Chakraborty, Samaddar, Das, Saha, and Basu: An insight of association of insulin resistance with polycystic ovary syndrome


Introduction

Polycystic ovary syndrome (PCOS), an emerging endocrinopathy, affects 5-10% of reproductive-aged women with unspecified etiology.1, 2, 3 Menstrual complications, hyperandrogenism, polycystic ovaries, excessive luteinized theca cells in ovarian stroma (hyperthecosis), and cutaneous manifestation like acanthosis nigricans indicate dysregulation of neuroendocrine axes in PCOS.1, 4, 5, 6, 7 Interactions of insulin resistance (IR) with hyperandrogenism and many confounding factors altered the activities of the hypothalamic-pituitary-adrenal axis, sympathoadrenal medullary system, and hypothalamic-pituitary-gonadal axis in PCOS.1, 4, 5, 6, 7 In this review the possible genetic and molecular basis of IR and its relationship with PCOS were illustrated in an approach to fulfill the missing links.

Materials and Methods

Terms including “Insulin resistance, PCOS, single nucleotide polymorphism (SNP), molecular biology and genetics of IR” were used in databases of PubMed and PMC to search the articles (timeline: 1947-2021) for writing the review article.

Molecular basis of insulin resistance (IR)

The metabolic effect of insulin is mediated by binding it with the α-subunit of heterotetrameric insulin receptors. It activates the tyrosine kinase of the receptor’s β-subunit triggering the phosphorylation of insulin receptor substrate (IRS) proteins and activation of phosphatidylinositol 3-kinase (PI3K).8 Protein kinase B (PKB) or Akt, a downstream molecule of the PI3K pathway, regulates insulin activities including glycogenesis and inhibition of glucose synthesis in the liver.8 In basal condition glucose transporter type 4 (GLUT4) often away from the cell membrane and resides in the endosomal system and “GLUT4 storage vesicles (GSVs)”.9 Insulin translocates the GLUT4 from the GSV pool to the cell membrane for glucose import into muscle and adipose tissue (Figure 1).8, 9 Studies suggest that PKB potentially phosphorylates AS160, a Rab-GAP (GTPase activating protein), and PtdIns3P 5-kinase (PIKfyve) which regulates insulin-stimulated GLUT-4 trafficking.9 PI3K can also regulate gluconeogenesis. Forehead box protein-o-1 (Foxo1) enters into the nucleus and activates transcription of few rate-limiting enzymes of gluconeogenesis like phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase).8, 10, 11, 12, 13, 14 PKB (Akt2) is responsible for phosphorylation of Foxo1 to restrict gluconeogenesis.8, 10, 11, 12, 13, 14 Mutation of PKB (Akt2) results in a reduction of phosphorylation of Foxo1 protein leading to enhancement of transcription rate of PEPCK and G6Pase as well as gluconeogenesis in hepatocyte.8, 10, 11, 12, 13, 14 This impairment is a key indicator of dysregulation of insulin action leading to IR, hyperglycemia, and type 2 diabetes mellitus (T2DM).8, 10, 11, 12, 13, 14 Studies suggest that IRS-1 knockout mice may have a mild form of IR due to the compensatory behavior of pancreatic β cells. On the contrary null IRS-2 shows IR with impairment of pancreatic β cell compensation. The variation in IR expressivity indicates the diversified activity of IRS-1 and IRS-2 on the β cell mass and functionality.8, 15 Intracellular serine kinases cause serine phosphorylation in IRS-1 that can lead to a decrement in the interaction of insulin receptor/IRS-1 and/or IRS-1/ PI3K and increment in IRS-1 dissociation.8 This deregulation is a key feature of IR and can be propagated in an inherited manner.8 Studies represent that adipokines like tumour-necrosis-factor (TNF) and circulating free fatty acids (FFA) can stimulate serine phosphorylation in IRS-1 leading to impairment in signal transduction of insulin. 8 TNF-α can activate stress-induced enzymes, a c-Jun-NH2-terminal kinase that also stimulates the phosphorylation phenomenon. 8, 16 Class 1a of PI3K consists of a more regulatory subunit (p85) and a less catalytic subunit (p110) that leads to the formation of the heterodimer (p85- p110) and free p85 monomer. Imbalance in these subunits of PI3K may lead to IR by negatively affecting the cell signaling cascade.8, 17

