Compensatory Hyperinsulinemia Research Articles

Comorbid conditions at chronic obstructive pulmonary disease: the questions under investigation and discussion

The second part of the review examines in detail the questions of diagnostics and peculiarities of the metabolic syndrome manifestations, which presents the link between most comorbid conditions at patients with chronic obstructive pulmonary disease. The metabolic syndrome is based on the insulin resistance and compensatory hyperinsulinemia, caused by both chronic low‑intensity inflammation and increased adipose tissue, often against the background of aggravated heredity at diabetes mellitus. The authors elucidate aspects of the effects of obesity, cachexia and some endocrine disorders on the disease course. The deficiency of researches on endocrine status, especially thyroid function and related metabolic disorders was emphasized. Possible pathogenetic mechanisms of osteoporosis development in this contingent of patients are considered. The need for further research of the pathogenetic role of vitamin D is discussed. Data on the role of the functional state of kidneys in the development of metabolic disorders in an organism have been presented, though kidney pathology in patients with chronic obstructive pulmonary disease is not currently considered as a comorbid condition. The contradictory literature data on the development of anemia in these patients were analysed. The authors presented data on the development of oncological processes as a systemic manifestation at COPD and performed analysis of common and mutually aggravating mechanisms of the development of these pathological conditions. Attention has been paid to the relationship between gastroesophageal reflux disease, bronchiectasis and obstructive sleep apnea with chronic obstructive pulmonary disease. The prospects of modern genetic research in chronic obstructive pulmonary disease and comorbid conditions have been determined.

Chromatin protein HMGB1 regulates hyperinsulinemia mediated insulin resistance: low‐dose naltrexone rescues insulin resistance associated with hyperinsulinemia

Insulin secretion with compensatory hyperinsulinemia where pancreatic β-cells are forced to secrete more insulin is central hallmark of peripheral insulin resistance and type 2 diabetes (T2DM). Considerable data have suggested that hyperinsulinemia itself leads to inflammation and Toll like Receptor-4 (TLR4) activation is critical determinant for this process. We found that hyperinsulinemia increases circulatory HMGB1 (an endogenous TLR4 ligand) by ensuring its nuclear-to-cytoplasmic shuttling and release into the extracellular space extracellular via secretory lysosomes. Our observations suggest that hyperinsulin promotes the hyperacetylation of HMGB1 via the inhibition of SIRT1, which reduces HMGB1 release. Further, a hypo-acetylation mutant HMGB1 (K 28,29,30 R), reduces HMGB1 release in hyperinsulin-activated cells, indicating that the acetylation-dependent interaction between HMGB1 and SIRT1 is critical for hyperinsulin induced-redistribution of HMGB1 from the nucleus to the cytosol and/or secretion to the extracellular medium. Besides, hyperinsulinemia induce elevated serum HMGB1 promotes proinflammatory responses in rodents as well humans and plays a crucial role in modulating hepatic insulin signalling. We further showed that Low Dose of Naltrexone (LDN) abrogates hyperinsulinemia-mediated SIRT1 repression and prevents hyperinsulinemia induced HMGB1 release into extracellular milieu and reinstates insulin sensitivity both in in vitro and in vivo diet-induced hyperinsulinemic mouse model. Taken together the data presented provides a completely new regulatory mechanisms within the insulin-TLR4 signaling axis of great significance to human health and diabetes. Finally, in therapeutic standpoint, instead of silencing HMGB1 use of LDN to correct HMGB1 intracellular distribution and LDN treatment may provide a novel therapeutic approach against hyperinsulinemia-associated insulin resistance.

Pregnancy Serum DLK1 Concentrations Are Associated With Indices of Insulin Resistance and Secretion.

