Compensatory Hyperinsulinemia Research Articles

8421 The Effect of Dietary Glycotoxins on Insulin Resistance in Polycystic Ovary Syndrome

Abstract Disclosure: A. Weidner: None. K. Vann: None. J. Zhang: None. A. Roy: None. O. Astapova: None. Polycystic ovary syndrome (PCOS) is a chronic systemic disorder that affects both metabolism and reproduction. PCOS is characterized by hyperandrogenism and insulin resistance, which are closely intertwined in this disease pathophysiology. PCOS affects an estimated 10% of people with ovaries and increases risk of endometrial cancer, type 2 diabetes, and major cardiovascular events. Furthermore, treatment options are generally poorly tolerated. Despite its prevalence, severity, and enormous public health burden, the etiology of PCOS is not well-understood. Insulin resistance likely plays a central role in PCOS pathogenesis, and often leads to hyperinsulinemia as the pancreas attempts to compensate for insulin’s decreased efficacy in the body. Moreover, the Western diet is becoming increasingly rich in advanced glycation end products (AGEs): non-enzymatically modified biomolecules that have recently been found to have a harmful effect on insulin sensitivity and are associated with diabetes, aging, and oxidative stress. Serum AGE levels have been reported to be higher in both lean and obese PCOS patients, regardless of PCOS subtype. We have also found higher levels of AGE precursors in the serum of our chronic dihydrotestosterone-induced mouse model of PCOS. Using this mouse model, we have shown that ovarian granulosa cells (GCs) remain insulin-sensitive despite systemic insulin resistance and hyperinsulinemia, manifested by impaired glucose tolerance and increased HOMA-IR. To assess whether GCs respond to insulin through alternative receptor pathways, we knocked down insulin receptor in human granulosa-derived KGN cells and found that insulin-stimulated AKT phosphorylation was only minimally reduced, suggesting that insulin may signal in large part through the insulin-like growth factor 1 receptor (IGF1R) in these cells. Therefore, we believe that compensatory hyperinsulinemia plays a key role in chronic GC hyperstimulation, possibly by rerouting the insulin signal through IGF1R to overcome the resistance to insulin receptor activation, suggesting a mechanism for AGE toxicity in PCOS. We hypothesize that in PCOS, this results in impaired GC function and exacerbation of ovarian dysfunction. We will use our PCOS mouse model to study the effects of a reduced-AGE diet in ameliorating the reproductive and metabolic phenotype of an androgenized PCOS mouse. In preliminary experiments, we have found that a low-AGE diet results in lower fasting glucose in C57BL/6J mice after only 4 weeks. We expect that reproductive symptoms, such as estrous cyclicity, and metabolic symptoms, such as GTT and circulating insulin, will improve in our PCOS mouse model when mice are fed a low-AGE diet throughout development and adulthood. This project has significant clinical implications, as reducing dietary AGEs could provide an effective, tolerable, non-drug therapy option for patients with PCOS. Presentation: 6/3/2024

Whole transcriptome sequencing analyses of islets reveal ncRNA regulatory networks underlying impaired insulin secretion and increased β-cell mass in high fat diet-induced diabetes mellitus.

Our study aims to identify novel non-coding RNA-mRNA regulatory networks associated with β-cell dysfunction and compensatory responses in obesity-related diabetes. Glucose metabolism, islet architecture and secretion, and insulin sensitivity were characterized in C57BL/6J mice fed on a 60% high-fat diet (HFD) or control for 24 weeks. Islets were isolated for whole transcriptome sequencing to identify differentially expressed (DE) mRNAs, miRNAs, IncRNAs, and circRNAs. Regulatory networks involving miRNA-mRNA, lncRNA-mRNA, and lncRNA-miRNA-mRNA were constructed and functions were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Despite compensatory hyperinsulinemia and a significant increase in β-cell mass with a slow rate of proliferation, HFD mice exhibited impaired glucose tolerance. In isolated islets, insulin secretion in response to glucose and palmitic acid deteriorated after 24 weeks of HFD. Whole transcriptomic sequencing identified a total of 1324 DE mRNAs, 14 DE miRNAs, 179 DE lncRNAs, and 680 DE circRNAs. Our transcriptomic dataset unveiled several core regulatory axes involved in the impaired insulin secretion in HFD mice, such as miR-6948-5p/Cacna1c, miR-6964-3p/Cacna1b, miR-3572-5p/Hk2, miR-3572-5p/Cckar and miR-677-5p/Camk2d. Additionally, proliferative and apoptotic targets, including miR-216a-3p/FKBP5, miR-670-3p/Foxo3, miR-677-5p/RIPK1, miR-802-3p/Smad2 and ENSMUST00000176781/Caspase9 possibly contribute to the increased β-cell mass in HFD islets. Furthermore, competing endogenous RNAs (ceRNA) regulatory network involving 7 DE miRNAs, 15 DE lncRNAs and 38 DE mRNAs might also participate in the development of HFD-induced diabetes. The comprehensive whole transcriptomic sequencing revealed novel non-coding RNA-mRNA regulatory networks associated with impaired insulin secretion and increased β-cell mass in obesity-related diabetes.