Figure 1

Insulin signaling cascade and insulin resistance. pY=phosphorylated tyrosine; Glut4 =Glucose-transporter-tyhpe-4; IRS= Insulin receptor substrate; PI3K =Phosphatidylinositol 3 kinase; PIP2 = Phosphatidyl-inositol-3,4-bisphosphate; PIP3+ Phosphatidyl-inositol-3,4,5-trisphosphate; PDK1= Phosphatide-dependentkinase-1; PKB = Protein-kinase B; PEPCK = Phosphoenopyruvate carboxykinase; pS= Phosphorylated serine, *= stimulation, - = inhibition

https://typeset-prod-media-server.s3.amazonaws.com/article_uploads/c8d96def-bfb0-403c-85e6-9dc75c4b3207/image/18dca813-2426-4fd0-b25c-5c808e54fbab-uimage.png

Mitochondria and insulin resistance (IR)

Intramyocellular and intrahepatic lipid accumulation are associated with a reduction in mitochondrial function like oxidative phosphorylation and electron transport chain (ETC).18 Decrement of mitochondrial density and activity are indicators of IR and T2DM.18, 19 Catabolism of oversupplied nutrients provides enhanced electron supply in ETC that induces proton gradient across the mitochondrial inner membrane.18 Failure in the coupling of this increased proton gradient and ATP synthesis leads to the generation of excess reactive oxygen species (ROS) resulting in oxidative stress.18 ROS as well as oxidative stress can damage various biomolecules including nuclear and mitochondrial DNA, lipid, and amino acids and cause dysfunctioning in signal transduction of insulin along with IR.18, 19 The exact mechanism behind the interaction between mitochondria and IR is still unclear. Emerging studies on skeletal muscle demonstrate that mitochondrial dynamics along with immunoreactivity and insulin sensitivity are interconnected with diet.18 Proper dietary patterns can reduce mitochondrial dysfunction and regain oxidative capacity.18, 20

Proposed methods for estimation of insulin resistance (IR)

IR along with altered fat distribution and hyperinsulinemia are major etiological factors of T2DM, dyslipidemia, cardiovascular disease, and PCOS.21, 22, 23, 24, 25 There are several proposed methods to estimate IR and sensitivity for clinical, epidemiological, and research purposes (Table 1).23, 26, 27, 28 Estimation of insulin sensitivity depends on two methods — (1) calculation based on fasting plasma concentration of glucose, insulin, and triglycerides and (2) calculated by using plasma concentration of glucose and insulin involving oral glucose tolerance test (OGTT).23

Table 1

Methods to estimate insulin sensitivity andresistance23, 26, 27, 28

Methods

Measurement / advantage

Accuracy

Disadvantage (s)

HECi

Insulin sensitivity

Body mass (g)

316 (Median value)

High consumption of money and time

Fasting glucose (mg/dl)

133 (Median value)

Fasting insulin (µU/ml)

52 (Median value)

GIRii (mg*kg-1.min-1)

14.5 (Median value)

Rd clamp

20 (Median value)

Clamp HGPiii ((mg*kg-1.min-1)

5.5 (Median value)

QUICKIiv

Insulin sensitivity (linear correlation)

QUICKI

0.263 (Median value)

Further studies are required for developing one universal method for IR detection

HOMA-IRv  

IRvi and functionality of pancreatic β cells. May detect high fat

Mean coefficient of variance

34.8%

HOMA-IR and AUC-ITTvii (correlation)

p=0.0248

McAuley index   

IR (in normoglycemic individuals)

Recorded ethnicity Black (n=13), brown (n=9), yellow (n=0), indigenous (n=3), undeclared (n=14)

Metabolic syndrome-Absent: 8.3 (7.5-9.7) and Present: 7.1 (6.3-8.3), P=0.001

[i] iHyperinsulinemic euglycemic clamp

[ii] iiGlucoseinfusion rate

[iii] iiiHepaticglucose production

[iv] ivQuantitative insulin sensitivity check index

[v] vHomeostatic model assessment-insulin resistance

[vi] viInsulin resistance

[vii] viiAreaunder curve-insulin tolerance test

Table 2

Genetic basis of association between insulin resistance and PCOSi 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39

