian wedge resection for PCOS have a significantly increased frequency of cardiovascular events compared with age-matched control women Women with PCO detected by ovarian ultrasound have more extensive coronary artery disease by angiography than women with sonographically normal ovaries The women with PCO also have higher free testosterone, triglyceride, and C-peptide levels and lower LDL levels than the women with normal ovaries, suggesting that they have both the endocrine and the metabolic derangements of PCOS Finally, increased carotid wall thickness measured by ultrasonography was found in PCOS women compared with case-controls The carotid wall thickness was significantly positively correlated with fasting insulin levels and body mass index, after adjustment for possible confounding variables However, since the PCOS women were significantly heavier than the controls, it was not possible to determine the independent impact of obesity on these findings As with studies of insulin action, studies of lipid metabolism in PCOS have been confounded by differences in body weight and ethnicity between patient and control groups.
Inconsistencies in diagnostic criteria, in particular, basing the diagnosis on ultrasound morphology rather than hormonal parameters, have resulted in heterogenous patient populations that have included women with regular ovulation and normal insulin sensitivity — Some investigators have found that LDL and HDL changes in PCOS can be accounted for by obesity and that only modest increases in total triglyceride levels appear secondary to PCOS-related insulin resistance , , A recent case control study does suggest that there are lipid abnormalities in PCOS after statistical adjustments for obesity However, Legro and colleagues found atherogenic alterations in lipoprotein levels in normal Hispanic women that did not differ further in Hispanic PCOS women.
Thus, there appear to be important additional genetic and environmental factors influencing lipid metabolism in PCOS. It has been suggested that insulin resistance causes hypertension; thus PCOS women would be expected to be hypertensive Significant increases in systolic blood pressure, albeit within the normal range, have been reported in obese PCOS women, but this study did not include a weight-matched control group Moreover, lean PCOS women in the study were not hypertensive, consistent with an effect of obesity rather than PCOS on blood pressure.
Careful studies of h blood pressures and left ventricular mass have failed to find evidence for hypertension in PCOS women in their second to fourth decades of life This has been confirmed in another recent study The studies discussed above in postmenopausal PCOS women, however, have found a significant increase in prevalence of hypertension It may be that hypertension is not manifested until later in life in PCOS women.
Conversely, it remains possible that the association between insulin resistance and hypertension does not exist in PCOS, analogous to observations in African Americans and in Pima Indians Gestational diabetes mellitus GDM. Women with a history of GDM are insulin resistant, at increased risk to develop NIDDM, and have defects in the β-cell function that can be detected in the absence of glucose tolerance , PCOS women share these traits, and it would be expected that they would be at increased risk to develop GDM, if GDM is yet another manifestation of insulin resistance.
Two small studies of this have yielded conflicting results: one study found no increase in GDM while another detected an increased risk for GDM in PCOS women , A large prospective study in PCOS women containing appropriately matched control women is required to address this issue.
Until such a study has been completed, it is prudent to advise PCOS women contemplating pregnancy that they may be at increased risk to develop GDM. Leptin in PCOS. Leptin, the recently identified product of the ob gene , has been investigated in PCOS.
Since leptin is a fat cell product that acts on the hypothalamus , it could link the metabolic and neuroendocrine derangements characteristic of PCOS. Leptin production is regulated by insulin and could be modulated in insulin-resistant PCOS women via this mechanism An initial report suggested that leptin levels were elevated in some PCOS women However, in this study the confounding effects of differences in body weight were not adjusted for appropriately.
Subsequent studies in PCOS that have contained appropriately weight- or fat mass-matched control women have not found significant differences in leptin levels in PCOS women.
Agents that exacerbate insulin resistance should probably be avoided in PCOS, particularly in women who are also obese. Oral contraceptives are widely used in PCOS to control menstrual irregularities and hyperandrogenism.
Norethindrone-only containing contraceptives do not cause insulin resistance in normal women and, thus, may provide an alternative agent for PCOS women. Specific studies should be performed, however, to verify this hypothesis. Glucocorticoids can exacerbate insulin resistance and should be avoided in PCOS.