ContextDelta like noncanonical notch ligand 1 (DLK1) is a paternally expressed imprinted gene that encodes an epidermal growth factor repeat-containing transmembrane protein. A bioactive, truncated DLK1 protein is present in the circulation and has roles in development and metabolism.ObjectiveWe sought to investigate links between maternal pregnancy circulating DLK1 concentrations and: (1) maternal and fetal DLK1 genotypes, (2) maternal insulin resistance and secretion, and (3) offspring size at birth.Patients, design, and settingWe measured third-trimester maternal serum DLK1 concentrations and examined their associations with parentally transmitted fetal and maternal DLK1 genotypes, indices of maternal insulin resistance and secretion derived from 75-g oral glucose tolerance tests performed around week 28 of pregnancy, and offspring size at birth in 613 pregnancies from the Cambridge Baby Growth Study.ResultsMaternal DLK1 concentrations were associated with the paternally transmitted fetal DLK1 rs12147008 allele (P = 7.8 × 10-3) but not with maternal rs12147008 genotype (P = 0.4). Maternal DLK1 concentrations were positively associated with maternal prepregnancy body mass index (P = 3.5 × 10-6), and (after adjustment for maternal body mass index) with both maternal fasting insulin resistance (Homeostatic Model Assessment of Insulin Resistance: P = 0.01) and measures of maternal insulin secretion in response to oral glucose (insulinogenic index: P = 1.2 × 10-3; insulin disposition index: P = 0.049). Further positive associations were found with offspring weight (P = 0.02) and head circumference at birth (P = 0.04).ConclusionThese results are consistent with a partial paternal or placental origin for the maternal circulating DLK1 which may lead to increased maternal circulating DLK1 concentrations, stimulation of maternal insulin resistance and compensatory hyperinsulinemia during pregnancy, and the promotion of fetal growth.

Obesity and polycystic ovary syndrome.

The increased global prevalence of obesity over the last 40-years has driven a rise in prevalence of obesity-related co-morbidities, including polycystic ovary syndrome (PCOS). On a background of genetic susceptibility, PCOS often becomes clinically manifest following weight gain, commonly during adolescence. A common endocrinopathy affecting between 6%-10% of reproductive-age women, PCOS presents with the cardinal features of hyperandrogenism, reproductive and metabolic dysfunction. PCOS associates with insulin resistance, independently of (but amplified by) obesity. Insulin resistance in PCOS is characterized by abnormal post-receptor signalling within the phosphatidylinositol-kinase (PI3-K) pathway. Multiple factors (including most notably, weight gain) contribute towards the severity of insulin resistance in PCOS. Compensatory hyperinsulinaemia ensues, resulting in over-stimulation of the (intact) post-receptor mitogen-activated protein kinase (MAP-K) insulin pathway, with consequent implications for steroidogenesis and ovarian function. In this concise review, we explore the effects of weight gain and obesity on the pathogenesis of PCOS from the perspective of its three cardinal features of hyperandrogenism, reproductive and metabolic dysfunction, with a focus on the central mediating role of the insulin pathway. We also consider key lifestyle strategies for the effective management of obese and overweight women with PCOS.

Human amylin aggregates release within exosomes as a protective mechanism in pancreatic β cells: Pancreatic β-hippocampal cell communication

Pancreatic β cells are essential in the maintenance of glucose homeostasis during the progression to type 2 Diabetes Mellitus (T2DM), generating compensatory hyperinsulinemia to counteract insulin resistance. It is well known, that throughout the process there is an increased mTORC1 signaling pathway, with an impairment in different quality control systems including ubiquitin-proteasome system and autophagy. In addition, under this situation, pancreatic β cells start to accumulate amylin protein (IAPP) in aggregates, and this accumulation contributes to the failure of autophagy, damaging different organelles such as plasma membrane, endoplasmic reticulum, mitochondria, and others. Here, we report that IAPP can be incorporated to multivesicular bodies (MVB) and secreted into exosomes, a mechanism responsible for the exportation of these toxic aggregates as vehicles of cell to cell communication. On this regard, we have demonstrated that the exosomes bearing toxic hIAPP released from pancreatic β cells are capable to induce hyperactivation of mTORC1 signaling, a failure in the autophagic cellular quality control, and favor pro-fission status of the mitochondrial dynamics in hippocampal cells. In summary, our results show that harmful accumulation of hIAPP in pancreatic β cells may be detoxified by the release of exosomes, which may be captured by endocytosis mechanism damaging neuronal hippocampal cells, which suggest an underlying molecular mechanism to the link between type 2 diabetes and neurodegenerative diseases.

