Majid Ali, M.D.
The incidence of pregnancy-associated insulin resistance is rising worldwide, I think it is appropriately designated as insulin toxicity of the unborn.
The incidence of pregnancy-associated insulin resistance is rising worldwide, and is commonly associated with many physiological bioenergetic, biochemical, metabolic, physiological, hematological and immunological alterations. Many of the factors involved with these alterations render cell membranes resistant to the action of insulin. At the end of healthy pregnancy, these changes are reversible after delivery . Healthy women pregnancy can be associated with resistance to the action of insulin on glucose uptake and utilization.
Here is an important link for expecting moms and dads
The Crank-Crank-Shaft Model
of Insulin Resistance Insulin Toxicity
Insulin resistance as the resistance of cells, most notably of the muscles, liver, and fatty tissue to the action of insulin. In 2000, I offered the analogy of a crank and crank-shaft to explain how insulin resistance develops.
I proposed The Crank-Crank-Shaft Model of Insulin Toxicity to offer a simple and visual model to explain insulin resistance, excess insulin activity (hyperinsulinemia), and insulin toxicity. In simple words, the “crank of insulin” fails to turn the “crank-shaft of insulin receptor” protein embedded in the cell membrane. This happens when the cell membrane is covered with grease—the crank-shaft is rusted, turned, and twisted, so to speak—so rendering insulin ineffective. I point out that the insulin receptor crankshaft is roughly 70 times larger than the insulin crank.
To illustrate injury to the cell membrane, I proposed The Grease and Detergent Model in which the cell innards, the cell membrane, and the cement that holds the cells together (the matrix) accumulate “cellular grease” due to insufficient detergents in the body. Cellular grease is composed of cellular waste, molecular debris, rancid fats, sticky sugars, and pulped proteins. The primary detergent in the body is oxygen, with secondary “oxy-detergents,” such as hydrogen peroxide, nitric oxide, hydroxyl radicals, oxygen-activated enzymes, and grease-eating phagocytes
In cellular grease, in scientific terms, rancid fats are oxidized and peroxidized lipids, sticky sugars are glycosylated proteins and lipids, and pulped proteins are cross-linked peptides (chains of amino acids that make up proteins). This is a vast subject which I address in several articles in my Insulin Toxicity Series. Here I point out that cellular grease buildup is caused by toxic foods, toxic environment, and toxic thoughts.
In The Crank-Crank-Shaft Model of Insulin Toxicity, the blood sugar level rises when insulin fails to drive sugar into the cells to be metabolized (“burned”) to produce energy. The pancreas senses the rising blood sugar levels and responds with overproduction of insulin hormone in order to overcome the resistance of cellular grease. This works for sometime. However, excess insulin is fattening, inflaming, and grease-building. So begins the vicious cycle of:
* More grease,
* More insulin resistance,
* Higher blood sugar,
* More insulin production,
* Yet more grease,
* Yet higher blood glucose level,
* Yet more insulin production, and
* Yet more grease.
Pregnant women require an additional energy of 300 kcal/day over routine energy intake  while the average glucose utilized by a growing fetus at the 3rd trimester reaches approximately to 33 μmol/kg/min . Maternal IR leads to more use of fats than carbohydrates for energy by mother and spares carbohydrates for fetus. Thus, the development of IR serves as a physiological adaptation of the mother to ensure adequate carbohydrate supply for the rapidly growing fetus .
As the pregnancy advances to third trimester, insulin sensitivity may gradually decline to 50% of the normal expected value . This decline is reported to be mediated by a number of factors such as increase in the levels of estrogen, progesterone, human placental lactogen (hPL), among other factors .
Normally, insulin binding to insulin receptor causes phosphorylation of β-subunit of receptor and it further leads to phosphorylation of Insulin Receptor Substrate-I (IRS-I) at tyrosine residue which act as docking site for further signal transduction molecules .
Progesterone suppresses the phosphoinositol 3-kinase-mediated pathway by reducing the expression of IRS-1. Gradually increasing progesterone concentration with advancement of normal pregnancy is associated with increased inhibition insulin-induced GLUT4 translocation and glucose uptake . Estrogen concentration is also high in pregnancy. 17β-estradiol diminishes insulin sensitivity at high concentrations .
hPL has both insulin-like and anti-insulin effects. In vitro, it has been shown to increase lipolysis and free fatty acids (FFAs) in adipocytes. Increased hPL level in pregnancy is found to increase glucose uptake, oxidation, and incorporation of glucose into glycogen, which may favor glycogen storage in the mother .
Human placental growth hormone (hPGH), a product of the human growth hormone variant gene, is not regulated by growth hormone- releasing hormone (GH-RH) and is secreted tonically rather than in a pulsatile fashion. hPGH has the same affinity for the growth hormone receptor as pituitary GH. The hPGH may also have the same diabetogenic effects as pituitary growth hormone such as hyperinsulinemia, decreased insulin-stimulated glucose uptake and glycogen synthesis, and impairment of the ability of insulin to suppress hepatic gluconeogenesis .
Other factors such as increased levels of serum cortisol, Tumor necrosis factor α ( TNF α, ILs etc., can interrupt the insulin signaling pathway and can lead to IR during normal pregnancy .
Available literature [12–14] suggests that there is a rise in IR in 3rd trimester of pregnancy. However literature is less on the 1st and 2nd trimester. So the present study was undertaken to evaluate the status of IR in different phases of normal pregnancy.