Pathogenesis of MASLD and MASH - role of insulin resistance and lipotoxicity.

Insulin resistance and lipotoxicity are extremely interconnected but fundamental in setting the stage for the development of MASLD/MASH. A comprehensive literature search was performed and key themes were synthesised to provide insight into the underlying molecular mechanisms of insulin resistance and lipotoxicity in the liver, muscle, pancreas and adipose tissue and how organ cross-talk is fundamental to driving disease pathogenesis. Classical thinking postulates that excess FFA load exceeds the storage capacity of adipose tissue, which is predicated upon both genetic and environmental factors. This results in insulin resistance and compensatory hyperinsulinaemia by pancreatic beta cells to overcome target organ insulin resistance. As adipocyte dysfunction worsens, not only are excess FFA delivered to other organs, including skeletal muscle, pancreas and liver but a pro-inflammatory milieu is established with increases in IL-6, TNF-α and changes in adipokine levels (increased leptin and decreased adiponectin). With increased intramuscular lipid accumulation, lipotoxic species decrease insulin signalling, reduce glucose uptake by downregulation of GLUT4 and decrease glycogen synthesis. With this additional reduced capacity, hyperglycaemia is further exacerbated and increased FFA are delivered to the liver. The liver has the largest capacity to oxidise fat and to adapt to these stressors and, therefore, has become the last line of defence for excess lipid storage and utilisation, the capacity of which may be impacted by genetic and environmental factors. However, when the liver can no longer keep up with increasing FFA delivery and DNL, lipotoxic species accumulate with ensuing mitochondrial dysfunction, increased ER stress, oxidant stress and inflammasome activation, all of which drive hepatocyte injury and apoptosis. The resulting wound healing response, marked by stellate cell activation, drives collagen accumulation, progressive fibrosis, and, ultimately, end organ failure and death. This vicious cycle and complex interplay between insulin resistance, hyperinsulinaemia, lipotoxicity and multi-directional cross-talk among different target organs are critical drivers of MASLD/MASH. Targeting tissue-specific insulin resistance and hyperinsulinaemia while decreasing FFA load (lipotoxicity) through dietary and lifestyle changes remain the best upstream interventions.

Ayurveda management of Polycystic Ovarian Syndrome by single herbs & combinations - A Case Report

Polycystic ovarian syndrome (PCOS) is one of the most common problems affecting approximately 12% of all woman. PCOS can effect menstrual cycle, hormonal level, fertility as well as appearance including acne, facial hair growth and balding, overweight, irregular menstrual cycle, amenorrhoea, dysmenorrhea etc. Some woman may suffer from depression. It is also a metabolic problem that affects several body systems. PCOS is the most common endocrinopathy which mostly occur in women of reproductive age, resulting into insulin resistance and the compensatory hyper insulinemia. According to ayurvedic view PCOS can be correlated with Aarthava Kshaya. Ayurveda scriptures describes gynaecological disorder mainly under the term “Yonivyapada”. It is difficult to find exact correlation of any specific condition in Ayurvedic text with PCOS. The sign & symptoms of condition like Anartava / Nashtarva, Arjaska Yonivyapada, Lohitakshaya Yonivyapada, Vandhya Yonivyapada, Shandi Yonivyapada, Aartava Kashya and Pushpaghani Jataharini mentioned in Ayurveda closely resemble the features of PCOS symptoms. While explaining Yoni Vyapada they also described some herbal formulations to treat such conditions which included Latakaranj seeds (Caesalpinia cristata), Shivlingi (Bryonopsis laciniosa), Shatpushpa (Anethum sowa) & Kounch (Mucuna prurita).

The Effects of Myo-Inositol and D-Chiro-Inositol in a Ratio 40:1 on Hormonal and Metabolic Profile in Women with Polycystic Ovary Syndrome Classified as Phenotype A by the Rotterdam Criteria and EMS-Type 1 by the EGOI Criteria