Insulin Resistance in Congenital Adrenal Hyperplasia is Compensated for by Reduced Insulin Clearance.

Congenital adrenal hyperplasia (CAH) patients have potential normal longevity. However, a greater risk for cardiovascular disease has been reported. Insulin resistance and hyperinsulinemia have been described in CAH patients, whereas the prevalence of overt type 2 diabetes is not higher in CAH than in normal population. To examine the contributions of insulin secretion and of hepatic insulin clearance to compensatory hyperinsulinemia in young insulin-resistant adults with classic CAH due to 21-hydroxylase deficiency (21-OHD). Cross-sectional. University outpatient clinics. Fifty-one participants: 21 controls, and 30 CAH (15 virilizing and 15 salt-wasting phenotypes), female/male (33/18), age (mean [SD]): 24.0 (3.6) years, body mass index: 24.6 (4.9)kg/m2 with normal glucose tolerance, were submitted to a hyperglycemic clamp study. Insulin sensitivity, beta cell function, and hepatic insulin clearance using appropriate modeling. We found an increased insulin resistance in 21-OHD. The systemic hyperinsulinemia (posthepatic insulin delivery) was elevated in CAH patients. No increases were observed in insulin secretory rate (beta cell function) in the first phase or during the hyperglycemic clamp. The increase in insulin concentrations was totally due to a ~33% reduction in insulin clearance. 21-OHD nonobese subjects have reduced insulin sensitivity and beta cell response unable to compensate for the insulin resistance, probably due to overexposure to glucocorticoids. Compensatory hyperinsulinemia is most related with reduced hepatic insulin clearance. The exclusive adaptation of the liver acts as a gating mechanism to regulate the access of insulin to insulin-sensitive tissues to maintain glucose homeostasis.

Mechanisms of Insulin Resistance at the Crossroad of Obesity with Associated Metabolic Abnormalities and Cognitive Dysfunction.

Obesity mediates most of its direct medical sequelae through the development of insulin resistance (IR). The cellular effects of insulin occur through two main postreceptor pathways that are the phosphatidylinositol 3-kinase (PI3-K) and the mitogen-activated protein kinase (MAP-K) pathways. Obesity-related IR implicates the PI3-K pathway that confers the metabolic effects of insulin. Numerous and complex pathogenic pathways link obesity with the development of IR, including chronic inflammation, mitochondrial dysfunction (with the associated production of reactive oxygen species and endoplasmic reticulum stress), gut microbiota dysbiosis and adipose extracellular matrix remodelling. IR itself plays a key role in the development of metabolic dysfunction, including hypertension, dyslipidaemia and dysglycaemia. Furthermore, IR promotes weight gain related to secondary hyperinsulinaemia, with a resulting vicious cycle of worsening IR and its metabolic sequelae. Ultimately, IR underlies obesity-related conditions such as type 2 diabetes mellitus (T2D) and polycystic ovary syndrome (PCOS). IR also underlies many obesity-related malignancies, through the effects of compensatory hyperinsulinaemia on the relatively intact MAP-K insulin pathway, which controls cellular growth processes and mitoses. Furthermore, the emergent data over recent decades support an important role of obesity- and T2D-related central IR in the development of cognitive dysfunction, including effects on hippocampal synaptic plasticity. Importantly, IR is largely reversible through the optimisation of lifestyle factors that include regular engagement in physical activity with the avoidance of sedentariness, improved diet including increased fibre intake and sleep sufficiency. IR lies at the key crossroad between obesity and both metabolic and cognitive dysfunction. Given the importance of IR in the pathogenesis of many 21st century chronic diseases and its eminent reversibility, it is important that we all embrace and facilitate optimised lifestyles to improve the future health and wellbeing of the populace.

