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The following article is an excerpt from Why We Get Sick by Levels medical advisor Ben Bikman, printed here with permission. Why We Get Sick is a ground-breaking book on insulin resistance, one of the most prevalent undiagnosed conditions in the world. The book connects the dots between insulin and several major illnesses and offers practical advice for turning around the epidemic of insulin resistance. Here, Bikman examines how insulin and glucose affect our reproductive health.
The connection between insulin resistance and reproductive disorders may be the most unexpected one. Most people would never imagine that insulin plays any role in reproduction, let alone an essential one. And yet, insulin is absolutely necessary for normal reproduction—which may be evidence of a simple yet profound link between our metabolic and reproductive function. After all, reproducing is risky business! It wouldn’t be prudent to bring off-spring into a dangerous or unhealthy situation, such as a period of starvation. Insulin, then, acts as a signal that tells our brain if our environment is metabolically safe. Normal insulin levels suggest the potential parent-to-be is healthy and their diet is sufficient to grow a fetus and even raise a newborn.
The fact that we need insulin for healthy reproduction is clear. Experiments with rodents have revealed that a lack of insulin leads to changes in brain and gonad function that decrease reproductive processes.(1) But too much insulin isn’t any better than too little. (Remember, insulin resistance is almost always a state of hyperinsulinemia—the pancreas is producing more insulin than normal in an effort to increase insulin’s actions.) Insulin-resistant men(2) and women(3) are more likely to be infertile than their insulin-sensitive counterparts. Additionally, insulin-resistant children are more likely to experience alterations in puberty.(4)
Exactly why this happens is fascinating and illustrates both how delicately fertility is regulated and the ways metabolic processes drive reproductive processes. In this excerpt, we’ll take a look at the many reproductive complications that can arise when women have insulin troubles.
Insulin and Women’s Reproductive Health
Reproduction is a complex process in women. Throughout a woman’s menstrual cycle, a series of hormonal changes lead to the development and eventual release of an egg, a process called ovulation, which generally happens each month. If she becomes pregnant, a woman’s reproductive capacities also include developing and sustaining the growing baby. And even after birth, her job isn’t done—her body continues to change, including the production of breast milk and other shifts that affect reproduction.
For women, reproduction involves a great deal of change and growth and demands a lot of energy. Perhaps for these reasons, women’s fertility and reproductive health appear to be much more intimately linked with insulin and insulin resistance than men’s.
Before we talk about the pathological side of insulin and reproductive disorders in women, I have to highlight the interesting—and normal—relationship between insulin and pregnancy. Insulin is a growth signal, turning on anabolic processes to increase the size of our cells and sometimes even their number. The pregnant body needs to grow, and insulin helps that happen. Insulin helps the placenta grow(5), helps breast tissue develop in preparation for lactation(6), and even helps ensure Mom has enough energy available for the demanding process of pregnancy by increasing her body’s inclination to store fat. In fact, to facilitate this, insulin receptors are increased in a woman’s fat tissue at the onset of pregnancy, then return to normal levels after birth.(7) Maternal fat tissue will grow more readily during pregnancy because of fat tissue’s heightened responsiveness to insulin than at other times in life.
Pregnancy is one of very few instances where insulin resistance appears to be a normal and even helpful event. Yes, pregnancy is a naturally insulin-resistant state. The average, healthy woman will become roughly half as insulin sensitive at the end of her pregnancy as she was at the beginning.(8) And in this case, insulin resistance is a good thing! The technical term for this is “physiological insulin resistance”—meaning it’s insulin resistance with a purpose. As a pregnant woman’s body becomes insulin resistant, insulin levels increase (although it’s just as likely that her body becomes insulin resistant because of the elevated insulin levels), which drives tissue growth, such as the placenta.
But the elevated insulin levels in pregnancy do more than prepare the mother-to-be; even more important, insulin also helps stimulate growth and development of the growing baby.(9) So, just as the elevated insulin is preparing the maternal body for optimal pregnancy function, it is also giving the fetus a critical growth signal.
That said, while insulin resistance is a natural occurrence in pregnancy, it can have other implications for women’s reproductive health, including fertility issues, polycystic ovarian syndrome, gestational diabetes, preeclampsia and more.
The most obvious reproduction-related disorder with insulin resistance in women is gestational diabetes mellitus. This happens when the woman becomes sufficiently insulin resistant during the course of her pregnancy that her insulin is not enough to keep blood glucose at normal levels. At this point, the normal, physiological insulin resistance has become pathological; the fine line between these two states is glucose control.
