The Impact of Type 1 and Type 2 Diabetes Mellitus on the Oocyte and the Preimplantation Embryo

ABSTRACT

Whereas the importance of close monitoring and tight glycemic control in diabetic pregnancies cannot be ignored, the growing body of knowledge surrounding the different effects of diabetes mellitus on the earliest stages of reproduction underscores the need for aggressive screening among reproductive-aged women at risk for diabetes and the importance of preconceptual counseling among women with known diabetes. This article reviews the salient pathophysiology of type 1 diabetes and type 2 diabetes in reproduction, specifically within the context of the preovulatory oocyte and the preimplantation embryo. In doing so, this review illustrates the need for novel and safe therapies and interventions tailored to address the specific characteristics of these diseases in the periconceptual period.

KEYWORDS

Diabetes - oocyte - embryo - glucose transport - insulin resistance

REFERENCES

• 1 Dunn P M. Dr Priscilla White (1900-1989) of Boston and pregnancy diabetes.  Arch Dis Child Fetal Neonatal Ed. 2004;  89 F276-F278
• 2 Gabbe S G, Graves C R. Management of diabetes mellitus complicating pregnancy.  Obstet Gynecol. 2003;  102 857-868
• 3 Fagot-Campagna A, Pettitt D J, Engelgau M M et al.. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective.  J Pediatr. 2000;  136 664-672
• 4 Dabelea D, Pettitt D J, Hanson R L, Imperatore G, Bennett P H, Knowler W C. Birth weight, type 2 diabetes, and insulin resistance in Pima Indian children and young adults.  Diabetes Care. 1999;  22 944-950
• 5 Dabelea D, Pettitt D J. Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility.  J Pediatr Endocrinol Metab. 2001;  14 1085-1091
• 6 Pearson D W, Kernaghan D, Lee R, Penney G C. The relationship between pre-pregnancy care and early pregnancy loss, major congenital anomaly or perinatal death in type I diabetes mellitus.  BJOG. 2007;  114 104-107
• 7 Yang J, Cummings E A, O'Connell C, Jangaard K. Fetal and neonatal outcomes of diabetic pregnancies.  Obstet Gynecol. 2006;  108(3 Pt 1) 644-650
• 8 Trounson A OGR. Biology and Pathology of the Oocyte: Its Role in Fertility and Reproductive Medicine. Cambridge, UK; Cambridge University Press 2003
• 9 Vozzi C, Formenton A, Chanson A et al.. Involvement of connexin 43 in meiotic maturation of bovine oocytes.  Reproduction. 2001;  122 619-628
• 10 Downs S M. The influence of glucose, cumulus cells, and metabolic coupling on ATP levels and meiotic control in the isolated mouse oocyte.  Dev Biol. 1995;  167 502-512
• 11 Fagbohun C F, Downs S M. Requirement for glucose in ligand-stimulated meiotic maturation of cumulus cell-enclosed mouse oocytes.  J Reprod Fertil. 1992;  96 681-697
• 12 Diamond M P, Moley K H, Pellicer A, Vaughn W K, DeCherney A H. Effects of streptozotocin- and alloxan-induced diabetes mellitus on mouse follicular and early embryo development.  J Reprod Fertil. 1989;  86 1-10
• 13 Colton S A, Pieper G M, Downs S M. Altered meiotic regulation in oocytes from diabetic mice.  Biol Reprod. 2002;  67 220-231
• 14 Kim K, Kim C H, Moley K H, Cheon Y P. Disordered meiotic regulation of oocytes by duration of diabetes mellitus in BBdp rat.  Reprod Sci. 2007;  14 445-455
• 15 Chang A S, Dale A N, Moley K H. Maternal diabetes adversely affects preovulatory oocyte maturation, development, and granulosa cell apoptosis.  Endocrinology. 2005;  146 2445-2453