Fortunately, there are several therapeutic agents for hyperandrogenism that do not worsen and may even improve insulin sensitivity in PCOS Fig. These are spironolactone, GnRH analogs, and flutamide , Although medroxyprogesterone acetate does decrease insulin sensitivity in normal women , intermittent progestin withdrawal with this agent in the minimally effective dose i.
Weight loss is well known to decrease androgen levels and restore ovulation in PCOS It now appears that a reduction in circulating insulin levels is the mechanism for weight loss-associated reproductive benefits , , since lowering insulin levels by other modalities has similar results , , Indeed, agents that lower insulin levels by improving insulin sensitivity may provide a new therapeutic modality for PCOS.
Metformin acts mainly by suppressing hepatic glucose production, and its insulin-sensitizing actions are primarily mediated through the weight loss that frequently occurs during therapy — In two studies in PCOS, both from Venezuela, metformin therapy resulted in significant decreases in insulin and androgen levels , In one study this was also associated with weight loss, whereas in the other it was not Weight loss accounted for metformin effects on sex hormone levels in the study of Crave et al.
Metformin has not altered androgen levels or insulin action in PCOS in other studies. In contrast, the thiazolidenedione troglitazone improves insulin sensitivity without altering body weight and lowers circulating androgen, estrogen, and LH levels in PCOS Fig.
Further studies are in progress to determine the role for troglitazone as a therapeutic agent for PCOS. It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS.
Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women Table 3. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, Pc It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women Fig.
Recent studies strongly suggest that insulin is acting through its own receptor rather than the IGF-I receptor in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth.
Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes.
Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.
Dunaif A , Givens JR , Haseltine F , Merriam GR eds The Polycystic Ovary Syndrome. Blackwell Scientific , Cambridge, MA. Google Scholar. Google Preview. Franks S Polycystic ovary syndrome. N Engl J Med : — Polson DW , Wadsworth J , Adams J , Franks S Polycystic ovaries — a common finding in normal women.
Lancet 1 : — Pettersson F , Fries H , Nillius SJ Epidemiology of secondary amenorrhea. Am J Obstet Gynecol : 80 — Hull MGR Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies.
Gynecol Endocrinol 1 : — Goldzieher JW , Green JA The polycystic ovary. Clinical and histologic features. J Clin Endocrinol Metab 22 : — Burghen GA , Givens JR , Kitabchi AE Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease.
J Clin Endocrinol Metab 50 : — Dunaif A , Hoffman AR Insulin resistance and hyperandrogenism: clinical syndromes and possible mechanisms.
In: Pancheri P, Zichella L eds Biorhythms and Stress in the Physiopathology of Reproduction. Hemisphere Publishing Co, Washington, DC, pp — Barbieri RL , Ryan KJ Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features.
Am J Obstet Gynecol : Poretsky L , Kalin MF The gonadotropic function of insulin. Endocr Rev 8 : — Poretsky L On the paradox of insulin-induced hyperandrogenism in insulin-resistant states.
Endocr Rev 12 : 3 — Ehrmann DA , Barnes RB , Rosenfield RL Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion.
Endocr Rev 16 : — Crowley WF New tools for pituitary-gonadal assessment. In: Filicori M, Flagmini C eds The Ovary: Regulation, Dysfunction and Treatment. Elsevier, Amsterdam, pp — Bull Acad Natl Med 86 : 51 — Kierland RR , Lakatos I , Szijarto L Acanthosis nigricans: An analysis of data in twenty-two cases and a study of its frequency in necropsy material.
J Invest Dermatol 9 : — Brown J , Winkelmann RK Acanthosis nigricans: a study of 90 cases. Medicine 47 : 33 — Barnes ND , Palumbo PJ , Hayles AM , Folgar H Insulin resistance, skin changes and virilization: a recessively inherited syndrome possibly due to pineal gland dysfunction.
Diabetologia 10 : — Colle M , Doyard P , Chaussain J , Battin J , Job J Acanthosis nigricans, hirsutisme et diabete insulin-resistant. Arch Fr Pediatr 36 : — Taylor SI , Cama A , Accili D , Barbetti F , Quon J , Sierra MDLL , Suzuki Y , Koller E , Levy-Toledano R , Wertheimer E , Moncada VY , Kadowaki H , Kadowaki T Mutations in the insulin receptor gene.
