Abstract
Pregnancy hypertensive disorders such as Preeclampsia (PE) are strongly correlated with insulin resistance, a condition in which the metabolic handling of D-glucose is deficient. In addition, the impact of preeclampsia is enhanced by other insulin-resistant disorders, including polycystic ovary syndrome and obesity. For this reason, there is a clear association between maternal insulin resistance, polycystic ovary syndrome, obesity and the development of PE. However, whether PE is a consequence or the cause of these disorders is still unclear. Insulin therapy is usually recommended to pregnant women with diabetes mellitus when dietary and lifestyle measures have failed. The advantage of insulin therapy for Gestational Diabetes Mellitus (GDM) patients with hypertension is still controversial; surprisingly, there are no studies in which insulin therapy has been used in patients with hypertension in pregnancy without or with an established GDM. This review is focused on the use of insulin therapy in hypertensive disorders in the pregnancy and its effect on offspring and mother later in life. PubMed and relevant medical databases have been screened for literature covering research in the field especially in the last 5-10 years.
Keywords: Preeclampsia, insulin resistant, insulin therapy, hypertension, DM, blood pressure.
Graphical Abstract
[1]
Tranquilli AL, Dekker G, Magee L, et al. The classification, diagnosis and management of the hypertensive disorders of pregnancy: A revised statement from the ISSHP. Pregnancy Hypertens 2014; 4: 97-104.
[2]
Sáez T, de Vos P, Sobrevia L, Faas MM. Is there a role for exosomes in foetoplacental endothelial dysfunction in gestational diabetes mellitus? Placenta 2018; 61: 48-54.
[3]
Kintiraki E, Goulis DG. Gestational diabetes mellitus: Multi-disciplinary treatment approaches. Metabolism 2018; 86: 91-101.
[4]
American Diabetes Association.Management of diabetes in pregnancy. Diabetes Care 2015; 38: 77-9.
[5]
Langer O. Pharmacological treatment of gestational diabetes mellitus: Point/counterpoint. Am J Obstet Gynecol 2018; 218: 490-9.
[6]
Colatrella A, Loguercio V, Mattei L, et al. Hypertension in diabetic pregnancy: Impact and long-term outlook. Best Pract Res Clin Endocrinol Metab 2010; 24: 635-51.
[8]
Alqudah A, Mckinley MC, Mcnally R, et al. Systematic review or meta-analysis risk of pre-eclampsia in women taking metformin: A systematic review and meta-analysis. Diabet Med 2018; 35: 160-72.
[9]
Silver B, Ramaiya K, Andrew SB, et al. EADSG guidelines: Insulin therapy in diabetes. Diabetes Ther 2018; 9: 449-92.
[10]
Norgaard K, Sukumar N, Rafnsson SB, Saravanan P. Efficacy and safety of rapid-acting insulin analogs in special populations with type 1 diabetes or gestational diabetes: Systematic review and meta-analysis. Diabetes Ther 2018; 9: 891-917.
[11]
Home PD. The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences. Diabetes Obes Metab 2012; 14: 780-8.
[12]
Heise T, Kaplan K, Haahr HL. Day-to-day and within-day variability in glucose-lowering effect between insulin degludec and insulin glargine (100 U/mL and 300 U/mL): A comparison across studies. J Diabetes Sci Technol 2018; 12: 356-63.
[13]
Frias PF, Frias JP. New basal insulins: A clinical perspective of their use in the treatment of type 2 diabetes and novel treatment options beyond basal insulin. Curr Diab Rep 2017; 17: 91.
[14]
De Meyts P. Insulin/receptor binding: The last piece of the puzzle? What recent progress on the structure of the insulin/receptor complex tells us (or not) about negative cooperativity and activation. BioEssays 2015; 37: 389-97.
[15]
Seino S, Seino M, Nishi S, Bell GI. Structure of the human insulin receptor gene and characterization of its promoter. Proc Natl Acad Sci USA 1989; 86: 114-8.
[16]
Echeverria GV, Cooper TA. Muscleblind-like 1 activates insulin receptor exon 11 inclusion by enhancing U2AF65 binding and splicing of the upstream intron. Nucleic Acids Res 2014; 42: 1893-903.