Setting: Insulin resistance (IR) and compensatory hyperinsulinemia are considered contributing factors toward polycystic ovary syndrome (PCOS). Objectives: This study evaluates the frequency of metabolic abnormalities in PCOS patients and the effects of myo-inositol (MI) and D-chiro-inositol (DCI), in a 40:1 ratio on hormonal and metabolic parameters. Participants: Thirty-four women with PCOS phenotype A (endocrine-metabolic syndrome [EMS-type 1]) between the ages of 20–40. Design: Open prospective study with phenotype A (EMS-type I, n = 34) supplemented with 2,255 mg/day of inositol (MI and DCI in a 40:1 ratio) for 3 months. Methods: The following were measured before and after treatment: serum levels of follicular stimulating hormone, luteinizing hormone (LH), estradiol, total and free testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), anti-Müllerian hormone, glucose, insulin, HOMA-IR, and body mass index (BMI). Results: 55.9% of the enrolled patients were overweight or obese, 50% affected by IR, 17.6% with a history of gestational diabetes mellitus, and 61.8% had familial diabetes mellitus. At the conclusion of the study, BMI (p = 0.0029), HOMA-IR (p < 0.001) significantly decreased, along with decreased numbers of patients with elevated insulin levels. The supplementation resulted in decreased total testosterone (p < 0.001), free testosterone (p < 0.001), FAI (p < 0.001), and LH (p < 0.001); increased SHBG (p < 0.001) and estradiol (p < 0.001). Limitations: The present analysis was limited to a 12-week follow-up, which precluded a long-term evaluation of the effects of MI and DCI combination. Also, this period was insufficient to achieve and analyze clinical changes such as restoration of the menstrual cycle, restoration of reproductive function, and clinical manifestations of hyperandrogenism. Conclusions: Supplementation improved metabolic and hormonal profile in PCOS phenotype A (EMS-type I) patients. This builds upon previous work that demonstrated that combined inositol treatment may be effective in PCOS. The study presented herein, used a reduced concentration than in prior literature; however, a significant change in hormonal and metabolic parameters was still observed.

An Update on the Genetics of Polycystic Ovary Syndrome

PCOS is a common endocrinopathy among women of reproductive age, with a worldwide prevalence of 8 to 13%, depending on the criteria used for diagnosis. It is characterized by a constellation of features, including oligo/anovulation, clinical and/or biochemical hyperandrogenism, and polycystic ovarian morphology. PCOS is one of the common causes of female infertility. It is also associated with metabolic derangements, including obesity, insulin resistance, and compensatory hyperinsulinemia, which increase the likelihood of developing type 2 diabetes mellitus. Despite extensive research, the etiology of PCOS remains largely unknown. It seems likely that the hypothalamic-pituitary-ovarian axis dysfunction, partial folliculogenesis arrest, insulin resistance, and ovarian and adrenal androgen secretion may play a role in the pathogenesis of PCOS. Familial clustering of the cases of PCOS points to a genetic component linked with it. The initial genetic studies suggest an autosomal dominant pattern of inheritance of the disorder in some families; however, most studies support multifactorial origin. Since PCOS is a complex trait, the typical form of inheritance of PCOS follows a non-Mendelian pattern and involves complex genetic mechanisms. Studies involving linkage and association have suggested a connection between genetic variations and the risk of developing PCOS in certain families or populations. Through genome-wide association studies and next-generation sequencing techniques, several candidate genes have been identified that play a role in the etiopathogenesis of the disorder. Pathogenic variants of various genes such as INSR, IRS1, GHRL, LDLR, MC4R, ADIPOQ, UCP1, UCP2, UCP3, FTO, PCSK9, FBN3, NEIL2, FDFT1, PCSK9, CYP11, CYP17, CYP21, HSD17, STAR, POR, AKR1C3, AMH, AMHR2, INHBA, AR, SHBG, LHR, FSHR, FSH β, SRD5A, GATA4, THADA, YAP1, ERBB2, DENND1A, FEM1B, FDFT1, NEIL2, TCF7L2, etc. in some PCOS cases are linked as underlying etiologic associations. This review aims to provide insight into the current genetic knowledge about PCOS. Discovering the genetic factors and pathways involved in the disorder will help us better comprehend the underlying mechanisms of the disorder.

Effects of Berberine on glucolipid metabolism among dehydroepiandrosterone-induced rats of polycystic ovary syndrome with insulin-resistance

Polycystic ovary syndrome (PCOS) is a set of endocrine disorder syndrome characterized by ovulation disorder. Increased insulin resistance (IR) and compensatory hyperinsulinemia play a vital role in the pathogenesis of PCOS. Therefore, insulin sensitizing agents have been studied in the treatment of PCOS. Berberine (BBR) has been proved to alleviate IR in patients with PCOS, but the mechanism remained unclear. This study was aimed to verify the regulatory mechanism of BBR on PCOS-IR rats. Firstly, we established a female rat PCOS-IR model induced by dehydroepiandrosterone (DHEA) and found that estrus cycle was disrupted in the PCOS-IR group, serum fasting insulin (FINS) level and the homeostasis model assessment of insulin resistance (HOMA-IR) index were significantly higher than normal control group. BBR treatment could recover estrous cycle, reduce abnormal serum hormone levels like luteotropic hormone (LH) and testosterone (T). Most importantly, BBR could concentration-dependently reduce serum FINS level in PCOS-IR rat model. Meanwhile, BBR may improve the abnormal lipid metabolism levels in PCOS-IR group by decreasing low density lipoprotein (LDL), total cholesterol (TC) and triglyceride (TG). Histological results showed that BBR can also protect normal histological structures of ovaries in PCOS-IR rats. Our results indicated that BBR plays a protective role in PCOS-IR, increasing insulin sensitivity, improving hyperandrogens and recovering abnormal blood lipids. Therefore, Our research provides novel insights for therapeutic treatment of BBR in patients with glucolipid metabolic disturbances.