Endocr Rev 13 : — Dunaif A Insulin resistance and ovarian hyperandrogenism. The Endocrinologist 2 : — Kahn CR , Flier JS , Bar RS , Archer JA , Gorden P , Martin MM , Roth J The syndromes of insulin resistance and acanthosis nigricans.
Flier JS , Kahn R , Roth J , Bar RS Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science : 63 — Diabetes 40 : — Flier JS , Eastman RC , Minaker KL , Matteson D , Rowe JW Acanthosis nigricans in obese women with hyperandrogenism.
Characterization of an insulin-resistant state distinct from the Type A and B syndromes. Diabetes 34 : — Dunaif A , Hoffman AR , Scully RE , Flier JS , Longcope C , Levy LJ , Crowley Jr WF The clinical, biochemical and ovarian morphologic features in women with acanthosis nigricans and masculinization.
Obstet Gynecol 66 : — Stuart CA , Peters EJ , Prince MJ , Richards G , Cavallo A , Meyer WJ Insulin resistance with acanthosis nigricans: the roles of obesity and androgen excess. Metabolism 35 : — Peters EJ , Stuart CA , Prince MJ Acanthosis nigricans and obesity: acquired and intrinsic defects in insulin action.
Pasquali R , Venturoli S , Paradisi R , Capelli M , Parenti N , Melchionda N Insulin and C-peptide levels in obese patients with polycystic ovaries. Horm Metab Res 14 : — Shoupe D , Kumar DD , Lobo RA Insulin resistance in polycystic ovary syndrome.
Am J Obstet Gynecol : — Chang RJ , Nakamura RM , Judd HL , Kaplan SA Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 57 : — Judd HL , Scully RE , Herbst AL , Yen SSC , Ingersol FM , Kliman B Familial hyperthecosis: comparison of endocrinologic and histologic findings with polycystic ovarian disease.
Nagamani M , Dinh TV , Kelver ME Hyperinsulinemia in hyperthecosis of the ovaries. Keettel WC , Bradbury JT , Stoddard FJ Observations on the PCO syndrome. Am J Obstet Gynecol 73 : — Yen SSC , Vela P , Rankin J Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease.
J Clin Endocrinol Metab 30 : — Rebar R , Judd HL , Yen SS , Rakoff J , Vandenberg G , Naftolin F Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome.
J Clin Invest 57 : — 9. Waldstreicher J , Santoro NF , Hall JE , Filicori M , Crowley Jr WF Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization.
J Clin Endocrinol Metab 66 : — Dunaif A , Anderson R , Chapin D , Scully RE , Crowley Jr WF The effects of continuous androgen secretion upon the hypothalamic-pituitary-axis in women: evidence from a luteinized thecoma of the ovary.
J Clin Endocrinol Metab 59 : — Lobo RA , Goebelsmann U Adult manifestation of congenital adrenal hyperplasia due to incomplete hydroxylase deficiency mimicking polycystic ovarian disease. Santen RJ , Bardin CW Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiologic mechanisms.
J Clin Invest 52 : — Ehrmann DA , Rosenfield RL , Barnes RB , Brigell DF , Sheikh Z Detection of functional ovarian hyperandrogenism in women with androgen excess. Yen SSC The polycystic ovary syndrome.
Clin Endocrinol Oxf 12 : — McKenna TJ , Moore A , Magee F , Cunningham S Amenorrhea with cryptic hyperandrogenemia. J Clin Endocrinol Metab 56 : — Mechanick J , Dunaif A Masculinization: a clinical approach to the diagnosis and treatment of hyperandrogenic women.
In: Mazzaferri E ed Advances in Endocrinology and Metabolism. Mosley Year Book, Inc, Chicago, IL, pp — Futterweit W , Dunaif A , Yeh H , Kingsley P The prevalence of hyperandrogenism in consecutive women presenting with diffuse alopecia.