[17]
Talukdar I, Sen S, Urbano R, Thompson J, Yates JR, Webster NJG. hnRNP A1 and hnRNP F modulate the alternative splicing of exon 11 of the insulin receptor gene. PLoS One 2011; 6e27869
[18]
Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 2009; 30: 586-623.
[19]
Yamaguchi Y, Flier JS, Benecke H, Ransil BJ, Moller DE. Ligand-binding properties of the two isoforms of the human insulin receptor. Endocrinology 1993; 132: 1132-8.
[20]
Frasca F, Pandini G, Scalia P, et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 1999; 19: 3278-88.
[21]
Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem 2002; 277: 39684-95.
[22]
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414: 799-806.
[23]
Leto D, Saltiel AR. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol 2012; 13: 383-96.
[24]
Westermeier F, Salomón C, González M, et al. Insulin restores gestational diabetes mellitus-reduced adenosine transport involving differential expression of insulin receptor isoforms in human umbilical vein endothelium. Diabetes 2011; 60: 1677-87.
[25]
De Meyts P. The insulin receptor and its signal transduction network Endotext [Online] 2016 [cited 2018] Available at: https://www.ncbi.nlm.nih.gov/books/NBK378978/
[26]
Beneit N, Fernández-García CE, Martín-Ventura JL, et al. Expression of Insulin Receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis. Cardiovasc Diabetol 2016; 15: 161.
[27]
Sciacca L, Prisco M, Wu A, Belfiore A, Vigneri R, Baserga R. Signaling differences from the A and B isoforms of the Insulin Receptor (IR) in 32D cells in the presence or absence of IR substrate-1. Endocrinology 2003; 144: 2650-8.
[28]
Kara I, Poggi M, Bonardo B, et al. The Paired Basic Amino Acid-Cleaving Enzyme 4 (PACE4) is involved in the maturation of insulin receptor isoform B: An opportunity to reduce the specific insulin receptor-dependent effects of Insulin-like Growth Factor 2 (IGF2). J Biol Chem 2015; 290: 2812-21.
[29]
Meakin PJ, Mezzapesa A, Benabou E, et al. The beta secretase BACE1 regulates the expression of insulin receptor in the liver. Nat Commun 2018; 9: 1306.
[30]
Frasca F, Pandini G, Sciacca L, et al. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem 2008; 114: 23-37.
[31]
Chettouh H, Fartoux L, Aoudjehane L, et al. Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. Cancer Res 2013; 73: 3974-86.
[32]
Wahner Hendrickson AE, Haluska P, Schneider PA, et al. Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukemia: Effect of the dual-receptor inhibitor BMS-536924 in vitro. Cancer Res 2009; 69: 7635-43.
[33]
Jones HE, Gee JMW, Barrow D, Tonge D, Holloway B, Nicholson RI. Inhibition of insulin receptor isoform-A signalling restores sensitivity to gefitinib in previously de novo resistant colon cancer cells. Br J Cancer 2006; 95: 172-80.
[34]
Björner S, Rosendahl AH, Simonsson M, et al. Combined and individual tumor-specific expression of insulin-like growth factor-I receptor, insulin receptor and phospho-insulin-like growth factor-I receptor/insulin receptor in primary breast cancer: Implications for prognosis in different treatment groups. Oncotarget 2017; 8: 9093-107.
[35]
Andres SF, Simmons JG, Mah AT, Santoro MA, Van Landeghem L, Lund PK. Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: Evidence that IR-B limits proliferation. J Cell Sci 2013; 126: 5645-56.
[36]
Cameron KE, Resnik J, Webster NJ. Transcriptional regulation of the human insulin receptor promoter. J Biol Chem 1992; 267: 17375-83.
[37]
Sobrevia L, Salsoso R, Sáez T, Sanhueza C, Pardo F, Leiva A. Insulin therapy and fetoplacental vascular function in gestational diabetes mellitus. Exp Physiol 2015; 100: 231-8.
[38]
Savkur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet 2001; 29: 40-7.
[39]
Westermeier F, Sáez T, Arroyo P, et al. Insulin receptor isoforms: An integrated view focused on gestational diabetes mellitus. Diabetes Metab Res Rev 2016; 32: 350-65.
[40]
Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nat Rev Dis Primers 2016; 2: 16057.