SNPii

Method

Population

*iiirs2252673 (INSRiv)

Case-control association and discovery, and replication cohort

Unrelated 275 White PCOS individuals and 173 White control at University of Alabama at Birmingham (UAB)

*C1008T at exon 17 (INSR) and CC genotype (C1085T)

Pilot study, PCR-RFLPv

Equal number of PCOS patients in Safdarjung Hospital, New Delhi and control

*rs2059807 and rs1799817-INSR

Case-control study

Indian women-253 PCOS individuals and 308 age-matched control

*Mutation exon 19     (His1130Arg)-INSR

Literature screening

Two sisters

*Gly972Arg (IRS-1vi)    Gly1057Asp (IRS-2vii)

Literature screening

Odd ration and 95% confidence interval

*Exon 17 C/T SNP

Case-control study, PCR-RFLP

99 PCOS individuals and 136 healthy women, approved by Mount Sinai School of Medicine institutional review board-SNP or linkage disequlibrium to be further investigated

#viii rs2059806 and rs1799817 (INSR)

PCR-RFLP

Iranian population-186 PCOS individuals and 156 healthy women

#rs1799817, rs2059807, rs8108622, rs10500204-INSR

PCR

260 Hans Chinise family trios-Center for Reproductive Meidcine, Provicinal Hospital affiliated to Shadong University

*rs3786681, rs17253937 and rs2252673-INSR

PCR and automated sequencer for sequencing

224 Chinese family trios-aproved by Institutional review board of Shandong University. Weak association in rs2252673

#rs1799817, and rs1799817 and rs2059806, *rs2059807

Meta-analysis

20 case control study (17460 PCOS patients and 23845 control), 98 SNPs (23 exons) and flanking regions of INSR

*Exon 17 C/T SNP of INSR

Case-control study, direct sequencing

Indian women-180 PCOS individuals and 144 age-matched control

*Gly972Arg (IRS-1) Gly1057Asp (IRS-2)

Literature screening-2975 PCOS patients and 3011 control

Odd ration and 95% confidence interval. PCOS associates with Gly972Arg (IRS-1) in Caucasian ethnicity and Gly1057Asp (IRS-2) in Asian ethnicity.

*rs1799817 (C/T His1058His)-INSR. Gly972Arg (IRS-1) and Gly1057Asp (IRS-2)

Review study

Caucasian (PCOS patients: 99 and healthy women: 136), Chinese (PCOS patients: 120 and healthy women: 40), Indian (PCOS patients: 180 and healthy women: 144) and Japanese (PCOS patients: 61 and healthy women: 99). Italian (PCOS patients: 65 and healthy women: 27), Greek (PCOS patients: 83 and healthy women: 88), Japanene (PCOS patients: 123 and healthy women: 380) and Turkish (PCOS patients: 60 and healthy women: 60).