J Am Acad Dermatol 19 : — Lobo RA , Goebelsmann U , Horton R Evidence for the importance of peripheral tissue events in the development of hirsutism in polycystic ovary syndrome. Dunaif A Polycystic ovary syndrome and obesity. In: Bjorntorp P, Brodoff BN eds Obesity. Lippincott Co. Quintana B , Chinchilli V , Sieber J , Fultz P , George N , Dunaif A High risk of glucose intolerance GI in women with oligomenorrhea oligo or with polycystic ovary syndrome PCOS.
Program of the 77th Annual Meeting of The Endocrine Society , Washington DC , Abstract OR3— J Clin Endocrinol Metab 65 : — Dunaif A , Green G , Phelps RG , Lebwohl M , Futterweit W , Lewy L Acanthosis nigricans, insulin action, and hyperandrogenism: clinical, histological, and biochemical findings.
J Clin Endocrinol Metab 73 : — Kahn CR Insulin action, diabetogenes, and the cause of Type II diabetes. Diabetes 43 : — Modan M , Harris MI , Halkin H Evaluation of WHO and NDDG criteria for impaired glucose tolerance.
Diabetes 38 : — Dahlgren E , Johansson S , Lindstedt G , Knutsson F , Oden A , Janson PO , Mattson L , Crona N , Lundberg P Women with polycystic ovary syndrome wedge resected in to a long-term follow-up focusing on natural history and circulating hormones.
Fertil Steril 57 : — Dunaif A , Futterweit W , Segal KR , Dobrjansky A Profound peripheral insulin resistance, independent of obesity, in the polycystic ovary syndrome. Dunaif A , Segal KR , Shelley DR , Green G , Dobrjansky A , Licholai T Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome.
Diabetes 41 : — Dunaif A , Sorbara L , Delson R , Green G Ethnicity and polycystic ovary syndrome are associated with independent and additive decreases in insulin action in Caribbean Hispanic women.
Diabetes 42 : — Dunaif A , Finegood DT β-Cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 81 : — Apter D , Butzow T , Laughlin GA , Yen SSC Metabolic features of polycystic ovary syndrome are found in adolescent girls with hyperandrogenism.
J Clin Endocrinol Metab 80 : — Harris MI , Hadden WC , Knowler WC , Bennett PH Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.
population aged 20—74 yr. Diabetes 36 : — DeFronzo RA The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37 : — DeFronzo RA , Tobin JD , Andres R Glucose clamp technique: a method for quantifying insulin secretion and resistance.
Am J Physiol : E — E Bergman RN , Hope ID , Yang YJ , Watanabe RM , Meador MA , Youn JH , Ader M Assessment of insulin sensitivity in vivo : a critical review. Diabetes Metab Rev 5 : — Yki-Jarvinen H , Koivisto VA Effects of body composition on insulin sensitivity.
Diabetes 32 : — Bogardus C , Lillioja S , Mott DM , Hollenbeck C , Reaven G Relationship between degree of obesity and in vivo insulin action in man. Caro JF , Dohm LG , Pories WJ , Sinha MK Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and Type II diabetes.
Kissebah AH , Peiris AN Biology of regional body fat distribution: relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 5 : 83 — Bagatell CJ , Bremner WJ Androgens in men — uses and abuses.
Morales AJ , Laughlin GA , Bützow T , Maheshwari H , Baumann G , Yen SSC Insulin, somatotropic, and luteinizing hormones axes in lean and obese women with polycystic ovary syndrome: common and distinct features.
Dunaif A , Xia J , Book C , Schenker E , Tang Z Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle: a potential mechanism for insulin resistance in the polycystic ovary syndrome.
J Clin Invest 96 : — Dunaif A Hyperandrogenic anovulation PCOS : a unique disorder of insulin action associated with an increased risk of NIDDM. Holte J , Bergh T , Berne C , Berglund L , Lithell H Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance.
J Clin Endocrinol Metab 78 : — Bergman RN , Phillips LS , Cobelli C Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose.