[41]
Amato MC, Vesco R, Vigneri E, Ciresi A, Giordano C. Hyperinsulinism and Polycystic Ovary Syndrome (PCOS): Role of insulin clearance. J Endocrinol Invest 2015; 38: 1319-26.
[42]
Polak K, Czyzyk A, Simoncini T, Meczekalski B. New markers of insulin resistance in polycystic ovary syndrome. J Endocrinol Invest 2017; 40: 1-8.
[43]
Yao K, Bian C, Zhao X. Association of polycystic ovary syndrome with metabolic syndrome and gestational diabetes: Aggravated complication of pregnancy. Exp Ther Med 2017; 14: 1271-6.
[44]
Ehrmann DA, Liljenquist DR, Kasza K, et al. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91: 48-53.
[45]
Aziz M, Naver KV, Wissing MLM, Mikkelsen AL, Nilas L, Skouby SO. Polycystic ovary syndrome: Infertility, cardiovascular, metabolic and obstetrical risks, laboratory and clinical outcomes -- the PICOLO Study. Gynecol Endocrinol 2012; 28: 253-8.
[46]
Palm CVB, Glintborg D, Kyhl HB, et al. Polycystic ovary syndrome and hyperglycaemia in pregnancy. A narrative review and results from a prospective Danish cohort study. Diabetes Res Clin Pract 2018; 145: 167-77.
[47]
Morgante G, Massaro MG, Di Sabatino A, Cappelli V, De Leo V. Therapeutic approach for metabolic disorders and infertility in women with PCOS. Gynecol Endocrinol 2018; 34: 4-9.
[48]
Desoye G, Hartmann M, Blaschitz A, et al. Insulin receptors in syncytiotrophoblast and fetal endothelium of human placenta. Immunohistochemical evidence for developmental changes in distribution pattern. Histochemistry 1994; 101: 277-85.
[49]
Burton GJ, Fowden AL. The placenta: A multifaceted, transient organ. Philos Trans R Soc B Biol Sci 2015; 37020140066
[50]
Newbern D, Freemark M. Placental hormones and the control of maternal metabolism and fetal growth. Curr Opin Endocrinol Diabetes Obes 2011; 18: 409-16.
[51]
Kniss DA, Shubert PJ, Zimmerman PD, Landon MB, Gabbe SG. Insulinlike growth factors. Their regulation of glucose and amino acid transport in placental trophoblasts isolated from first-trimester chorionic villi. J Reprod Med 1994; 39: 249-56.
[52]
Roos S, Lagerlöf O, Wennergren M, Powell TL, Jansson T. Regulation of amino acid transporters by glucose and growth factors in cultured primary human trophoblast cells is mediated by mTOR signaling. Am J Physiol Cell Physiol 2009; 297: 723-31.
[53]
Hiden U, Glitzner E, Ivanisevic M, et al. MT1-MMP expression in first-trimester placental tissue is upregulated in type 1 diabetes as a result of elevated insulin and tumor necrosis factor-α levels. Diabetes 2008; 57: 150-7.
[54]
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: A patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55: 1577-96.
[55]
Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational giabetes. N Engl J Med 2008; 358: 2003-15.
[56]
Beyuo T, Obed SA, Adjepong-Yamoah KK, Bugyei KA, Oppong SA, Marfoh K. Metformin versus insulin in the management of pre-gestational diabetes mellitus in pregnancy and gestational diabetes mellitus at the Korle Bu teaching hospital: A randomized clinical trial. PLoS One 2015; 10e0125712
[57]
Zhao LP, Sheng XY, Zhou S, et al. Metformin versus insulin for gestational diabetes mellitus: A meta-analysis. Br J Clin Pharmacol 2015; 80: 1224-34.
[58]
Brown J, Grzeskowiak L, Williamson K, Downie MR, Crowther CA. Insulin for the treatment of women with gestational diabetes. Cochrane Database Syst Rev 2017; 11CD012037
[59]
Bogdanet D, Egan AM, Reddin C, et al. Atlantic dip: Insulin therapy for women with IADPSG diagnosed gestational diabetes mellitus. Does it work? J Clin Endocrinol Metab 2017; 102: 849-57.