Adipose-specific knockout of ubiquitin-conjugating enzyme E2L6 (Ube2l6) reduces diet-induced obesity, insulin resistance, and hepatic steatosis

Ubiquitin/ISG15-conjugating enzyme E2 L6 (UBE2L6/Ube2l6) catalyzes protein ISGylation and ubiquitylation, post-translational modifications which regulate protein stability. Ube2l6 plays a role in promoting in vitro adipogenesis; however, its mechanism(s) of action and in vivo effects remain unknown. Here, we discovered that UBE2L6 levels were upregulated, and UBE2L6 and adipose triglyceride lipase (ATGL/Atgl) levels were negatively correlated, in white adipose tissue (WAT) from obese humans and obese mice. Therefore, we employed adipose-specific Ube2l6 knockout (Ube2l6AKO) mice and age-matched Ube2l6flox/flox controls to assess adipocyte Ube2l6's role in high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis. HFD-fed Ube2l6AKO mice displayed lower subcutaneous and visceral WAT mass levels relative to controls. HFD-fed Ube2l6AKO mice also showed WAT adipocyte hypoplasia and hypotrophy as well as enhanced whole-body metabolic activity relative to controls. Furthermore, glucose intolerance, insulin resistance, compensatory hyperinsulinemia, hypercholesterolemia, and hepatic steatosis were lower in HFD-fed Ube2l6AKO mice as compared to controls. Mechanistically, we found that Atgl protein expression and Atgl-mediated lipolysis were negatively regulated by Ube2l6's promotion of Atgl protein ubiquitylation. Collectively, adipocyte Ube2l6 functions as a negative regulator of Atgl protein stability and, consequently, promotes HFD-induced obesity, insulin resistance, and hepatic steatosis.

Влияние синдрома Х на развитие сердечно-сосудистой патологии (обзор литературы)

Metabolic syndrome, also known as syndrome X, is defined by WHO as a pathological condition characterized by abdominal obesity, insulin resistance, hypertension and hyperlipidemia. While there are some differences in definitions adopted by other health organizations, the differences are minor. Successfully defeating infectious diseases, this new noncommunicable disease has become a leading cause of morbidity and mortality not only in the developed world, but also in underdeveloped countries. As highlighted in the literature, multiple factors such as obesity, abnormal lipid profiles and insulin resistance play a key role in the onset of cardiovascular disease. In this brief review, we present an updated hypothesis that insulin resistance and compensatory hyperinsulinemia are major factors in elevated blood pressure in metabolic syndrome and obesity. Obesity is a worldwide epidemic closely linked to the development of type 2 diabetes and CVD. Obesity-related visceral and epicardial obesity are the main causes of heart disease in these individuals. Obesity has a major impact on changes in blood pressure, lipid profile, and factors associated with systemic and vascular inflammation, as well as endothelial dysfunction.

Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model.

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.

MANAGEMENT OF GRANTHIBHUTA AARTAVA DUSHTI W.S.R. TO PCOD- A CASE REPORT

Poly Cystic Ovarian Disease is a heterogeneous multisystem endocrinopathy in women of reproductive age with the ovarian expression of various metabolic disturbances and clinical features like hyperandrogenism, chronic anovulation, and obesity, resulting from insulin resistance and the compensatory hyperinsulinemia. Poly Cystic Ovarian Disease is a condition where cysts on the ovaries are present that prevent the ovaries from performing normally. On the basis of ultrasound evaluation there will be presence of peripherally tiny follicles. Clinically the PCOS can be understood based on assessment for Granthibhuta Aartava Dushti. (PCOS) can be correlated with Aartava Kshaya, Arajaska Yonivyapad, Lohitakshaya Yonivyapad, Shushka Yonivyapad and Shandhi Yonivyapad. PCOD affects 5-6 % women in childbearing age and is increasing due to change in lifestyle and stress. It is also becoming the common problem in adolescents. So, the man-agement of PCOD is very helpful when it is done by the way which doesn’t affect other hormonal levels and without any further complications. In Ayurveda there are some medications and treatment protocols which are very helpful to manage the PCOS in such a way that doesn’t affect the health of woman. Also, Ayurvedic management of PCOS gives relief in other features of disease like Obesity. So, here attempt has been made for the management of Granthibhuta Aartava Dushti w.s.r. to PCOD.

Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes.

Beta cells adapt their function to respond to fluctuating glucose concentrations and variable insulin demand. The highly specialized beta cells have well-established endoplasmic reticulum to handle their high metabolic load for insulin biosynthesis and secretion. Beta cell endoplasmic reticulum therefore recognize and remove misfolded proteins thereby limiting their accumulation. Beta cells function optimally when they sense glucose and, in response, biosynthesize and secrete sufficient insulin. Overnutrition drives the pathogenesis of obesity and diabetes, with adverse effects on beta cells. The interleukin signaling system maintains beta cell physiology and plays a role in beta cell inflammation. In pre-diabetes and compromised metabolic states such as obesity, insulin resistance, and glucose intolerance, beta cells biosynthesize and secrete more insulin, i.e., hyperfunction. Obesity is entwined with inflammation, characterized by compensatory hyperinsulinemia, for a defined period, to normalize glycemia. However, with chronic hyperglycemia and diabetes, there is a perpetual high demand for insulin, and beta cells become exhausted resulting in insufficient insulin biosynthesis and secretion, i.e., they hypofunction in response to elevated glycemia. Therefore, beta cell hyperfunction progresses to hypofunction, and may progressively worsen towards failure. Preserving beta cell physiology, through healthy nutrition and lifestyles, and therapies that are aligned with beta cell functional transitions, is key for diabetes prevention and management.

Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and multiple small subcapsular cystic follicles in the ovary during ultrasonography, and affects 5–10% of women of reproductive age. PCOS is frequently associated with insulin resistance (IR) accompanied by compensatory hyperinsulinemia and, therefore, presents an increased risk of type 2 diabetes mellitus (DM). The pathophysiology of PCOS is unclear, and many hypotheses have been proposed. Among these hypotheses, IR and hyperandrogenism may be the two key factors. The first line of treatment in PCOS includes lifestyle changes and body weight reduction. Achieving a 5–15% body weight reduction may improve IR and PCOS-associated hormonal abnormalities. For women who desire pregnancy, clomiphene citrate (CC) is the front-line treatment for ovulation induction. Twenty five percent of women may fail to ovulate spontaneously after three cycles of CC treatment, which is called CC-resistant PCOS. For CC-resistant PCOS women, there are many strategies to improve ovulation rate, including medical treatment and surgical approaches. Among the various surgical approaches, one particular surgical method, called laparoscopic ovarian drilling (LOD), has been proposed as an alternative treatment. LOD results in an overall spontaneous ovulation rate of 30–90% and final pregnancy rates of 13–88%. These benefits are more significant for women with CC-resistant PCOS. Although the intra- and post-operative complications and sequelae are always important, we believe that a better understanding of the pathophysiological changes and/or molecular mechanisms after LOD may provide a rationale for this procedure. LOD, mediated mainly by thermal effects, produces a series of morphological and biochemical changes. These changes include the formation of artificial holes in the very thick cortical wall, loosening of the dense and hard cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response, and the continuing leakage or drainage of “toxic” follicular fluid in these immature and growth-ceased pre-antral follicles. All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; the re-starting of normal follicular recruitment, development, and maturation, and finally, the normalization of the “hypothalamus–pituitary–ovary” axis and subsequent spontaneous ovulation. The detailed local and systematic changes in PCOS women after LOD are comprehensively reviewed in the current article.