Disentangling Dual Threats: Premature Coronary Artery Disease and Early-Onset Type 2 Diabetes Mellitus in South Asians.

South Asian individuals (SAs) face heightened risks of premature coronary artery disease (CAD) and early-onset type 2 diabetes mellitus (T2DM), with grave health, societal, and economic implications due to the region's dense population. Both conditions, influenced by cardiometabolic risk factors such as insulin resistance, hypertension, and central adiposity, manifest earlier and with unique thresholds in SAs. Epidemiological, demographic, nutritional, environmental, sociocultural, and economic transitions in SA have exacerbated the twin epidemic. The coupling of premature CAD and T2DM arises from increased obesity due to limited adipose storage, early-life undernutrition, distinct fat thresholds, reduced muscle mass, and a predisposition for hepatic fat accumulation from certain dietary choices cumulatively precipitating a decline in insulin sensitivity. As T2DM ensues, the β-cell adaptive responses are suboptimal, precipitating a transition from compensatory hyperinsulinemia to β-cell decompensation, underscoring a reduced functional β-cell reserve in SAs. This review delves into the interplay of these mechanisms and highlights a prediabetes endotype tied to elevated vascular risk. Deciphering these mechanistic interconnections promises to refine stratification paradigms, surpassing extant risk-prediction strategies.

Absence of Slc39a14/Zip14 in mouse pancreatic beta cells results in hyperinsulinemia.

Zinc is an essential component of the insulin protein complex synthesized in β cells. The intracellular compartmentalization and distribution of zinc are controlled by 24 transmembrane zinc transporters belonging to the ZnT or Zrt/Irt-like protein (ZIP) family. Downregulation of SLC39A14/ZIP14 has been reported in pancreatic islets of patients with type 2 diabetes (T2D) as well as mouse models of high-fat diet (HFD)- or db/db-induced obesity. Our previous studies observed mild hyperinsulinemia in mice with whole body knockout of Slc39a14 (Zip14 KO). Based on our current secondary data analysis from an integrative single-cell RNA-seq dataset of human whole pancreatic tissue, SLC39A14 (coding ZIP14) is the only other zinc transporter expressed abundantly in human β cells besides well-known zinc transporter SLC30A8 (coding ZnT8). In the present work, using pancreatic β cell-specific knockout of Slc39a14 (β-Zip14 KO), we investigated the role of SLC39A14/ZIP14-mediated intracellular zinc trafficking in glucose-stimulated insulin secretion and subsequent metabolic responses. Glucose-stimulated insulin secretion, zinc concentrations, and cellular localization of ZIP14 were assessed using in vivo, ex vivo, and in vitro assays using β-Zip14 KO, isolated islets, and murine cell line MIN6. Metabolic evaluations were done on both chow- and HFD-fed mice using time-domain nuclear magnetic resonance and a comprehensive laboratory animal monitoring system. ZIP14 localizes on the endoplasmic reticulum regulating intracellular zinc trafficking in β cells and serves as a negative regulator of glucose-stimulated insulin secretion. Deletion of Zip14 resulted in greater glucose-stimulated insulin secretion, increased energy expenditure, and shifted energy metabolism toward fatty acid utilization. HFD caused β-Zip14 KO mice to develop greater islet hyperplasia, compensatory hyperinsulinemia, and mild insulin resistance and hyperglycemia. This study provided new insights into the contribution of metal transporter ZIP14-mediated intracellular zinc trafficking in glucose-stimulated insulin secretion and subsequent metabolic responses.NEW & NOTEWORTHY Metal transporter SLC39A14/ZIP14 is downregulated in pancreatic islets of patients with T2D and mouse models of HFD- or db/db-induced obesity. However, the function of ZIP14-mediated intracellular zinc trafficking in β cells is unknown. Our analyses revealed that SLC39A14 is the only Zn transporter expressed abundantly in human β cells besides SLC30A8. Within the β cells, ZIP14 is localized on the endoplasmic reticulum and serves as a negative regulator of insulin secretion, providing a potential therapeutic target for T2D.