[60]
Poolsup N, Suksomboon N, Amin M. Efficacy and safety of oral antidiabetic drugs in comparison to insulin in treating gestational diabetes mellitus: A meta-analysis. PLoS One 2014; 9e109985
[61]
Ruiz-Palacios M, Prieto-Sánchez M, Ruiz-Alcaraz A, et al. Insulin treatment may alter fatty acid carriers in placentas from gestational diabetes subjects. Int J Mol Sci 2017; 18: 1203.
[62]
Feig DS, Shah BR, Lipscombe LL, et al. Preeclampsia as a risk factor for diabetes: A population-based cohort study. PLoS Med 2013; 10e1001425
[63]
Seppä S, Voutilainen R, Tenhola S. Markers of insulin sensitivity in 12-year-old children born from preeclamptic pregnancies. J Pediatr 2015; 167: 125-30.
[64]
Festa C, Mattei L, Bitterman O, et al. Hypertensive disorders during pregnancy and 3 years after delivery in women with gestational hyperglycemia. J Endocrinol Invest 2018; 41: 1075-82.
[65]
Villalobos-Labra R, Silva L, Subiabre M, et al. Akt/mTOR role in human foetoplacental vascular insulin resistance in diseases of pregnancy. J Diabetes Res 2017; 20175947859
[67]
Vambergue A, Nuttens MC, Goeusse P, Biausque S, Lepeut M, Fontaine P. Pregnancy induced hypertension in women with gestational carbohydrate intolerance: The diagest study. Eur J Obstet Gynecol Reprod Biol 2002; 102: 31-5.
[68]
Subiabre M, Silva L, Villalobos-Labra R, et al. Maternal insulin therapy does not restore foetoplacental endothelial dysfunction in gestational diabetes mellitus. Biochim Biophys Acta Mol Basis Dis 2017; 1863: 2987-98.
[69]
Dongerkery SP, Schroeder PR, Shomali ME. Insulin and its cardiovascular effects: what is the current evidence? Curr Diab Rep 2017; 17: 120.
[70]
Tsapas A, Matthews DR. Using n-of-1 trials in evidence-based clinical practice. JAMA 2009; 301: 1022.
[71]
Genev NM, Lau IT, Willey KA, et al. Does insulin therapy have a hypertensive effect in type 2 diabetes? J Cardiovasc Pharmacol 1998; 32: 39-41.
[72]
Holman RR, Paul SK, Bethel MA, Matthews DR, Andrew H, Neil W. 0-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577-89.
[73]
Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: Meta-analysis of randomised controlled trials. BMJ 2011; 343: 4169.
[74]
Vanhoutte PM, Zhao Y, Xu A, Leung SWS. Thirty years of saying NO: Sources, fate, actions, and misfortunes of the endothelium-derived vasodilator mediator. Circ Res 2016; 119: 375-96.
[75]
Holden SE, Jenkins-Jones S, Morgan CL, Schernthaner G, Currie CJ. Glucose-lowering with exogenous insulin monotherapy in type 2 diabetes: Dose association with all-cause mortality, cardiovascular events and cancer. Diabetes Obes Metab 2015; 17: 350-62.
[76]
Arcio M, Bittencourt S, Hajjar LA. Insulin therapy in insulin resistance: Could it be part of a lethal pathway? Atherosclerosis 2015; 240: 400-1.
[77]
Hauth JC, Clifton RG, Roberts JM, et al. Maternal insulin resistance and preeclampsia. Am J Obstet Gynecol 2011; 204 327.e1-327.e6.
[78]
Partiksha P, Bhatia R, Vij C, Bedi G. Evaluation and correlation of insulin resistance and lipid profile in normal pregnancy and preeclampsia. IOSR J Dent Med Sci 2017; 16: 121-5.
[80]
Salsoso R, Guzmán-Gutiérrez E, Sáez T, et al. Insulin restores l-arginine transport requiring adenosine receptors activation in umbilical vein endothelium from late-onset preeclampsia. Placenta 2015; 36: 287-96.
[81]
D’Anna R, Baviera G, Corrado F, et al. Adiponectin and insulin resistance in early- and late-onset pre-eclampsia. BJOG 2006; 113: 1264-9.
[82]
Pardo F, Villalobos-Labra R, Chiarello DI, et al. Molecular implications of adenosine in obesity. Mol Aspects Med 2017; 55: 90-101.
[83]
Howell KR, Powell TL. Effects of maternal obesity on placental function and fetal development. Reproduction 2017; 153: R97-R108.
