Polycystic Ovary Syndrome in Type 1 Diabetes

BACKGROUND Functional ovarian hyperandrogenism, including the polycystic ovary syndrome (PCOS), is very prevalent in women with type 1 diabetes (T1D). The pathogenic mechanisms of this association remain unclear. HYPOTHESIS Individual factors expose or protect women with T1D to/from the development of androgen excess and PCOS. Such androgen excess in women with T1D may increase their cardiometabolic risk. MAIN OBJECTIVE Unveiling the pathogenic mechanisms behind functional hyperandrogenism in women with T1D from a sex/gender-medicine and sexual dimorphism perspective. MATERIAL AND METHOS We have designed a cross-sectional comparative clinical study, including 5 groups of study subjects with 12 participans per group: i) Women with T1D \& PCOS. ii) Women with T1D without PCOS. iii) Men with T1D and normal gonadal function. iv) Women with PCOS without diabetes mellitus v) Non-hyperandrogenic control women without T1D. All groups will show similar age and body mass index. T1D groups will be matched for duration of disease. OUTCOMES 1.1 Insulin sensitivity (hyperinsulinaemic euglycaemic clamping). 1.2 Body composition (dual-energy x-ray absorptiometry, bioelectrical impedance analysis \& sonographic studies). 1.3 Ovarian and adrenal steroidogenesis. 2.1 Differential pattern in genetic variants related with insulin signalling and response, inflammation, adiposity, gonadal function, steroidogenesis, and PCOS itself by whole exome sequencing. 2.2 Microbiopsy studies in deep subcutaneous adipose tissue and skeletal muscle tissue: 2.2.1 Differential DNA methylation patterns in genes associated with PCOS. 2.2.2 Differential transcriptomic pattern in genes associated with PCOS. 2.2.3 Differential proteomic patterns in adipose and muscle tissues. 3. Interaction between T1D and PCOS on parameters of metabolic control (intersticial blood glucose monitoring) and morbidities associated with T1D itself.

Functional ovarian hyperandrogenism, and its most frequent phenotypic expression, polycystic ovary syndrome (PCOS), has a worldwide prevalence similar to that of other pandemic metabolic entities such as type 2 diabetes, with figures ranging from 6.5% of women in our environment using strict classical criteria to 17-21% of premenopausal women from Europe and the United States, according to the most recent and inclusive diagnostic criteria. Almost all classic and non-classic cardiovascular risk factors cluster in women with this condition from their early lifespan. Conditions such as obesity, type 2 diabetes, hypertension, or dyslipidaemia, place this prevalent population at a higher risk of cardiovascular events compared to non-hyperandrogenic women. PCOS is a complex syndrome with familial aggregation, in which protective and facilitating environmental factors trigger the onset of the hyperandrogenic phenotype and its metabolic repercussions on a predisposing genotype. POLYCYSTIC OVARY SYNDROME AND TYPE 1 DIABETES MELLITUS One of the metabolic events inherent to PCOS is a deficient organ-dependent insulin action primarily at the liver. Acting upon this central defect, obesity is the major contributor to peripheral insulin resistance in these women. Since insulin acts as a co-gonadotrophin on theca cells by stimulating various enzymes involved in ovarian and adrenal steroidogenesis, any condition associating endogenous hyperinsulinism, such as obesity or type 2 diabetes, may be associated with PCOS. However, our research group first described the association between PCOS and T1D more than 20 years ago. In that pivotal publication these adolescent and young adult women, who suffered from complete impairment of insulin secretion as the primary mechanism of disease instead of insulin resistance and compensatory hyperinsulinism, had a 3-fold increase in the prevalence of classic PCOS compared with unselected non-hyperandrogenic women from the general population. This association has been confirmed in subsequent studies conducted by different groups worldwide. In a recent meta-analysis and systematic review by our group, we reported an increased prevalence of PCOS; in its upper range, such prevalence might reach 34% of patients with T1D, tripling the figures observed in the general population for the classic PCOS phenotype, which is the most severe in terms of cardiometabolic consequences. From a pathophysiological view, and given the obvious absence of endogenous hyperinsulinism in T1D, this relationship must be necessarily supported by exogenous subcutaneous insulin delivery. In healthy subjects, insulin directly reaches the liver through the portal circulation after its pancreatic secretion. After exerting its actions at this level, with its subsequent hepatic clearance, insulin passes into the systemic circulation at much lower concentrations than those found in the portal circulation. In PCOS and other insulin-resistant states, insulin resistan Покажи пълното описание...