DHT and Insulin Upregulate Secretion of the Soluble Decoy Receptor of IL-33 From Decidualized Endometrial Stromal Cells.

Interleukin 33 (IL-33) signaling regulates most of the key processes of pregnancy, including decidualization, trophoblast proliferation and invasion, vascular remodeling, and placental growth. Accordingly, dysregulation of IL-33, its membrane-bound receptor (ST2L, transducer of IL-33 signaling), and its soluble decoy receptor (sST2, inhibitor of IL-33 signaling) has been linked to a wide range of adverse pregnancy outcomes that are common in women with obesity and polycystic ovary syndrome, that is, conditions associated with hyperandrogenism, insulin resistance, and compensatory hyperinsulinemia. To reveal if androgens and insulin might modulate uteroplacental IL-33 signaling, we investigated the effect of dihydrotestosterone (DHT) and/or insulin on the expression of ST2L and sST2 (along with the activity of their promoter regions), IL-33 and sIL1RAP (heterodimerization partner of sST2), during in vitro decidualization of endometrial stromal cells from 9 healthy women. DHT and insulin markedly upregulated sST2 secretion, in addition to the upregulation of its messenger RNA (mRNA) expression, while the proximal ST2 promoter, from which the sST2 transcript originates, was upregulated by insulin, and in a synergistic manner by DHT and insulin combination treatment. On the other hand, sIL1RAP was slightly downregulated by insulin and IL-33 mRNA expression was not affected by any of the hormones, while ST2L mRNA expression and transcription from its promoter region (distal ST2 promoter) could not be detected or showed a negligibly low level. We hypothesize that high levels of androgens and insulin might lead to subfertility and pregnancy complications, at least partially, through the sST2-dependent downregulation of uteroplacental IL-33 signaling.

Mechanisms and treatment of obesity-related hypertension-Part 1: Mechanisms.

The prevalence of obesity has tripled over the past five decades. Obesity, especially visceral obesity, is closely related to hypertension, increasing the risk of primary (essential) hypertension by 65%-75%. Hypertension is a major risk factor for cardiovascular disease, the leading cause of death worldwide, and its prevalence is rapidly increasing following the pandemic rise in obesity. Although the causal relationship between obesity and high blood pressure (BP) is well established, the detailed mechanisms for such association are still under research. For more than 30 years sympathetic nervous system (SNS) and kidney sodium reabsorption activation, secondary to insulin resistance and compensatory hyperinsulinemia, have been considered as primary mediators of elevated BP in obesity. However, experimental and clinical data show that severe insulin resistance and hyperinsulinemia can occur in the absence of elevated BP, challenging the causal relationship between insulin resistance and hyperinsulinemia as the key factor linking obesity to hypertension. The purpose of Part 1 of this review is to summarize the available data on recently emerging mechanisms believed to contribute to obesity-related hypertension through increased sodium reabsorption and volume expansion, such as: physical compression of the kidney by perirenal/intrarenal fat and overactivation of the systemic/renal SNS and the renin-angiotensin-aldosterone system. The role of hyperleptinemia, impaired chemoreceptor and baroreceptor reflexes, and increased perivascular fat is also discussed. Specifically targeting these mechanisms may pave the way for a new therapeutic intervention in the treatment of obesity-related hypertension in the context of 'precision medicine' principles, which will be discussed in Part 2.

SAT048 Insulin Signaling Through The Insulin Receptor Increases Bone Mineral Density And Linear Growth Through Its Effects On Bone