• 16 Ratchford A M, Chang A S, Chi M M, Sheridan R, Moley K. Maternal diabetes adversely affects AMP-activated protein kinase activity and cellular metabolism in murine oocytes.  Am J Physiol Endocrinol Metab. 2007;  293 E1198-E1206
• 17 Colton S A, Humpherson P G, Leese H J, Downs S M. Physiological changes in oocyte-cumulus cell complexes from diabetic mice that potentially influence meiotic regulation.  Biol Reprod. 2003;  69 761-770
• 18 Leese H J. Metabolism of the preimplantation mammalian embryo. In: Mulligan SR Oxford Reviews of Reproductive Biology. Vol. 13 Oxford, UK; Oxford University Press 1991: 35-72
• 19 Newsholme P, Gordon S, Newsholme E A. Rates of utilization and fates of glucose, glutamine, pyruvate, fatty acids and ketone bodies by mouse macrophages.  Biochem J. 1987;  242 631-636
• 20 Moley K H, Chi M M, Mueckler M M. Maternal hyperglycemia alters glucose transport and utilization in mouse preimplantation embryos.  Am J Physiol. 1998;  275(1 Pt 1) E38-E47
• 21 Moley K H, Vaughn W K, DeCherney A H, Diamond M P. Effect of diabetes mellitus on mouse pre-implantation embryo development.  J Reprod Fertil. 1991;  93 325-332
• 22 Pampfer S, de Hertogh R, Vanderheyden I, Michiels B, Vercheval M. Decreased inner cell mass proportion in blastocysts from diabetic rats.  Diabetes. 1990;  39 471-476
• 23 Lea R G, McCracken J E, McIntyre S S, Smith W, Baird J D. Disturbed development of the preimplantation embryo in the insulin-dependent diabetic BB/E rat.  Diabetes. 1996;  45 1463-1470
• 24 Diamond M P, Pettway Z Y, Logan J, Moley K, Vaughn W, DeCherney A H. Dose-response effects of glucose, insulin, and glucagon on mouse pre-embryo development.  Metabolism. 1991;  40 566-570
• 25 Johnson Jr E M, Deckwerth T L, Deshmukh M. Neuronal death in developmental models: possible implications in neuropathology.  Brain Pathol. 1996;  6 397-409
• 26 Kan O, Baldwin S A, Whetton A D. Apoptosis is regulated by the rate of glucose transport in an interleukin 3 dependent cell line.  J Exp Med. 1994;  180 917-923
• 27 Miyashita T, Reed J C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.  Cell. 1995;  80 293-299
• 28 Moley K H, Chi M M, Knudson C M, Korsmeyer S J, Mueckler M M. Hyperglycemia induces apoptosis in pre-implantation embryos through cell death effector pathways.  Nat Med. 1998;  4 1421-1424
• 29 Chi M M, Pingsterhaus J, Carayannopoulos M, Moley K H. Decreased glucose transporter expression triggers BAX-dependent apoptosis in the murine blastocyst.  J Biol Chem. 2000;  275 40252-40257
• 30 Keim A L, Chi M M, Moley K H. Hyperglycemia-induced apoptotic cell death in the mouse blastocyst is dependent on expression of p53.  Mol Reprod Dev. 2001;  60 214-224
• 31 Heilig C W, Saunders T, Brosius III F C et al.. Glucose transporter-1-deficient mice exhibit impaired development and deformities that are similar to diabetic embryopathy.  Proc Natl Acad Sci USA. 2003;  100 15613-15618
• 32 Wang D, Pascual J M, Yang H et al.. A mouse model for Glut-1 haploinsufficiency.  Hum Mol Genet. 2006;  15 1169-1179
• 33 Pantaleon M, Harvey M B, Pascoe W S, James D E, Kaye P L. Glucose transporter GLUT3: ontogeny, targeting, and role in the mouse blastocyst.  Proc Natl Acad Sci USA. 1997;  94 3795-3800
• 34 Ganguly A, McKnight R A, Raychaudhuri S et al.. Glucose transporter isoform-3 mutations cause early pregnancy loss and fetal growth restriction.  Am J Physiol Endocrinol Metab. 2007;  292 E1241-E1255
• 35 Chi M M, Hoehn A, Moley K H. Metabolic changes in the glucose-induced apoptotic blastocyst suggest alterations in mitochondrial physiology.  Am J Physiol Endocrinol Metab. 2002;  283 E226-E232