[85]
Moran TH, Bi S. Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1211-8.
[86]
Gage MC, Yuldasheva NY, Viswambharan H, et al. Endothelium-specific insulin resistance leads to accelerated atherosclerosis in areas with disturbed flow patterns: A role for reactive oxygen species. Atherosclerosis 2013; 230: 131-9.
[87]
Szabo S, Mody M, Romero R, et al. Activation of villous trophoblastic p38 and ERK1/2 signaling pathways in preterm preeclampsia and HELLP syndrome. Pathol Oncol Res 2015; 21: 659-68.
[88]
Zhang LJ, Han YH, Han YZ. Serum soluble endoglin, plasma endothelin-1 and coagulation function in early onset severe preeclampsia with organ dysfunction. Chinese Crit Care Med 2010; 22: 371-4.
[89]
Kaitu’u-Lino TJ, Hastie R, Hannan NJ, et al. Loss of Akt increases soluble endoglin release from endothelial cells but not placenta. Pregnancy Hypertens 2016; 6: 95-102.
[90]
Xiang W, Chen H, Xu X, Zhang M, Jiang R. Expression of endothelial nitric oxide synthase traffic inducer in the placentas of women with pre-eclampsia. Int J Gynaecol Obstet 2005; 89: 103-7.
[91]
Scioscia M, Gumaa K, Kunjara S, et al. Insulin resistance in human preeclamptic placenta is mediated by serine phosphorylation of insulin receptor substrate-1 and -2. J Clin Endocrinol Metab 2006; 91: 709-17.
[92]
Aiko Y, Askew DJ, Aramaki S, et al. Differential levels of amino acid transporters System L and ASCT2, and the mTOR protein in placenta of preeclampsia and IUGR. BMC Preg Childb 2014; 14: 181.
[93]
Ferreira GD, Orcy RB, Martins-Costa SH, et al. Insulin stimulation of Akt/PKB phosphorylation in the placenta of preeclampsia patients. Sao Paulo Med J 2011; 129: 387-91.
[94]
Cudmore MJ, Ahmad S, Sissaoui S, et al. Loss of Akt activity increases circulating soluble endoglin release in preeclampsia: Identification of inter-dependency between Akt-1 and heme oxygenase-1. Eur Heart J 2012; 33: 1150-8.
Call for Papers in Thematic Issues
31 December, 2025
Advancements in Arterial Stiffness: Novel Therapeutic Frontiers
Arterial stiffness, a hallmark of cardiovascular disease, poses significant challenges in contemporary healthcare. This thematic issue delves into the multifaceted landscape of arterial stiffness and explores cutting-edge therapeutic interventions aimed at mitigating its adverse effects. Within these pages, readers will find a comprehensive overview of the mechanisms underlying arterial stiffness, ...read more
31 December, 2025
TREATMENT OF CARDIOVASCULAR DISEASE IN CHRONIC AND END STAGE KIDNEY DISEASE
Cardiovascular disease still remains the leading cause of death in Chronic and End Stage Kidney Disease, accounting for more than half of all deaths in dialysis patients. During the past decade, research has been focused on novel therapeutic agents that might delay or even reverse cardiovascular disease and vascular calcification, ...read more
Related Journals
Anti-Cancer Agents in Medicinal Chemistry
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Current Bioactive Compounds
Current Cancer Drug Targets
Combinatorial Chemistry & High Throughput Screening
Current Cancer Therapy Reviews
Current Diabetes Reviews
Current Drug Safety
Current Drug Targets
Current Drug Therapy
Related Books
Anthocyanins: Pharmacology and Nutraceutical Importance
The Roles and Responsibilities of Clinical Pharmacists in Hospital Settings
Bioactive Compounds from Medicinal Plants for Cancer Therapy and Chemoprevention
Drug Addiction Mechanisms in the Brain
Software and Programming Tools in Pharmaceutical Research
Objective Pharmaceutics: A Comprehensive Compilation of Questions and Answers for Pharmaceutics Exam Prep
Medicinal Chemistry of Drugs Affecting Cardiovascular and Endocrine Systems
Advanced Pharmacy
Plant-derived Hepatoprotective Drugs
The Role of Chromenes in Drug Discovery and Development
Article Metrics
70
4