Gestational diabetes can happen to any pregnant woman, though the usual risk factors that apply to insulin resistance are the most relevant. For gestational diabetes, they include pre-pregnancy body weight, age, family history of diabetes, and ethnicity (with those of Asian, Hispanic, and Middle Eastern descent having the highest risk; they’re all ethnicities with greater risk of insulin resistance).(10)
Unfortunately, even if the woman had no evidence of insulin resistance or Type 2 diabetes before pregnancy, developing gestational diabetes increases her likelihood of developing Type 2 diabetes later in life. In fact, on average, her risk of developing Type 2 diabetes is sevenfold higher when compared with a woman who did not have gestational diabetes during pregnancy.(11)
More severe insulin resistance during pregnancy, which usually manifests as gestational diabetes, increases the risk of developing one of the most lethal pregnancy disorders, preeclampsia—a dangerous change in kidney function. Women who develop more dramatic insulin resistance during early pregnancy are significantly more likely to develop preeclampsia during the second half.(12)
The connection between the two disorders is not fully understood, but it very likely has to do with at least some of the blood pressure problems that arise from insulin resistance, including activation of the sympathetic nervous system and reduced nitric oxide production.(13)
However it may happen, the altered blood pressure with insulin resistance creates a situation where blood flow to tissues in the mother, including the placenta, is less than ideal.(14) When it’s not getting enough blood, the placenta creates a signal protein called vascular endothelial growth factor (VEGF) for itself and the rest of the body. VEGF stimulates the formation of blood vessels, and in releasing this protein, the placenta is trying to increase the amount of blood that it receives.(15) In a healthy pregnancy, this is exactly what happens; the placenta needs more blood and VEGF helps it happen. But in the case of preeclampsia, the placenta inexplicably releases a second protein called the soluble VEGF receptor, which sticks to VEGF and prevents it from working. So, even though the placenta is making VEGF, the protein can’t do anything.
Not only does this scenario hurt the placenta (by not letting it create new blood vessels), but the kidneys suffer a serious setback—they need the VEGF that the placenta makes. The kidneys normally use VEGF to maintain normal blood filtration, which is their main job and absolutely necessary for health. When the kidneys don’t get enough VEGF, they start to lose their functionality. They stop filtering properly, and toxins and excess water start to accumulate in the blood. Higher blood volume via excess water is the main cause of increased blood pressure. But the toxins are the more dangerous feature, potentially leading to seizures and death as they affect the brain. Meanwhile, the kidneys’ lack of VEGF also causes them to become “leaky,” allowing protein from the blood to spill into the urine. This is why we monitor not only the blood pressure of women with preeclampsia, but also the amount of urinary protein as an indicator of kidney health.
If it isn’t caught early and treated, preeclampsia can lead to liver or kidney failure and future heart issues for the mother. For the baby, less blood flow to the placenta means the fetus gets less food and oxygen—leading to lower-than-normal birthweight. The only real solution for preeclampsia is to remove the placenta, which means removing the baby as soon as it is developed enough to deliver safely. That means inducing labor or a very early caesarean section to protect the mother’s health.
Over- and Underweight Babies
Being born on either end of the weight spectrum can have consequences later in life, and having a mother with hyperinsulinemia and insulin resistance has a surprisingly strong influence on this.
Before we go on, I want to clarify that when I refer to a newborn’s weight in this section, I don’t mean a baby that is naturally smaller or bigger because of family genetics. I’m discussing the situation when, all things considered, a baby is born smaller or larger than anticipated.
A mother’s metabolic health and the health of her baby are closely connected. Some of the strongest evidence for this comes from the Dutch Famine Study, which tracked the health of people who were conceived during the Dutch famine of 1944–1945 at the end of World War II.(16) The researchers were able to explore the effects the famine had on these individuals depending on whether it had occurred early, late, or in the middle of the mother’s pregnancy. Individuals whose mothers endured famine at the beginning of pregnancy were significantly more likely to be obese later in life compared with normal. Importantly, these observations weren’t necessarily associated with the infant being“born larger or smaller than normal—it was independent of newborn body weight. (As we will see in later chapters, obesity and insulin resistance are closely connected.)
For a mother with more dramatic pregnancy insulin resistance (such as maternal gestational diabetes and/or polycystic ovarian syndrome—more on that later), the most common result is that the infant is born with a higher birthweight than normal. The fetus has developed in an insulin- and possibly glucose-rich environment, thriving beyond what is typical. This may seem benign, but it has lasting effects. These infants are roughly 40% more likely to be obese and have metabolic complications in their teenage years and beyond.(17)
On the other end of the spectrum are infants born below the normal and expected birthweight (common when the mother develops preeclampsia(18)). It “might be tempting to assume that any child born with a high birthweight is much more likely to become obese and insulin resistant than a normal-birthweight baby and certainly more than a low-birthweight (LBW) baby. But it’s not so simple.