Abstract Disclosure: R.M. Tuska: None. M.C. Okawa: None. M. Lightbourne: None. J.C. Reynolds: None. A. Layne: None. R.J. Brown: None. Context: Overnutrition and obesity associates with increased childhood growth and higher bone mineral density (BMD), whereas undernutrition associates with impaired growth and lower BMD. Increased vs decreased insulin signaling in bone may be partly responsible for these phenotypes. Patients with lipodystrophy syndromes (LD, characterized by deficient adipose tissue) have pathway selective insulin resistance (IR) causing impairment of some insulin signaling pathways while others are overstimulated by compensatory hyperinsulinemia. These patients thus serve as models of increased insulin signaling in bone without confounding by increased body mass. By contrast, patients with homozygous pathogenic variants of the insulin receptor (INSR-/-), have impairment of all insulin signaling pathways and thus model decreased insulin signaling in bone. We hypothesized that patients with LD would have tall stature and high BMD due to hyperinsulinemia, whereas those with INSR would have short stature and low BMD due to lack of insulin signaling despite hyperinsulinemia. Methods. We compared patients with genetic forms of generalized LD (GLD, (N=30), partial LD (PLD, (N=104), and INSR-/- (N=10). Whole body and site-specific (1/3 radius, Total Hip, femoral neck, and spine) DXA scans were obtained. Height Standard Deviation Scores (SDS) were calculated based on sex and age-matched normative data for patients &amp;lt;20 y old and based on sex-specific 20-y-old normative data for patients ≥ 20 y. Similarly, height-adjusted BMD SDS were calculated using BMDCS reference data. Blood was collected after an 8-12 hour fast for measurement of insulin. Results. All groups had hyperinsulinemia, which was highest in INSR-/- followed by PLD and CGL (423.3 mcU/ml [161.0,1000]; 31.0 mcU/ml [17.1,62.2]; 26.1 mcU/ml [11.2, 52.4]; p&amp;lt;0.0001). Patients with GLD and PLD had tall stature and high BMD vs the general population, whereas INSR -/- had short stature and low BMD. GLD had the greatest whole-body and site-specific BMD SDS followed by PLD and INSR -/- (Whole Body: 1.9±0.9, 0.4±1.3, -1.9± 0.1, p &amp;lt;0.0001; 1/3 Radius: 1.2± 1.2, 0.1± 1.6, -1.5± 1.2, p = 0.0002; Femoral Neck: 1.4±1.0, -0.7±1.3, -1.9±0.8, p &amp;lt;0.0001; Total Hip: 2.0±1.0, -0.3±1.3, -2.0±1.2, p &amp;lt;0.0001; Spine: 1.5±1.0, 0.5±1.6, -1.7±0.7, p &amp;lt;0.0001). All BMD SDS in each group differed from the population mean of 0, except for 1/3 radius in PLD. Similarly, GLD had the greatest height SDS followed by PLD and INSR-/- (0.5± 1.0, 0.3± 1.2, -2.5± 1.4, p&amp;lt;0.0001), all of which differed from the population mean. Conclusions: Patients with non-selective insulin resistance (INSR-/-) lack insulin signaling in bone, contributing to short stature and low BMD. Pathway selective insulin resistance, as observed in patients with GLD and PLD, contributes to compensatory hyperinsulinemia thus increasing insulin signaling in bone, which contributes to tall stature and high BMD. Presentation: Saturday, June 17, 2023

SAT065 Developmental Programming: Sex-specific Programming Of Pancreas In A Sheep Model Of Polycystic Ovary Syndrome

Abstract Disclosure: K.M. Halloran: None. A.K. Vyas: None. N. Saadat: None. V. Padmanabhan: None. Prenatal testosterone (T) treatment from gestational days (GD) 30-90 (sexually dimorphic window of fetal development where male fetuses naturally see elevated T) leads to reproductive and metabolic disruptions in female sheep that includes dyslipidemia, insulin resistance, and compensatory hyperinsulinemia similar to that seen in women with PCOS. The effects of excess T are seen as decreased pancreatic/fetal weight in female fetuses as opposed to an increase in beta cell size and lipid/collagen accumulation in adult females. We addressed the prenatal T-induced gene expression changes contributing to pancreatic compromise to determine if 1) the programmed event persists after cessation of T treatment, 2) T females (TF) are similar to control males (CM), and 3) it is exacerbated in the T males (TM). Time-mated pregnant sheep were administered T propionate (100 mg in 2 ml corn oil) or vehicle between GD 30-90 to obtain control female (CF), TF, CM, and TM fetuses (n=6/group). On ∼GD 120 (term: 147), fetuses were weighed and pancreas was collected, weighed, and the tail portion stored at -80°C until next-generation sequencing for gene expression profiling to identify potential pathways influenced by T and fetal sex. After removal of outliers (determined by Principal Component Analysis-PCA using SIMCA), 3D PCA plots showed clear separation of the treatment groups after stratifying by fetal sex. DESeq2 R package was used to identify differentially expressed genes (DEGs) between the comparisons of interest (CF vs TF, TF vs CM, and CM vs TM). Overall, T fetuses weighed less (P&amp;lt;0.05). Cohen’s effect size analysis found a large magnitude (Cohen’s d&amp;gt;0.8) decrease in fetal weight for TF vs CF, TM vs CM, and TF vs CM and a medium magnitude (d=0.5) decrease in pancreas weight for TF vs CM. Pancreatic:fetal weight ratios did not differ by treatment or fetal sex. 16 DEGS (1 up, 15 down) were identified between TF and CF, 7 DEGs (2 up, 4 down) between TF and CM, and 2 DEGs (up) between TM and CM (Adj P&amp;lt;0.1) with no overlap amongst them, suggesting that the effect of T in females is distinct from males and that TF are more similar to CM. Preliminary analysis indicates that the majority of the DEGs affected in TF are related to immune-signaling pathways, including c-type lectin domain family 4 member G (CLEC4G), cluster of differentiation 52 (CD52), and interleukin 21 receptor (IL21R); CD52, IL21R, and members of the CLEC4 family are implicated in autoimmune pathways linked to Type 1 diabetes. The 2 DEGs affected in TM are involved in plasma membrane dynamics: fer-1 like family member 6 (FER1L6) and chloride voltage gated channel 2 (CLCN2). These changes evident at the gene expression level a month after the cessation of T treatment is suggestive of sexually dimorphic reprogramming of fetal pancreas by exposure to excess T. Further, the endogenous increases in T seen in males may at least in part be responsible for sexually dimorphic programming. Presentation: Saturday, June 17, 2023