J Clin Invest 68 : — Bergman RN Toward physiological understanding of glucose tolerance. Minimal model approach. Kahn SE , Prigeon RL , McCulloch DK , Boyko EJ , Bergman RN , Schwartz MW , Neifing JL , Ward WK , Beard JC , Palmer JP , Porte Jr D Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects.
J Clin Endocrinol Metab 76 : — Ehrmann DA , Sturis J , Byrne MM , Karrison T , Rosenfield RL , Polonksy KS Insulin secretory defects in polycystic ovary syndrome.
Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. Weber RFA , Pache TD , Jacobs ML , Docter R , Loriaux DL , Fauser BCJM , Birkenhager JC The relation between clinical manifestations of polycystic ovary syndrome and beta-cell function.
Clin Endocrinol Oxf 38 : — Flier JS , Minaker KL , Landsberg L , Young JB , Pallotta J , Rowe JW Impaired in vivo insulin clearance in patients with severe target-cell resistance to insulin. Diabetes 31 : — Marshall S Kinetics of insulin receptor internalization and recycling in adipocytes. Shunting of receptors to a degradative pathway by inhibitors of recycling.
J Biol Chem : — Mahabeer S , Jialal I , Norman RJ , Naidoo C , Reddi K , Joubert SM Insulin and C-peptide secretion in non-obese patients with polycystic ovarian disease. Horm Metab Res 21 : — Peiris AN , Mueller RA , Struve MF , Smith GA , Kissebah AH Relationship of androgenic activity to splanchnic insulin metabolism and peripheral glucose utilization in premenopausal women.
J Clin Endocrinol Metab 64 : — Cheatham B , Kahn CR Insulin action and the insulin signaling network. Kahn CR The molecular mechanism of insulin action. Annu Rev Med 36 : — Kasuga M , Hedo JA , Yamada KM , Kahn CR The structure of the insulin receptor and its subunits: evidence for multiple non-reduced forms and a kD possible proreceptor.
Ullrich A , Bell JR , Chen EY , Herrera R , Petruzzelli LM , Dull TJ , Gray A , Coussens L , Liao Y-C , Tsubokawa M , Mason A , Seeburg PH , Grunfeld C , Rosen OM , Ramachandran J Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes.
Nature : — Ebina Y , Ellis L , Jarnagin K , Edery M , Graf L , Clauser E , Ou J , Masiarz F , Kan YW , Goldfine ID , Roth RA , Rutter WJ The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling.
Cell 40 : — Kasuga M , Karlsson FA , Kahn CR Insulin stimulates the phosphorylation of the 95,dalton subunit of its own receptor. Science : — Ullrich A , Schlessinger J Signal transduction by receptors with tyrosine kinase activity.
Cell 61 : — Cantley LC , Auger KR , Carpenter C , Duckworth B , Graziani A , Kapeller R , Soltoff S Oncogenes and signal transduction.
Cell 64 : — [published erratum appears in Cell May 31; 65 5 : following ]. Cobb MH , Sang BC , Gonzalez R , Goldsmith E , Ellis L Autophosphorylation activates the soluble cytoplasmic domain of the insulin receptor in an intermolecular reaction.
Shoelson SE , Boni-Schnetzler M , Pilch PF , Kahn CR Autophosphorylation within insulin receptor β-subunits can occur as an intramolecular process. Biochemistry 30 : — Frattali AL , Treadway JL , Pessin JE Transmembrane signaling by the human insulin receptor kinase.
Relationship between intramolecular β subunit trans - and cis -autophosphorylation and substrate kinase activation. Myers Jr MG , Sun XJ , White MF The IRS-1 signaling system. Trends Biochem Sci 19 : — Sun XJ , Rothenberg P , Kahn CR , Backer JM , Araki E , Wilden PA , Cahill DA , Goldstein BJ , White MF Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein.
Nature : 73 — Sun XJ , Wang LM , Zhang Y , Yenush L , Myers Jr MG , Glasheen E , Lane WS , Pierce JH , White MF Role of IRS-2 in insulin and cytokine signalling.