While individuals with a high birthweight do indeed have an increased likelihood of obesity and insulin resistance later in childhood(19), the risk is actually greater in those with LBW. Paradoxically, just like the high-birthweight infants, these children are more likely than average to develop obesity and metabolic disorders later in life. The metabolic complications of LBW have been particularly well documented in the UK, where researchers have consistently observed that children born thin don’t stay that way for long.(20) Yes, it’s true—infants born below the normal weight are the most likely to become obese and insulin resistant.(21) This trend can start to appear as early as four years old—by this age, the child has often caught up to normal-weight peers and begins to surpass them in weight, though it can happen later in the teenage years as well and last into late adulthood.(22) A part of this effect may be related to the physical stress of being born LBW and potentially confounding events surrounding the birth(23).
- Seethalakshmi, L., M. Menon, and D. Diamond, The effect of streptozotocin-induced diabetes on the neuroendocrine-male reproductive tract axis of the adult rat. J Urol, 1987. 138(1): p. 190-4; Tesone, M., et al., Ovarian dysfunction in streptozotocin-induced diabetic rats. Proc Soc Exp Biol Med, 1983. 174(1): p. 123-30.
- Pitteloud, N., et al., Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab, 2005. 90(5): p. 2636-41.
- Dunaif, A., Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev, 1997. 18(6): p. 774-800.
- Dimartino-Nardi, J., Premature adrenarche: findings in prepubertal African-American and Caribbean-Hispanic girls. Acta Paediatr Suppl, 1999. 88(433): p. 67-72.
- Hiden, U., et al., Insulin and the IGF system in the human placenta of normal and diabetic pregnancies. J Anat, 2009. 215(1): p. 60-8.
- Berlato, C. and W. Doppler, Selective response to insulin versus insulin-like growth factor-I and -II and up-regulation of insulin receptor splice variant B in the differentiated mouse mammary epithelium. Endocrinology, 2009. 150(6): p. 2924-33.
- Hadden, D.R. and C. McLaughlin, Normal and abnormal maternal metabolism during pregnancy. Semin Fetal Neonatal Med, 2009. 14(2): p. 66-71.
- Catalano, P.M., et al., Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol, 1991. 165(6 Pt 1): p. 1667-72.
- Milner, R.D. and D.J. Hill, Fetal growth control: the role of insulin and related peptides. Clin Endocrinol (Oxf), 1984. 21(4): p. 415-33.
- Berkowitz, G.S., et al., Race/ethnicity and other risk factors for gestational diabetes. Am J Epidemiol, 1992. 135(9): p. 965-73.
- Bellamy, L., et al., Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet, 2009. 373(9677): p. 1773-9.
- Wolf, M., et al., First trimester insulin resistance and subsequent preeclampsia: a prospective study. J Clin Endocrinol Metab, 2002. 87(4): p. 1563-8.
- Kaaja, R., Insulin resistance syndrome in preeclampsia. Semin Reprod Endocrinol, 1998. 16(1): p. 41-6.
- Anim-Nyame, N., et al., Relationship between insulin resistance and tissue blood flow in preeclampsia. J Hypertens, 2015. 33(5): p. 1057-63.
- Koga, K., et al., Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab, 2003. 88(5): p. 2348-51.
- Ravelli, A.C., et al., Obesity at the age of 50 in men and women exposed to famine prenatally. Am J Clin Nutr, 1999. 70(5): p. 811-6.
- Gillman, M.W., et al., Maternal gestational diabetes, birth weight, and adolescent obesity. Pediatrics, 2003. 111(3): p. e221-6.
- Xiong, X., et al., Impact of preeclampsia and gestational hypertension on birth weight by gestational age. Am J Epidemiol, 2002. 155(3): p. 203-9.
- Ayyavoo, A., et al., Pre-pubertal children born post-term have reduced insulin sensitivity and other markers of the metabolic syndrome. PLoS One, 2013. 8(7): p. e67966.
- Phillips, D.I., et al., Thinness at birth and insulin resistance in adult life. Diabetologia, 1994. 37(2): p. 150-4; Byberg, L., et al., Birth weight and the insulin resistance syndrome: association of low birth weight with truncal obesity and raised plasminogen activator inhibitor-1 but not with abdominal obesity or plasma lipid disturbances. Diabetologia, 2000. 43(1): p. 54-60.
- Friedrichsen, M., et al., Muscle inflammatory signaling in response to 9 days of physical inactivity in young men with low compared with normal birth weight. Eur J Endocrinol, 2012. 167(6): p. 829-38.
- Li, C., M.S. Johnson, and M.I. Goran, Effects of low birth weight on insulin resistance syndrome in Caucasian and African-American children. Diabetes Care, 2001. 24(12): p. 2035-42.
- Phillips, D.I., et al., Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab, 1998. 83(3): p. 757-60.