The Intensity of Degradation and Synthesis of Derma Intercellular Matrix in Rats after Local Cold Injury in the Presence of Metabolic Syndrome

Studies of tissue regeneration processes in the post-cold period are currently in demand in connection with the development of the Arctic, which is characterized by extremely low temperatures. Metabolic or hormonal abnormalities based on insulin resistance and compensatory hyperinsulinemia, which can lead to the development of cardiovascular diseases, and, consequently, to microcirculation disorders, are aggravating factors that increase the consequences of cold injuries. In this work, we studied the processes of degradation and synthesis of the intercellular matrix of the dermis, as well as the concentration of sialic acids in the blood serum after a local cold injury of the third degree. It was revealed that the regenerative process after local cold damage began on day 3 and was characterized by an increase in the collagen content of the dermis and the thickness of collagen fibers. Regeneration in the case of metabolic syndrome was accompanied by a slowdown in tissue repair processes. The course of the recovery process was associated with a change in the content of sialic acids in the blood serum, while a distinctive feature of the dynamics of this indicator was an increase in the concentration of sialic acids in metabolic disorders on day 7 and a slow slight decrease throughout the experiment, reaching the control values by day 21.

Role of Metformin in Polycystic Ovary Syndrome (PCOS)-Related Infertility.

Polycystic ovarian syndrome (PCOS) is considered the most prevalent endocrinological disorder, whichaffects some women and it is characterized by anovulation and hyperandrogenism, with morphologic changes in the ovary, inappropriate gonadotropin secretion, and insulin resistance (IR) with accompanying compensatory hyperinsulinemia. PCOS was associated with some degree of IR which probably contributes to hyperandrogenism. Many studies showed that metformin, when used to treat PCOS, significantly reduced serum androgen levels, improved insulin sensitivity, restored menstrual cyclicity, and was successful in triggering ovulation. As a result, metformin may be useful in treating PCOS-related infertility. The aim of this review was to clarify PCOS, its prevalence, particularly in Saudi Arabia, its pathogenesis, its impact on the patient's health, and to explain the uses of metformin, its mechanism of action, and its role in the treatment of PCOS-related infertility.

Ayurvedic management of Poly Cystic Ovarian Syndrome (Aarthava Kshaya)

Poly Cystic Ovarian Syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, resulting from insulin resistance and the compensatory hyperinsulinemia. This results in adverse effect on multiple organ systems and may result in alteration in serum lipids, anovulation, abnormal uterine bleeding and infertility. According to Ayurvedic view PCOS can be correlated with Aarthava Kshaya. It was revealed that most of subfertility patients who were presented in Osuki Ayurveda Centre suffered from the PCOS. Here is a case report of 28 year old women who presented with irregular menstruation, rapid weight gain and hair loss. On USG she was detected to have bilateral PCO pattern. Based on the clinical features, treated with ayurvedic management.

The Effect and Safety Assessment of Metformin and DLBS3233 (A Bioactive Fraction of Lagerstroemia speciosa and Cinnamomum burmannii) on Improving Metabolic Parameters in Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) can lead to compensatory hyperinsulinemia with consequent metabolic abnormalities in women. In this study, DLBS3233 and Metformin were used to be tested. DLBS3233 itself is the new insulin-sensitizing drug, a combination-bioactive-fraction derived from two Indonesian herbals, Lagerstroemia speciosa and Cinnamomum burmannii. DLBS3233 alone and in combination with metformin were evaluated for efficacy and safety in insulin-resistant women with polycystic ovary syndrome (PCOS). A randomized, double-blind, 3-arm, double-dummy, non-inferiority, and also a controlled clinical study was conducted at the Dr. Kariadi Hospital, Indonesia, between October 2014 and February 2019. The study involved 60 female subjects (with 20 female subjects in each group) that had polycystic ovary syndrome (PCOS).Treatment I consists of one placebo capsule twice per day and one 100 mg DLBS3233 capsule once per day. Treatment II consists of one placebo caplet once per day and one 750 mg Metformin XR caplet twice per day. Treatment III consists of one 750 mg Metformin XR caplet twice per day and one 100 mg DLBS3233 capsule once per day. In treatment I, the homeostatic model assessment for insulin resistance (HOMA-IR) levels were 3.55, 3.59, and 3.80 at pretest, 3 months, and 6 months after intervention, respectively. In treatment II, the HOMA-IR level were 4.00, 2.21, and 4.40 at pretest, 3 months, and 6 months after intervention respectively. In treatment III, the HOMA-IR levels were 3.30, 2.86, and 3.12 at pretest, 3 months, and 6 months after intervention, respectively. There was no apparent difference existed in the fasting plasma glucose (FPG), high-density lipoprotein (HDL), triglycerides, ferriman-gallwey scores (FGS), and safety assessment on vital signs and laboratory examinations (liver function and renal function) in all groups. Either DLBS3233 alone or the DLBS3233/Metformin combination showed no significant efficacy and did not negatively affect cardiovascular function, liver and kidney function in PCOS subjects. NCT01999686 Date: 3rd of December, 2013.