[i] iPolycystic ovary syndrome

[ii] iiSingle nucleotide polymorphism

[iii] iiiAssociation

[iv] ivInsulin receptor

[v] vPolymerase chain reaction- restriction fragment length polymorphism

[vi] viInsulin receptor substrate-1

[vii] viiInsulin receptor substrate-2

[viii] viiiNo association

Crosstalk between insulin resistance (IR) and PCOS

Insulin is an essential hormone that regulates the metabolism of carbohydrates, lipids, and protein.40 Abnormal activity of pancreatic β cells and decrement in cellular sensitivity for circulating insulin can lead to IR.1, 8, 22 This unusual condition alters fat distribution pattern, obesity, muscle mass, and hormonal function such as hyperandrogenism and induces multiple health complications including dysfibrinolysis, intravascular thrombosis, dyslipidemia, cardiovascular risks, and PCOS (Figure 2). 1, 8, 22, 41, 42 Insulin stimulates gonadotrophin-releasing hormone (GnRH) secretion from the hypothalamus involving mitogen-activated protein kinase (MAPK) pathway and GnRH induces secretion of luteinizing hormone (LH) from adenohypophysis that augments ovarian steroidogenesis, specifically androgens.22, 43 Insulin suppresses insulin-like-growth-factor binding protein-1 (IGFBP-1) via PI3K pathway in hepatocyte and ovary that induces insulin-like-growth-factor-1 (IGF-1) availability.22, 44 IGF-1 facilitates insulin-induced suppression of sex hormone-binding globulin (SHBG) level in the blood leading to increased availability of androgens, a key component of PCOS.22 Monosaccharides like fructose and glucose also participate in the inhibition of SHBG expression by down-regulation of hepatic-nuclear-factor-4-α (HNF-4α).45 Decrement in IGFBP-1 activity induces hyperandrogenism that triggers PCOS. Insulin can inhibit IGFBP-1 via regulating thymine-rich insulin response elements (TIRE) in DNA involving activation of PI-3K.22, 46 Presence of IGF-1 receptor and insulin receptor (INSR) in granulosa cells (GC), stromal cells, and theca cell (TC) indicate insulin activity in ovarian function such as steroidogenesis.22, 47, 48 Insulin stimulates the excess synthesis of various steroids including testosterone, progesterone, and 17-α-hydroxyprogesterone by facilitating the activity of the steroidogenic acute regulatory protein (StAR) and enzymes such as 17α-hydroxylase/17, 20-lyase (CYP17A1), 3β-hydroxysteroid dehydrogenase (3β-HSD), aromatase (CYP19A1) and CYP11A1 in polycystic-ovaries.22, 49, 50 The “selective insulin resistance” theory illustrates ovarian sensitivity to insulin and subsequent synthesis of androgen during systemic IR. 51 Insulin and LH synergistically stimulates low-density lipoprotein cholesterol (LDL-C) receptors transcription in GC via PI3K, PKA, and MAPK pathways.22 Insulin also induces steroidogenesis by upregulating aromatase activity in GC cells that subsequently acts as a key component for transformation to androgen in TC cells.22 Further study is required to understand the basis of ethnic, anthropometric, and genetic contribution for differential metabolic, endocrine and phenotypic expression of IR in the PCOS population.

Figure 2

Possible pathways of role of insulin in PCOS

https://typeset-prod-media-server.s3.amazonaws.com/article_uploads/c8d96def-bfb0-403c-85e6-9dc75c4b3207/image/4b491eb4-cdb2-4f1f-bc22-cf3c449ccd81-uimage.png

Insulin resistance (IR) and PCOS – Role of genetic polymorphism

PCOS and IR both are genetically regulated and the prevalence of IR with or without PCOS can be found in the first-degree relatives of women with PCOS.29, 52 This phenomenon indicates crosstalk between PCOS, and genes of insulin signaling pathways that regulate the interaction of insulin with INSR and are associated with other signaling cascades which participate in the regulation of metabolism and cell proliferation.29, 53 The twisting and meshing of different components of insulin signaling and PCOS are not clear. Analysis of genetic variation involving single nucleotide polymorphism (SNP) study is a cardinal approach to understand the association between PCOS and insulin signaling. IR polymorphism studies of the PCOS population were illustrated in (Table 2). 29, 30, 31, 32, 33, 34, 54, 35, 36, 37, 38, 39 Genome-wide association study (GWAS) along with genetic polymorphism study are implicated to understand the genetic background in association with epigenetic factors, ethnicity, and lifestyle alternations of disease and syndrome. Goodarzi et al. performed a study on components of an insulin signaling pathway to find out its interaction with PCOS where genotyping of INSR and 27 genes coding for different pathways including PI3K were incorporated.29 In their study genotyping of 11 genes controlling glycogen synthase kinase 3β reflected that INSR and IRS-2 are key factors of PCOS.29 Another study of a meta-analysis involving 889 cases and 1303 controls, and 795 cases and 576 controls was performed where the results of the analysis suggest that IRS-1 Gly972Arg polymorphism is a key component of PCOS development with enhanced insulin level.53 This outcome also indicates the association between lowering of PI3K activity with impairment of insulin-stimulated signaling.53