An animal model of gestational obesity and prediabetes: HISS-dependent insulin resistance induced by a high-sucrose diet in Sprague Dawley rats.

This study developed an animal model of gestational obesity and prediabetes in Sprague Dawley rats using 35% sucrose supplementation (SS). Postprandially, insulin stimulates glucose uptake and nutrient partitioning via insulin-dependent action as well as hepatic insulin sensitizing substance (HISS) - dependent action. HISS is glycogenic in heart, kidney, and skeletal muscle (contrasting insulin's lipogenic actions in liver and adipose tissue) and is responsible for the vasodilatory action of insulin. Postprandial insulin sensitivity was quantified using the rapid insulin sensitivity test (RIST). Animals at 15-day gestation and virgin animals received SS for 8 weeks (with a 2-week recovery), 10 weeks, or 22 weeks. SS in pregnant and virgin rats eliminated HISS-dependent glucose uptake, resulting in compensatory hyperinsulinemia and resultant hypertriglyceridemia and obesity. In groups with SS for 8 weeks followed by a 2-week recovery, there was spontaneous partial recovery of HISS-dependent glucose uptake in virgins and complete recovery in pregnancy. The 10-week SS resulted in complete absence of HISS-dependent glucose uptake and produced a model of gestational obesity and prediabetes. The 22-week SS did not produce hyperglycemia or worsen hyperinsulinemia but did increase hypertriglyceridemia above 10-week SS. This substantiates the use of 10-week SS as a model of gestational obesity and (or) prediabetes, allowing further studies into treatments of gestational obesity and insulin resistance.

Mechanisms of fertility disorders in obese women

Obesity is a common problem among women of reproductive age. Overweight is known to negatively affect a woman’s fertility. So, women of reproductive age who are obese may experience menstrual irregularities, endometrial pathology and, ultimately, infertility. The pathogenetic mechanisms of reproductive dysfunction in obesity remain actively studied issues. It was established that leptin synthesized by adipose tissue inhibits granulosis, cell steroidogenesis and interferes with the ovulation process, which can directly affect reproductive function. Insulin resistance and compensatory hyperinsulinemia, which accompany obesity in women, can contribute to menstrual irregularities, ovulation and, ultimately, fertility. Obesity is also characterized by a state of «relative functional hyperandrogenism», which can affect ovarian function, contributing to the development of infertility. Moreover, obesity is characterized by a state of hyposomatotropinism, which can affect fertility, through changes in ovarian and endometrial function. Weight loss is most likely able to restore fertility in most cases, but there are no practical guidelines that would help the clinician choose the best method to reduce body weight from increased physical activity, dietary restrictions, drug therapy and bariatric surgery.

Direct and indirect modulation of LPS-induced cytokine production by insulin in human macrophages

Overweight and obesity are accompanied by insulin resistance, impaired intestinal barrier function resulting in increased lipopolysaccharide (LPS) levels, and a low-grade chronic inflammation that results in macrophage activation. Macrophages produce a range of interleukins as well as prostaglandin E2 (PGE2). To cope with insulin resistance, hyperinsulinemia develops. The purpose of the study was to elucidate how LPS, insulin and PGE2 might interact to modulate the inflammatory response in macrophages. Human macrophages were either derived by differentiation from U937 cells or isolated from blood mononuclear cells. The macrophages were stimulated with LPS, insulin and PGE2. Insulin significantly enhanced the LPS-dependent expression of interleukin-1β and interleukin-8 on both the mRNA and protein levels. Additionally, insulin increased the LPS-dependent induction of enzymes involved in the PGE2-synthesis and the production of PGE2 by macrophages. PGE2 in turn further enhanced the LPS-dependent expression of cytokines via its Gs-coupled receptors EP2 and EP4, the latter of which appeared to be more relevant. The combination of all three stimuli resulted in an even higher induction than the combination of LPS plus insulin or LPS plus PGE2. Thus, the compensatory hyperinsulinemia might directly and indirectly enhance the LPS-dependent cytokine production in obese individuals.