Insulin Resistance, Compensatory Hyperinsulinemia and its Role in Fetal Programming of Polycystic Ovarian Syndrome.

Insulin Resistance, Compensatory Hyperinsulinemia and its Role in Fetal Programming of Polycystic Ovarian Syndrome.

Regulation and mechanism of action of miRNAs on insulin resistance in skeletal muscles.

The term "insulin resistance" is commonly understood as a decrease in the response of insulin-sensitive tissues to insulin at its sufficient concentration, leading to chronic compensatory hyperinsulinemia. Type 2 diabetes mellitus is based on mechanisms consisting in the development of resistance to insulin in target cells (hepatocytes, adipocytes, skeletal muscle cells), resulting in the termination of an adequate response of these tissues to interaction with insulin. Since in healthy people 75-80% of glucose is utilized by skeletal muscle, it is more likely that the main cause of insulin resistance is impaired insulin-stimulated glucose utilization by skeletal muscle. With insulin resistance, skeletal muscles do not respond to insulin at its normal concentration, thereby determining an increase in glucose levels and a compensatory increase in insulin production in response to this. Despite many years of studying diabetes mellitus (DM) and insulin resistance, the molecular genetic basis for the development of these pathological conditions is still the subject of numerous studies. Recent studies point to the involvement of microRNAs (miRNAs) as dynamic modifiers in the pathogenesis of various diseases. MiRNAs are a separate class of RNA molecules that play a key role in the post-transcriptional regulation of gene expression. Recent studies have shown that miRNAs dysregulation in DM is closely related to miRNAs regulatory abilities in skeletal muscle insulin resistance. This gave grounds to consider an increase or decrease in the expression of individual microRNAs in muscle tissue and consider them as new biomarkers for diagnosing and monitoring insulin resistance and promising directions for targeted therapy. This review presents the results of scientific studies examining the role of miRNAs in skeletal muscle insulin resistance.

Comparative Analysis of the Structure and Function of the Pancreas in Patients with a Combination of Chronic Pancreatitis and Metabolic Syndrome

Metabolic syndrome (MS) is the most urgent problem of modern medicine, which is associated with an unhealthy lifestyle. This is a complex metabolic disorder based on insulin resistance and compensatory hyperinsulinemia. MS is a risk factor for the development of a significant number of various diseases. The objective: to determine the structural and functional state of the liver and pancreatic gland (PG) in patients with chronic pancreatitis (CP) depending on the presence of MS. Materials and methods. 137 patients with CP of biliary genesis (CBP) were included in the study. Patients were divided into two groups: the 1st group – 22 persons with isolated CBP, the 2nd group – 115 patients with CBP+MS. The control group included 20 practically healthy subjects. The age of the study participants ranged from 30 to 71 years. The presence of MS was determined, the state and structure of the PG and liver were examined. Results. A statistically significant higher content of HbA1c was determined in patients with CBP and MS compared to the group of patients with only CBP (6.10±0.14% vs. 5.47±0.15%). A significantly higher blood glucose level was found in the patients with CBP+MS (5.99±0.29 mmol/l vs. 5.31±0.12 mmol/l) compared to patients with CBP. A significantly higher level of the HOMA index was also determined in the group of patients with CBP+MS compared to the CBP group (2.60±0.10 vs.1.84±0.09). A higher level of liver stiffness was found in patients with CBP compared to the control group. The indicator of fecal α-elastase in patients with CBP+MS was 114.52±2.79 mcg/g, which was significantly lower than that in the group of patients with CBP without MS (158.60±5.55 mcg/g). Conclusions. In the presence of MS in patients with chronic biliary pancreatitis, more significant structural disorders in the liver and pancreas were established in the direction of increased density according to shear wave elastometry. The results of the study demonstrated the aggravating effect of concomitant MS on the structural state of the liver and on the structural and functional state of the pancreas in patients with chronic biliary pancreatitis.