Sasaoka T , Rose DW , Jhun BH , Saltiel AR , Draznin B , Olefsky JM Evidence for a functional role of Shc proteins in mitogenic signaling induced by insulin, insulin-like growth factor-1, and epidermal growth factor. Rose DW , Saltiel AR , Majumdar M , Decker SJ Insulin receptor substrate 1 is required for insulin-mediated mitogenic signal transduction.
Proc Natl Acad Sci USA 91 : — Waters SB , Yamauchi K , Pessin JE Functional expression of insulin receptor substrate-1 is required for insulin-stimulated mitogenic signaling.
Okada T , Kawano Y , Sakakibara T , Hazeki O , Ui M Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Cheatham B , Vlahos CJ , Cheatham L , Wang L , Blenis J , Kahn CR Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis and glucose transporter translocation.
Mol Cell Biol 14 : — Kruszynska YT , Olefsky JM Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus.
J Invest Med 44 : — Theroux SJ , Latour DA , Stanley K , Raden DL , Davis RJ Signal transduction by the epidermal growth factor receptor is attenuated by a COOH-terminal domain serine phosphorylation site.
Cochet C , Gill GN , Meisenhelder J , Cooper JA , Hunter T C-kinase phosphorylates the epidermal growth factor receptor and reduces its epidermal growth factor-stimulated tyrosine protein kinase activity. Bollage GE , Roth RA , Beaudoin J , Mochly-Rosen D , Koshland Jr DE Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity.
Proc Natl Acad Sci USA 83 : — Takayama S , White MF , Kahn CR Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity. Karasik A , Rothenberg PL , Yamada K , White MF , Kahn CR Increased protein kinase C activity is linked to reduced insulin receptor autophosphorylation in liver of starved rats.
Chin JE , Liu F , Roth RA Activation of protein kinase Cα inhibits insulin-stimulated tyrosine phosphorylation of insulin receptor substrate Mol Endocrinol 8 : 51 — Muller HK , Kellerer M , Ermel B , Muhlhofer A , Obermaier-Kusser B , Vogt B , Haring HU Prevention by protein kinase C inhibitors of glucose-induced insulin-receptor tyrosine kinase resistance in rat fat cells.
Hotamisligil GS , Peraldi P , Budavari A , Ellis R , White MF , Spiegelman BM IRSmediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance.
Boyle WJ , van der Geer P , Hunter T Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates. Methods Enzymol : — Fadden P , Haystead TAJ Quantitative and selective fluorophore labeling of phosphoserine on peptides and proteins: characterization at the attomole level by capillary electrophoresis and laser-induced fluorescence.
Anal Biochem : 81 — Jialal I , Naiker P , Reddi K , Moodley J , Joubert SM Evidence for insulin resistance in nonobese patients with polycystic ovarian disease.
Marsden PJ , Murdoch A , Taylor R Severe impairment of insulin action in adipocytes from amenorrheic subjects with polycystic ovary syndrome. Metabolism 43 : — Ciaraldi TP , El-Roeiy A , Madar Z , Reichart D , Olefsky JM , Yen SSC Cellular mechanisms of insulin resistance in polycystic ovarian syndrome.
J Clin Endocrinol Metab 75 : — Ciaraldi TP , Morales AJ , Hickman MG , Odom-Ford R , Olefsky JM , Yen SSC Cellular insulin resistance in adipocytes from obese polycystic ovary syndrome subjects involves adenosine modulation of insulin sensitivity. J Clin Endocrinol Metab 82 : — Rosenbaum D , Haber RS , Dunaif A Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes.
Caro JF Clinical Review Insulin resistance in obese and nonobese man. Freidenberg GR , Reichart D , Olefsky JM , Henry RR Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus.
J Clin Invest 82 : — Sorbara LR , Tang Z , Cama A , Xia J , Schenker E , Kohanski RA , Poretsky L , Koller E , Taylor SI , Dunaif A Absence of insulin receptor gene mutations in three women with the polycystic ovary syndrome.
Dunaif A , Diamanti E Defective insulin receptor signaling in vivo in the polycystic ovary syndrome PCOS. Program of the 57th Annual Scientific Meeting of the American Diabetes Association, Boston, MA , Abstract Lewis RL , Cao L , Perregaux D , Czech MP Threonine of the human insulin receptor is a major target for phosphorylation by protein kinase C.
