Diabetes

Diabetes type II

A number of studies have shown APOE4 does not increase the risk of diabetes 2. However, prevention of diabetes is of paramount importance, in APOE4 carriers, as diabetes markedly increases the risk of AD and cardiovascular disease in APOE4 carriers.

 

Also the presence of diabetes very much complicates use of rapamycin.


In Honolulu-Asia Aging Study, the risk of AD in APOE4 carriers was 1.7 without Diabetes  and 5.5 in APOE4 carriers with Diabetes.(53)


In 2016 study,  "Apolipoprotein E gene polymorphism and the risk of type 2 diabetes and cardiovascular disease"; presence of diabetes increased risk of Cardiovascular Disease 3.2 fold in E4 allele carriers.(54)


The Amylin Story

Most people frequently have asked themselves: Why does my pet cat get type 2 diabetes; but not my pet rat. On that tail hangs the "cause in fact" of type 2 diabetes.  


In law there are two types of causation; proximate cause (legal cause) and the cause-in-fact, the "but for" test.


In type diabetes, we could say insulin resistance is the proximate cause and amylin is the cause-in-fact.


In microscopic examination of pancreatic tissue from type 2 diabetes the pathology is amyloid deposits in the islets which contain Beta cells. "Islet amyloid has been recognized as the pathologic entity in type 2 diabetes since the turn of the century." (55). What is new is the specific identification of this substance as islet amyloid polypeptide (IAPP) or AMYLIN. 


The pancreas secretes three hormones to regulate glucose metabolism: Insulin, Amylin and Glucagon. "Amylin are co-localized, co-packaged and co-secreted with insulin from pancreatic islet B cells to maintain glucose homeostasis." (56). Insulin and Amylin are co-secreted in a constant fixed ratio. 


"Overview of physiologic action of amylin:(56)

1. Amylin suppresses glucagon secretion from islet alpha cells at mealtime and thus, inhibits glucagon-induced glucose release from the liver. 

2. Amylin delays nutrient delivery from the stomach to the small intestine for absorption.

3. Amylin reduces food intake by a signal mediated through the central nervous system.

4. Amylin may stimulate Renin-Angiotensin system.

5. Amylin and insulin coordinate storage of carbohydrate.


The problem is not with the physiologic function of Amylin; the problem is in conformation.


Amylin has three conformations: MONOMER ----> OLIGOMER-----> FIBRIL


Monomers of amylin have physiologic functions and contribute to glucose homeostasis. At high levels monomers tend to form into cytotoxic oligomers. In a self-driven process the accumulating misfolded oligomers form insoluble nontoxic amylin fibrils with  B-sheet structure. 


The soluble oligomer of amylin is toxic to insulin-producing B cells.


Getting back to the original question of the cat, the rat, and humans. The rat forms amylin which does not aggregate. The cat produces amylin which is moderately amyloidogenic and human amylin is highly amyloidogenic. (56).


"We conclude that the sequence ala-LLe-Leu-Ser-Ser. corresponding to positions 25-29 of human IAPP (Amylin), is strongly amyloidogenic and that a proline-for-serine substitution in position 28, as in several rodents, almost completely inhibits formation of amyloid fibrils. (57).


The "cause-in-fact" of type 2 diabetes is humans have serine instead of proline in position 28 (like a smart rat) and therefore humans have highly amyloidogenic amylin which when secreted in large amounts forms toxic oligomers which destroy the Beta-cells.


However, insulin resistance is the proximate cause of type 2 diabetes. This is because insulin and amylin are secreted in A FIXED RATIO. 


No insulin resistance means low levels of insulin secreted, low levels of Amylin co-secreted with insulin and no formation of toxic oligomers of amylin and no destruction of beta cells and no type 2 diabetes.


It should be noted that amylin and amyloid-beta have identical structure in the amyloidogenic portion of molecule making both prone to form oligomers and insoluble beta-sheet structure. Also like amyloid-beta in AD, it is the soluble oligomers which is considered toxic to neurons.


Prevention of Type 2 Diabetes 


Prevention of diabetes 2 is about prevention of IR.  Major causes of IR are high calorie diet, obesity/overweight and physical inactivity. OBESITY is most important cause of diabetes 2.(52)


High calorie diet causes elevated mTOR and elevated mTOR causes IR.


Overweight and Obesity causes IR which elevates insulin. Elevated insulin causes elevation of mTOR which increases IR.


Physical inactivity causes IR because leg muscle are major users of glucose. If do not have sufficient physical activity such as walking, leg muscles block transport of glucose into muscle cells and develop IR. 


Overeating, overweight, decreased physical activity all act through positive feedback loops increasing mTOR, IR and insulin. Meanwhile, back in the beta cells of pancreas, the increase in glucose and increase demand for insulin means more production of amylin and amylin oligomers destroy the beta cells.


For better understanding of diabetes and complications of diabetes 2 see, "TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists, Blagosklonny, 2013.(58) The basic concepts are overactivated mTOR causes IR. Low calorie diet reduces IR. Insulin resistance causes elevated mTOR. Elevated mTOR causes the complication of type 2 diabetes including cardiovascular disease, diabetic nephropathy, diabetic retinopathy and blindness, and neuropathy. As part of evidence, Blagosklonny points out that 15% of persons have these secondary complications of diabetes at time of initial diagnosis; before they had diabetes with elevation of glucose. Even though they did not have marked elevation of glucose, they still had insulin resistance and elevated mTOR, hence were at risk for diabetic-type complications.