Developmental programming: Prenatal testosterone excess disrupts pancreatic islet developmental trajectory in female sheep

Prenatal testosterone (T)- treated female sheep manifest juvenile insulin resistance, post-pubertal increase in insulin sensitivity and return to insulin resistance during adulthood. Since compensatory hyperinsulinemia is associated with insulin resistance, altered pancreatic islet ontogeny may contribute towards metabolic defects. To test this, pregnant sheep were treated with or without T propionate from days 30–90 of gestation and pancreas collected from female fetuses at gestational day 90 and female offspring at 21 months-of-age. Uterine (maternal) and umbilical (fetal) arterial blood insulin/glucose ratios were determined at gestational day 90. The morphological and functional changes in pancreatic islet were assessed through detection of 1) islet hormones (insulin, glucagon) and apoptotic beta cells at fetal day 90 and 2) islet hormones (insulin, glucagon and somatostatin), and pancreatic lipid and collagen accumulation in adults. At gestational day 90, T-treatment led to maternal but not fetal hyperinsulinemia, decrease in pancreatic/fetal weight ratio and alpha cells, and a trend for increase in beta cell apoptosis in fetal pancreas. Adult prenatal T-treated female sheep manifested 1) significant increase in beta cell size and a tendency for increase in insulin and somatostatin stained area and proportion of beta cells in the islet; and 2) significant increase in pancreatic islet collagen and a tendency towards increased lipid accumulation. Gestational T-treatment induced changes in pancreatic islet endocrine cells during both fetal and adult ages track the trajectory of hyperinsulinemic status with the increase in adult pancreatic collagen accumulation indicative of impending beta cell failure with chronic insulin resistance.

Racial and ethnic differences in the metabolic response of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a highly prevalent disorder associated with insulin resistance (IR) and compensatory hyperinsulinemia. Although variations in cardiometabolic risks across race and ethnicities have been reported in the general population, racial/ethnic disparities in the metabolic dysfunction of PCOS remain relatively unstudied. To determine whether markers of metabolic function differ in nondiabetic Asian American (AS), African American (AA), Hispanic White (HW), compared to non-Hispanic White (NHW) women with PCOS. Prospective cross-sectional study in a tertiary institution. A total of 259 nondiabetic women with PCOS (by NIH 1990 criteria) who completed a 2-hour 75-g oral glucose tolerance test measuring plasma glucose and insulin levels. Basal IR and insulin secretion, assessed by the homeostasis model assessment (HOMA-IR and HOMA-β%, respectively), and two-hour hyperglycaemia and hyperinsulinemia after an oral glucose load, were compared in 21 AS, 24 AA, 53 HW and 161 NHW consecutive nondiabetic adult PCOS women. After adjusting for age and body mass index, HW and AA PCOS women demonstrated higher fasting and post-glucose challenge insulin levels, and higher HOMA-IR and HOMA-β%, than NHW women, although glucose levels were similar. In contrast, AS PCOS women had or tended to have lower HOMA-β% than any other racial/ethnic groups, lower HOMA-IR, and fasting and post-challenge insulin levels than AA or HW, and also hadhigher (albeit still normal) mean post-challenge glucose levels than NHW women with PCOS despite similar HOMA-IR, and fasting insulin and post-challenge insulin levels. Waist-hip ratio was similar across the four groups. Both HW and AA women with PCOS have increased basal state IR and higher β-cell response, and post-challenge hyperinsulinemia compared to NHW and AS subjects. The trend towards a lesser insulin response among Asian women requires further investigation. These findings suggest that the screening and management of metabolic dysfunction in PCOS should consider patients' race/ethnicity.

Letrozole Rat Model Mimics Human Polycystic Ovarian Syndrome and Changes in Insulin Signal Pathways.