• 36 Velazquez E M, Mendoza S G, Wang P, Glueck C J. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome.  Metabolism. 1997;  46 454-457
• 37 Wood J R, Dumesic D A, Abbott D H, Strauss III J F. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis.  J Clin Endocrinol Metab. 2007;  92 705-713
• 38 Petro A E, Cotter J, Cooper D A, Peters J C, Surwit S J, Surwit R S. Fat, carbohydrate, and calories in the development of diabetes and obesity in the C57BL/6J mouse.  Metabolism. 2004;  53 454-457
• 39 Beckles GLA, Thompson-Reid PE Diabetes and Women's Health Across the Life Stages: A Public Health Perspective. Atlanta, GA; U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Diabetes Translation 2001
• 40 Pantaleon M, Kaye P L. IGF-I and insulin regulate glucose transport in mouse blastocysts via IGF-I receptor.  Mol Reprod Dev. 1996;  44 71-76
• 41 Chi M M, Schlein A L, Moley K H. High insulin-like growth factor 1 (IGF-1) and insulin concentrations trigger apoptosis in the mouse blastocyst via down-regulation of the IGF-1 receptor.  Endocrinology. 2000;  141 4784-4792
• 42 Carayannopoulos M O, Chi M M, Cui Y et al.. GLUT8 is a glucose transporter responsible for insulin-stimulated glucose uptake in the blastocyst.  Proc Natl Acad Sci USA. 2000;  97 7313-7318
• 43 Pinto A B, Carayannopoulos M O, Hoehn A, Dowd L, Moley K H. Glucose transporter 8 expression and translocation are critical for murine blastocyst survival.  Biol Reprod. 2002;  66 1729-1733
• 44 Pinto A B, Schlein A L, Moley K H. Preimplantation exposure to high insulin-like growth factor I concentrations results in increased resorption rates in vivo.  Hum Reprod. 2002;  17 457-462
• 45 Eng G S, Sheridan R A, Wyman A et al.. AMPK activation increases glucose uptake, decreases apoptosis and improves pregnancy outcome in embryos exposed to high IGF-1 concentrations.  Diabetes. 2007;  56 2228-2234
• 46 Bertacca A, Ciccarone A, Cecchetti P et al.. Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts.  Metabolism. 2005;  54 1687-1693
• 47 Shepherd P R, Kahn B B. Glucose transporters and insulin action-implications for insulin resistance and diabetes mellitus.  N Engl J Med. 1999;  341 248-257
• 48 Brozinick Jr J T, Roberts B R, Dohm G L. Defective signaling through Akt-2 and -3 but not Akt-1 in insulin-resistant human skeletal muscle: potential role in insulin resistance.  Diabetes. 2003;  52 935-941
• 49 Lu D P, Chandrakanthan V, Cahana A, Ishii S, O'Neill C. Trophic signals acting via phosphatidylinositol-3 kinase are required for normal pre-implantation mouse embryo development.  J Cell Sci. 2004;  117(Pt 8) 1567-1576
• 50 Riley J K, Carayannopoulos M O, Wyman A H, Chi M, Ratajczak C K, Moley K H. The PI3K/Akt pathway is present and functional in the preimplantation mouse embryo.  Dev Biol. 2005;  284 377-386
• 51 Riley J K, Carayannopoulos M O, Wyman A H, Chi M, Moley K H. Phosphatidylinositol 3-kinase activity is critical for glucose metabolism and embryo survival in murine blastocysts.  J Biol Chem. 2006;  281 6010-6019
• 52 Kozka I J, Holman G D. Metformin blocks downregulation of cell surface GLUT4 caused by chronic insulin treatment of rat adipocytes.  Diabetes. 1993;  42 1159-1165
• 53 Jakubowicz D J, Iuorno M J, Jakubowicz S, Roberts K A, Nestler J E. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 2002;  87 524-529
• 54 Endres L K, Sharp L K, Haney E, Dooley S L. Health literacy and pregnancy preparedness in pregestational diabetes.  Diabetes Care. 2004;  27 331-334