Biochemistry 29 : — Pillay TS , Whittaker J , Lammers P , Ullrich A , Siddle K Multisite serine phosphorylation of the insulin and IGF-1 receptors in transfected cells.
FEBS Lett : — Rapuano M , Rosen OM Phosphorylation of the insulin receptor by a casein kinase I-like enzyme. Roth RA , Beaudoin J Phosphorylation of purified insulin receptor by cAMP kinase.
Stadtmaurer L , Rosen OM Increasing the cAMP content of IM-9 cells alters the phosphorylation state and protein kinase activity of the insulin receptor. Kemp BE , Graves DJ , Benjamin E , Krebs EG Role of multiple basic residues in determining the substrate specificity of cyclic AMP-dependent protein kinase.
Guo H , Damuni Z Autophosphorylation-activated protein kinase phosphorylates and inactivates protein phosphatase 2A. Proc Natl Acad Sci USA 90 : — Maddux BA , Sbraccia P , Kumakura S , Sasson S , Youngren J , Fisher A , Spencer S , Grupe A , Henzel W , Stewart TA , Reaven GM , Goldfine ID Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus.
Sbraccia P , Goodman PA , Maddux BA , Wong KY , Chen YI , Reaven GM , Goldfine ID Production of inhibitor of insulin-receptor tyrosine kinase in fibroblasts from patient with insulin resistance and NIDDM. Legro RS , Fox J , Dunaif A Insulin resistance is a potential phenotypic marker for familial polycystic ovary syndrome PCOS.
Proceedings of the 50th Annual Meeting of the American Fertility Society , San Antonio, TX , Abstract. Jahanfar S , Eden JA , Warren P , Seppala M , Nguyen TV A twin study of polycystic ovary syndrome. Fertil Steril 63 : — Norman RJ , Masters S , Hague W Hyperinsulinemia is common in family members of women with polycystic ovary syndrome.
Fertil Steril 66 : — Ovesen P , Moller J , Ingerslev HJ , Jorgensen JOL , Mengel A , Schmitz O , George K , Alberti MM , Moller N Normal basal and insulin-stimulated fuel metabolism in lean women with the polycystic ovary syndrome. J Clin Endocrinol Metab 77 : — Holte J , Bergh T , Berne C , Wide L , Lithell H Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome.
Robinson S , Kiddy D , Gelding SV , Willis D , Niththyananthan R , Bush A , Johnston DG , Franks S The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries.
Clin Endocrinol Oxf 39 : — Sampson M , Kong C , Patel A , Unwin R , Jacobs HS Ambulatory blood pressure profiles and plasminogen activator inhibitor PAI-1 activity in lean women with and without the polycystic ovary syndrome.
Clin Endocrinol Oxf 45 : — Carmina E , Koyama T , Chang L , Stanczyk FZ , Lobo RA Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome?
Norman RJ , Mahabeer S , Masters S Ethnic differences in insulin and glucose response to glucose between white and Indian women with polycystic ovary syndrome. Fertil Steril 63 : 58 — Tattersall RB , Fajans SS A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people.
Diabetes 24 : 44 — Ghosh S , Schork NJ Genetic analysis of NIDDM. The study of quantitative traits. Diabetes 45 : 1 — Lillioja S , Mott DM , Zawadzki JK , Young AA , Abbott WGH , Knowler WC , Bennett PH , Moll P , Bogardus C In vivo insulin action is familial characteristic in nondiabetic Pima indians.
Ever senstiivity of sehsitivity ovary syndrome Senxitivity Just about everyone else? Probably not. This lifelong Herbal remedies for bloating Customizing diet to align with performance aspirations continues far beyond the Insulin sensitivity and PCOS years. They Inuslin have higher levels of androgens male hormones that females also havewhich can stop eggs from being released ovulation and cause irregular periods, acne, thinning scalp hair, and excess hair growth on the face and body. PCOS is also linked to depression and anxietythough the connection is not fully understood.
Ich denke es schon wurde besprochen, nutzen Sie die Suche nach dem Forum aus.