Conclusion

PCOS is intertwined with various pathophysiological conditions and IR might be the most important of them. Disruption in insulin action by different means such as pancreatic deregulation and declination in insulin signaling associates and/or induces the onset and progression of PCOS or vice versa. Females of the Asian population reported a higher prevalence of central adiposity that could be a silent contributor to PCOS and they are prone to fall under cardiometabolic threat in post-reproductive life. Rapidly changing lifestyle patterns, diet, and increasing exposure to stress promote to worsen the situation, and the heterogenic disorders like PCOS 'tends' to rise. Considering these facts, it is essential to pursue further studies combining all the possible associated areas of a particular ethnic population for a better understanding of the divergent nature of PCOS. To apprehend the causes and progression of PCOS, the genetic predispositions and their contribution in response to epigenetic factors, and differential manifestation are needed to be evaluated in a precise and individualistic manner.

Source(s) of Financial Support

Department of Science and Technology, Biotechnology, Government of West-Bengal.

Acknowledgement

This review article is based on scientific research and reviews conducted on the molecular basis of insulin resistance and its association with polycystic ovary syndrome (PCOS). Financial assistance provided by the Department of Science and Technology, Biotechnology, Government of West-Bengal for carrying out the research work on polymorphism study of PCOS based on which the present review article was written and appreciated. The authors take full responsibility for the content of this article.

Notes

[16] Hyperinsulinemic euglycemic clamp

[17] Glucose infusion rate

[18] Hepatic glucose production

[19] Quantitative insulin sensitivity check index

[20] Homeostatic model assessment-insulin resistance

[21] Insulin resistance

[22] Area under curve-insulin tolerance test

[23] Polycystic ovary syndrome

[24] Single nucleotide polymorphism

[25] Association

[26] Insulin receptor

[27] Polymerase chain reaction- restriction fragment length polymorphism

[28] Insulin receptor substrate-1

[29] Insulin receptor substrate-2

[30] No association

References

1 

A Dunaif Insuin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesisEndocr Rev1997186774800

2 

V Borzan E Lerchbaum C Missbrenner M Goschnik C Trummer VT Schwetz Risk of insulin resistance and metabolic syndrome in women with hyperandrogemia: a comparison between PCOS phenotypes and beyondJ Clin Med2021104829

3 

N Vijaykumar SP Badiger TM Sharankumar SC Nallulwar Cardiovascular autonomic functional modulation in polycystic ovarian syndrome – a cross sectional studyIndian J Clin Anat Physiol201631279

4 

BR Basu O Chowdhury SK Saha Possible link between stress-related factors and altered body composition in women with polycystic ovarian syndromeJ Hum Reprod Sci2018111108

5 

BR Basu S Chakrabarty SK Saha N Das Evaluation of association of anthropometric indices with stress response in PCOS populationInt J Sci Res20209107983

6 

S Gainder B Sharma Update on management of polycystic ovarian syndrome for dermatologistsIndian Dermatol Online J201910297105

7 

RR Kierland Acanthosis nigricans; an analysis of data in 22 cases and a study of its frequency in necropsy materialJ Invest Dermatol194796299305

8 

V Saini Molecular mechanisms of insulin resistance in type 2 diabetes mellitusWorld J Diabetes2010136875

9 

GI Welsh I Hers DC Berwick G Dell M Wherlock R Birkin Role of protein kinase B in insulin-regulated glucose uptakeBiochem Soc Trans20053323469

10 

H Cho L Thorvaldsen Q Chu F Feng M J Birnbaum Akt1/PKB is required for normal growth but dispensable for maintenance of glucose homeostasis in miceJ Biol Chem2001276423834952

11 

H Cho J Mu JK Kim JL Thorvaldsen Q Chu EB Crenshaw 3rd Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta)Science20012925522172831

12 

S George JJ Rochford C Wolfrum SL Gray S Schinner JC Wilson A family with severe insulin resistance and diabetes due to a mutation in Akt2Science2004304567513258

13 

RK Hall T Yamasaki T Kucera ML Waltner RO Brien DK Granner Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor- binding protein-1 gene expression by insulin. The role of winged helix/forkhead proteinsJ Biol Chem2000275393016975

14 

C Wolfrum D Baeer E Luca M Stoffel Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localizationProc Natl Acad Sci200310020116249

15 

N Kubota Y Terauchi K Eto T Yamauchi R Suzuki Y Tsubamota Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasiaDiabetes2000491118809

