A Synopsis of the Basis of Type 2 Diabetes Based on Testosterone, Dehydroepiandrosterone (DHEA), and Glucose Transporter Genes

I suggest type 2 diabetes is triggered by reductions in testosterone in adulthood. Testosterone naturally begins to decline in the 20s / 30s. Reduced testosterone reduces intracellular dehydroepiandrosterone (DHEA) availability which affects glucose transporter activity.

It is my hypothesis that human evolution is driven by increases in testosterone in the population with time. ("Androgens in Human Evolution," Rivista di Biologia / Biology Forum 2001; 94: 345-362. If your library does not subscribe to "Rivista ... ," you may find this at: http://anthropogeny.com/Androgens%20in%20Human%20Evolution.htm .)

The mechanism of testosterone effects is increased entrance of DHEA into cells because of increased androgen receptors which occurred with the increase of testosterone. Human evolution is an extension of mammalian evolution. ("Hormones in Mammalian Evolution," Rivista di Biologia / Biology Forum 2001; 94: 177-184. If your library does not subscribe to "Rivista ... ," you may find this at: http://anthropogeny.com/Hormones%20in%20Mammalian%20Evolution.htm .)

The natural reduction in testosterone reduces the production of androgen receptors which, therefore, reduces DHEA effects in cells.

Reduced entrance of DHEA into cells reduces the activity GLUT1 (glucose transporter 1). It has been determined that DHEA stimulates transport of GLUT1 to the cell surface where it transports glucose into the cell, therefore, keeping plasma glucose levels "normal." High plasma glucose is the hallmark of type 2 diabetes.

So, reduced testosterone reduces availability of DHEA which reduces cellular uptake of glucose.

(My explanation of human evolution suggests that periodically testosterone increases substantially. This causes a problem with high testosterone. I think we are currently in one of those periods which results in a high, early peak of testosterone followed by an early, deep decline in testosterone during the life span.

It is my hypothesis that evolution selected dehydroepiandrosterone because it optimizes replication and transcription of DNA, that is, genes. Therefore, DHEA levels affect all tissues and all tissues compete for available DHEA, especially the brain. (I think evolutionary selection of DHEA produced mammalia. "Hormones in Mammalian Evolution," Rivista di Biologia / Biology Forum 2001; 94: 177-184, http://anthropogeny.com/Hormones%20in%20Mammalian%20Evolution.htm ). DHEA naturally begins to decline around the ages of twenty to twenty-five, reaching very low levels in old age. When DHEA is low or decreasing, all tissues are adversely affected; when DHEA is too low, death occurs.

Type 2 diabetes often produces pathological changes in various tissues. I suggest that these diabetes-associated diseases are caused by the loss of DHEA, as in high plasma glucose. Loss of DHEA adversely affects gene activation in other tissues which appear as these symptoms. For example: “...skeletal muscle tissue GLUT1 protein expression is reduced in type 2 diabetes...” (J Clin Endocrinol Metab. 2005 Jan;90(1):352-8) and for contrast in normal tissue: Nutr Metab (Lond). 2012 May 30;9:47 and Am J Physiol Endocrinol Metab. 2008 May;294(5):E961-8. Obesity is often named as the cause of T2 diabetes and other phenomena which are also all increasing simultaneous with T2 diabetes. Low DHEA / low testosterone expose less than optimally functioning genes when these two androgens naturally decline (early onset diseases) and when their production is so low that optimally functioning genes are affected (late onset diseases).

I am not satisfied that treatment of glucose levels will "cure" type 2 diabetes.

It is also my hypothesis that low DHEA is involved in cancer initiation. In 1994, I first suggested that low DHEA is directly involved in initiation of oncogenes: "An Explanation of Cancer and the Increase in Cancer: High Testosterone, Low DHEA and Breast Cancer," at: http://anthropogeny.com/An%20Explanation%20of%20Cancer%20and%20the%20Increase%20in%20Cancer.htm which appeared first in publication: Annals of Internal Medicine 2005; 142: 471-472 . This may explain the "Epidemiological bases and molecular mechanisms linking obesity, diabetes, and cancer," (Endocrinología, Diabetes y Nutrición (English ed.) Volume 64, Issue 2, February 2017, Pages 109–117). The natural decline of estradiol may exert a similar effect.)

I suggest the base cause of type 2 diabetes is loss of available DHEA for gene function, precipitated by the loss of testosterone.