1. Non--hyperandrogenic women with type 1 diabetes INCLUSION CRITERIA * Premenopausal women between 18 and 45 years old. * Diagnosis of type 1a diabetes at least 12 months before inclusion in the study, confirmed by positive autoimmunity and complete insulin deficiency. * Treatment with subcutaneous insulin therapy (multiple doses or continuous infusion). * Availability of metabolic control data (continuous interstitial blood glucose monitoring) at least in the month prior to study entry. * Menarche at least three years prior to study entry. EXCLUSION CRITERIA * Honeymoon period of T1D. * Pregnancy or lactation. * Thyroid hormone dysfunction or hyperprolactinaemia. * Diagnosis of non-classical congenital adrenal hyperplasia or other secondary causes of hyperandrogenism. * Diagnosis of other serious chronic disease. * Treatment with oral contraceptives or glucocorticoid therapy in the 3 months prior to inclusion in the study. 2. Women with type 1 diabetes and polycystic ovary syndrome INCLUSION CRITERIA * Women between 18 and 45 years old. * Diagnosis of type 1a diabetes at least 12 months before inclusion in the study, confirmed by positive autoimmunity and complete insulin deficiency. * Treatment with subcutaneous insulin therapy (multiple doses or continuous infusion). * Availability of metabolic control data (continuous interstitial blood glucose monitoring) at least in the month prior to study entry. * Menarche at least three years prior to study entry. * PCOS diagnosis based on the 2012 American NIH consensus criteria, including the Rotterdam and AE-PCOS. EXCLUSION CRITERIA * Honeymoon period of T1D. * Pregnancy/lactation. * Thyroid hormone dysfunction or hyperprolactinaemia. * Diagnosis of non-classical congenital adrenal hyperplasia or other secondary causes of hyperandrogenism. * Diagnosis of other serious chronic disease. reatment with oral contraceptives or glucocorticoid therapy in the 3 months prior to inclusion in the study. 3. Men with T1D and normal gonadal function of similar age, BMI, and duration of diabetes. INCLUSION CRITERIA * Age between 18 and 45 years old. * Diagnosis of type 1a diabetes at least 12 months before inclusion in the study, confirmed by positive autoimmunity and complete insulin deficiency. * Treatment with subcutaneous insulin therapy (multiple doses or continuous infusion). * Availability of metabolic control data (continuous interstitial blood glucose monitoring) at least in the month prior to study entry. EXCLUSION CRITERIA * Honeymoon period of T1D. * Thyroid hormone dysfunction or hyperprolactinaemia. * Diagnosis of non-classical congenital adrenal hyperplasia. * Diagnosis of male hypogonadism. 4. Women with PCOS of similar age and BMI. INCLUSION CRITERIA * Women between 18 and 45 years old. * Menarche at least three years prior to study entry. * PCOS diagnosis based on the 2012 American NIH consensus criteria, including the Rotterdam and AE-PCOS. EXCLUSION CRITERIA * Pregnancy/lactation. * Previously known carbohydrate metabolism abnormalities (prediabetes or type 2 diabetes). * Thyroid hormone dysfunction or hyperprolactinaemia. * Diagnosis of non-classical congenital adrenal hyperplasia or other secondary causes of hyperandrogenism. * Diagnosis of other serious chronic disease. * Treatment with oral contraceptives or glucocorticoid therapy in the 3 months prior to inclusion in the study. 5. Non-hyperandrogenic control women with regular menses of similar age and BMI. INCLUSION CRITERIA * Women between 18 and 45 years old. * Menarche at least three years prior to study entry. * Presence of regular menses. * Lack of signs or symptoms of functional hyperandrogenism. EXCLUSION CRITERIA * Pregnancy/lactation. * Previously known carbohydrate metabolism disturbances. * Thyroid hormone dysfunction or hyperprolactinaemia. * Diagnosis of non-classical congenital adrenal hyperplasia or other secondary causes of hyperandrogenism. * Diagnosis of other serious chronic disease. * Treatment with oral contraceptives or glucocorticoid therapy in the 3 months prior to inclusion in the study.