16 

V Aguirre T Uchida L Yenush R Davis MF White The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307)J Biol Chem200027512924754

17 

K Ueki DA Fruman SM Brachmann YH Tseng LC Cantley CR Kaha Molecular balance between the regulatory and catalytic subunits of phosphatidylinositol 3-kinase regulates cell signaling and survivalMol Cell Biol200222396577

18 

D Sergi M Abeywardena N O’calaghan NL Marsh LK Heibronn N Naumovski Mitochondrial (Dys)function and insulin resistance: from pathophysiological molecular mechanisms to the impact of dietFront Physiol20191053210.3389/fphys.2019.00532

19 

EJ Aderson ME Lustig KE Boyle TL Woodlief DA Kane CT Lin Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humansJ Clin Invest2009119357381

20 

BR Basu The crosstalk between dietary constituents and immunity: a preventive approach to fight against viral disease like COVID-19J Nutr Food Sci Forecast20203119

21 

GA Bray Medical consequences of obesityJ Clin Endocrinol Metab200489625839

22 

J Rojas M Chavez L Olivar M Rojas J Morillo J Mejias Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinthInt J Reprod Med2014117

23 

M Gutch SM Razi KK Gupta A Gupta A Kumar Assessment of insulin sensitivity/resistanceIndian J Endocrinol Metab20151911604

24 

V Nagashree N Rumana ML Rd A comparative study of lipid parameters in obese and nonobese femalesIndian J Clin Anat Physiol2015211620

25 

R Bhanu MSV Shankar K Kutty Influence of short term integrated approach of yoga therapy on quality of living in patients with type 2 diabetes mellitus Indian J Clin Anat Physiol2016321136

26 

R Muniyappa H Chen RH Muzumder FH Eintein X Yan LQ Yue Comparison between surrogate indexs of insulin sensitivity/resistance and hyperinsulinemic euglycemic clamp estimates in ratsAm J Physiol Endocrinol Metab2009297510239

27 

L Antunes MN Jornada JL Elkfury KC Foletto Valiadtion of HOMA-IR in a model of insulin-resistance induced by a high fat diet in Wistar ratsArch Endocrinol Metab201660213842

28 

LP Antoniolli BL Nedel TC Pazinato LDA Mesquita F Gerchman Accuracy of insulin resistnce indices for metabolic syndrome: a cross-sectional study in adultsDiabetol Metab Syndr2018106510.1186/s13098-018-0365-y

29 

MO Goodarzi YV Louwers KD Tayor MR Jones J Cui S Kwon Replication of association of a novel insulin receptor gene polymorphism with polycystic ovary syndromeFeril Steril2011955173641

30 

J Dakshinamoorthy PR Jain T Ramamoorthy R Ayyappan Balasundaram Association of GWAS identified INSR variants with polycystic ovary syndrome in Indian womenInt J Macromol202014466370

31 

S Gangopadhyay N Agarwal BC Kabi A Batra A Gupta Single-nucleotide polymorphism on exon 17 of insulin receptor gene influences insulin resistance in PCOS: A pilot study on North Indian womenBiochem Genet201654215868

32 

N Prapas A Karkanaki I Prapas I Kalogiannidis I Katsikis D Panidis Genetics of polycystic ovary syndromeHippokratia200913421623

33 

S Siegel W Futterweit TF Davies ES Cocepcion DA Greenberg R Villanueva A C/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor is associated with polycystic ovary syndromeFertil Stril200278612403

34 

FR Tehrani S Hashemi M Daneshpour M Zarkesh M Zarkesh F Azizi Relationship between polymorphism of insulin receptor gene, and adiponectin gene with PCOSIran J Reprod Med201311318594

35 

J Du J Wang X Sun X Xu F Zhang B Wang Family-based analysis of INSR polymorphisms in Chinese PCOSReprod Biol Endocrinol20142923944

36 

C Feng PP Lv TT Yu M Jin JM Shen X Wang The association between polymorphism of INSR and polycystic ovary syndrome: A meta-analysisInt J Mol Sci200916221623