BackgroundThe aim of this study was to explore whether letrozole and high-fat diets (HFD) can induce obese insulin-resistant polycystic ovary syndrome (PCOS) with all reproductive and metabolic phenotypes in a rat model.Material/MethodsTwenty-four 3-week-old female Sprague-Dawley rats were randomized into 4 groups: control, Letrozole, HFD, and Letrozol+HFD. The PCOS model was induced by 12 weeks of Letrozole treatment (1 mg/kg p.o. dissolved in 0.5% CMC solutions once daily) and HFD. Ovarian morphology, estrous cyclicity, hormonal status, body weight, glucose and insulin tolerance, lipid profile, and insulin signaling pathway were investigated.ResultsThe rat model manifests anovulatory cycles and PCO morphology, increased body weight, elevated testosterone levels, abnormal glucose and lipid metabolism, and insulin resistance. The rat model also expresses significantly decreased phosphorylation of 6 essential signaling proteins – INSR, IRS, PI3K, AKT, ERK1, ERK2 – in the PI3K/AKT and MAPK/ERK pathways in the classic insulin-sensitive tissues (e.g., quadriceps femoris muscle, omentum majus, and liver), as well as non-classic target ovary tissues. Disrupted insulin signaling contributes to the decrease in insulin sensitivity and compensatory hyperinsulinemia in PCOS rats.ConclusionsContinuous administration of letrozole and high-fat diets can induce PCOS, metabolic phenotypes, and disrupted activation of the insulin signaling pathway.

MON-002 The Effect of GNRHR Autoantibody on Reproduction Function and Insulin Signaling Intermediates in a New Animal Model of Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS), a metabolic and reproductive associated disease, defined as hyperandrogenism with reproductive dysfunction including menstrual disorder, anovulation, infertility, polycystic ovary and so on. We previously showed reported a high percentage of activating autoantibodies (AAb) directed toward the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR) in PCOS patients, and further demonstrated elevated GnRHR-autoantibody (GnRHR-AAb) could induced insulin resistance in energy storage and peripheral tissue in immunized animals. In the present study, we have now induced specific GnRHR-ECL2 AAb in rats and explored the underlying mechanisms of their resultant reproductive dysfunction. Methods: Sixteen SD rats were randomly divided into 2 groups: a GnRHR group (n=8) and a control group (n=8). Rats in the GnRHR group were immunized with GnRHR ECL2 peptide while the controls were not. Epitope mapping of GnRHR-ECL2-directed AAb was performed using octapeptide multipin solid-phase peptides. Rat estrus cycle was measured through pudendum appearance and vaginal smears. Ovarian and pituitary tissues were collected to observe ovarian morphological changes, to examine the expressions of proteins and genes of insulin signaling pathway by Quantitative real-time PCR respectively. The concentration of inflammatory cytokines in the ovary was detected by Bio-plex Pro™ magnetic bead-based assays on the Bio-plex®. Results: The GnRHR-AAb titers and activity in the GnRHR group were significantly higher than the control group, and the GnRHR-AAb from the immunized rats reacted predominantly with the peptide sequence FSQCVTHC of the GnRHR-ECL2. Numbers of LH pulses and concentration of testosterone in GnRHR group were significantly higher than control group. The GnRHR group exhibited lower frequency of in the appearance of proestrus and estrous phases while the control group represented had a higher frequency in the appearance of metestrus and diestrus stages on estrus cyclicity. The GnRHR-immunized group showed demonstrated increased atretic follicles, decreased corpora lutea, loosely packed granulosa cells, and thecal cell hyperplasia in ovarian tissue compared with controls group. There was GnRHR group represented increased expressions of IRS-1, PI3K and GLUT-1 in ovarian and pituitary tissues compared with control group. However, no obvious changes of inflammatory cytokines are observed in ovarian tissues between two groups. Conclusion: Chronic elevated GnRHR-AAb exerts induced reproductive dysfunction through increased ovarian LH secretion and androgen production, thus likely leading to compensatory hyperinsulinemia which ultimately enhanced insulin signaling in reproductive tissues to exert more and androgen production to, which may provide a novel etiological mechanism for PCOS.