37 

S Mukherjee N Shaikh S Khavale G Shinde P Meherji N Shah Genetic variation in exon 17 of INSR is associated with insulin resistance and hyperandrogenemia among lean Indian women with polycystic ovary syndromeEuro J Endocrinol2009160585562

38 

X Shi X Xie Y Jia S Li Associations of insulin receptor and insulin receptor substrates genetic polymorphisms with polycystic ovary syndrome: A systematic review and meta-analysisJ Obstet Gynaecol Res201642784454

39 

N Shaikh R Dadachanji S Mukherjee Genetic markers of polycystic ovary syndrome: emphasis on insulin resistanceInt J Med Genet20141010.1155/2014/478972

40 

G Dimitriadis P Mitrou V Labadiari E Maratou SA Raptis Insulin effects in muscle and adipose tissueDiabetes Res Clin Pract201193529

41 

S Singh S Acharya Waist hip ratio as predictor of incident diabetes in young adultsIndian J Clin Anat Physiol202071325

42 

FKH Shirazi Z Khdamoradi M Jeddi Insulin resistance and high molecular weight adiponectin in obese and non-obese patients with polycystic ovarian syndromeBMC Endocr Disord20212145

43 

HH Kim SA Divall RM Deneau A Wolfe Insulin regulation of GnRH gene expression through MAP kinase signaling pathwaysMol Cell Endocrinol20052421-2429

44 

S Patel JVD Kaay C Sutherland Insulin regulation of hepatic insulin-like growth factor- binding protein-1 (IGFBP-1) gene expression and mammalian target of ramycin (mTOR) signaling is impaired by the presence of hydrogen peroxideBiochem J2002365Pt 253745

45 

DM Selva KN Hogeveen SM Innis GL Hammond Monosaccharide-induced lipogenesis regulates the human hepatic sex hrmone-binding globulin geneJ Clin Invest200711712397987

46 

D Finlay S Patel LM Dickson N Shpiro R Marquez CJ Rhodes Glycogen synthase kinase-3 regulates IGFBP-1 gene transcription through the thymine rich insulin response elementBMC Mol Biol200451510.1186/1471-2199-5-15

47 

A Dunaif X Wu A Lee DE Kandarakis Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS)Am J Physiol Endocrinol Metab200128123929

48 

S Mukherjee A Maitra Molecular and genetic factors contributing to insulin resistance in polycystic ovary syndromeIndian J Med Res201013174360

49 

G Zhang JC Garmey JD Veldhuis Interactive stimulation by luteinizing hormone and insulin steroidogenic acute regulatory (StAR) protein and 17alpha-hydroxylase/17,20-lyase (CYP17) gene in porcine theca cellsEndocrinology20001418273542

50 

M Jamnongjit SR Hammes Ovarian steroids: the good, the bad, and the signals that raise themCell Cycle2006511117883

51 

CB Book A Dunaif Selective insulin resistance in the polycystic ovary syndromeJ Clin Endocrinol Metab199984931106

52 

S Ashraf M Nabi S Amin SUA Rasool MA Ganie SR Masoodi Impact of rs2414096 polymorphism of CYP19 gene on susceptibility of polycystic ovary syndrome and hyperandrogenism in Kasmiri womenSci Rep202111129421038/s41598-021-92265-1

53 

A Loannidis E Lkonomi NL Dimou L Douma Polymorphism of the insulin receptor and the insulin receptor substrates genes in polycystic ovary syndrome: A Mendelian randomization meta-analysisMol Genet Metab201099217483

54 

X Xu H Zhao Y Shi Y Bian Y Zhao ZJ Chen Family association study between INSR gene polymorphism and PCOS in Han ChineseReprod Biol Endocrinol2011976



jats-html.xsl

© This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


  • Article highlights
  • Article tables
  • Article images

Article History

Received : 14-09-2021

Accepted : 21-08-2021

Available online : 07-12-2021


View Article

PDF File   Full Text Article


Copyright permission

Get article permission for commercial use

Downlaod

PDF File   XML File   ePub File


Digital Object Identifier (DOI)

Article DOI

https://doi.org/10.18231/j.ijcap.2021.055


Article Metrics






Article Access statistics

Viewed: 303

PDF Downloaded: 78



Open Abstract (Increase article citation) Wiki in hindi