Published On: Mon, Jun 10th, 2013

Molecular Links

The Quintessential Molecular Links  Between Diabetes and Pancreatic Cancer

by Dr. Bob Berger, MS, MVSc, PhD.

 “Do not let what you cannot do interfere with what you can do” John Robert Wooden (1910-2010)

 

Undoubtedly the greatest basketball coach of all time, the “Wizard of Westwood” accomplished what no other head coach had ever done before him, and most probably, what no other coach will ever do!!!!  As Head Coach of the UCLA  Bruins, Wooden won an unprecedented 10 National Championships and was named “National Coach of the Year” 6 timesbut just as important, he was also a magnificent mentor to his players. So, how do these accolades for Coach Wooden coincide with the title of this article?!!!!  

For decades,  the majority of  Type 2, Non-Insulin-Dependent diabetics have been  brainwashed to believe that the only way to truly control their disease was by the use of [varying doses of] insulin. Now, this is not what I was taughtmy professors called it “Non-Insulin Dependent Diabetes Mellitus” because if you are diagnosed with this ailment your body doesn’t require exogenous insulinthis is what NIDDM means!  In Type 2 diabetes, it is evident that something “molecular” transpires between fat cells and blood-sugar levels, since, (in many cases), the loss of a specific percentage of weight and/or body fat, (which varies from subject to subject), also improves and/or regulates blood-sugar levels, virtually normalizing  the resultant high blood-glucose levels and “temporarily” reverses this condition. 

There are two distinct types of diabetes, Type 1 and Type 2…and just coincidentally, there are also two distinct types of pancreatic cancer; Pancreatic Adenocarcinoma and Pancreatic Neuroendocrine carcinoma.  We all know the difference between Type 1 and Type 2 diabetes; the former type is where the body’s immune system destroys specific cells (i.e., Beta (β-) cells) of the pancreas which produce insulin, and the latter is where the body presents what is known as “insulin resistance”. In Type 2, although the body is capable and usually does produce insulin, (where in Type 1 is doesn’t), the cells and tissues do not respond well, (if at all, many times), to endogenous insulin it produces.  In Type 2 diabetes, either cell receptors have “sunken” below the cellular membrane or the receptors themselves have been structurally altered, changed, or deformed, so that they no longer efficiently recognize insulin. Frequently, when a person loses 10-15 lbs of body fat, it is amazing how efficiently his or her body responds [again] to endogenous insulin production, normalizing blood-glucose levels. Once again, this might be due to the “sunken” insulin receptors surfacing and becoming available to “recognize” glucose.

About 95% of pancreatic cancer cases involve the exocrine component of the pancreas and is called ductal adenocarcinoma, whereas the other 5% of cases involves the endocrine component, arises from pancreatic islet cells, and is called neuroendocrine carcinoma. The later type is much less aggressive and has a much better prognosis for longer-term survival. [Islet cells are clusters of cells contained within the pancreas that produce hormones. There are several types of cells in an “islet”, and examples are; Alpha cells (these produce glucagon which, when secreted, raises blood-glucose levels) and Beta (β-) cells (these produce insulin which, when secreted, lowers blood-glucose levels)] According to the American Cancer Society, about 20% of patients with exocrine pancreatic cancer live at least 1 year post-diagnosis, while less than 4% survive after 5 years post-diagnosis. For neuroendocrine pancreatic cancer, the overall 5-year survival rate is approximately 42%. For more information on these survival statistics and “stages”, go to; www.cancer.org/Cancer/PancreaticCancer/DetailedGuide/pancreatic-cancer-survival-rates.  

So…once again, how do the accolades for Coach Wooden coincide with the title of this article? Wooden never wanted his players on the basketball court, nor anyone just going through life itself, to ever let anyone make them believe that they couldn’t accomplish (even remarkable) things, just because the bearers of this doleful advise did not believe it themselves…this is one way that I interpret the Wooden quote. As a scientist I would be derelict to believe (or to say) that one can beat a disease such as pancreatic cancer or diabetes by a change in attitude, but a positive outlook and/or disposition along with an intelligent lifestyle of good dietary habits, exercise, and the avoidance of known causes of these diseases can change our physiology by actually  redirecting various molecular aspects of it. For instance, we do know and thus, should accept the fact that there is a correlation/relationship between diabetes and pancreatic cancer. This is especially valid in the less deleterious form of pancreatic cancer (neuroendocrine) in correlation to Type 2 diabetesmany neuroendocrine tumors of the pancreas (PNETs) arise from the β-cells which produce and secrete insulin, and this only makes logistical sense. A significant study from the Mayo Clinic (Rochester, Minnesota) presented research data indicating that many patients with pancreatic cancer do develop diabetes months to even years before they are ever diagnosed with this dread disease [Pannala, R. and Basu, A., et al. (2009) “New-Onset Diabetes: A Potential Clue to the Early Diagnosis of Pancreatic Cancer”.  Lancet Oncology, 10, 88]This research paper brings up a number of important points…many of which are supported by other ancillary studies.  Because the incidence of pancreatic cancer is generally low, (as compared to that of breast or lung cancer, for instance), asymptomatic pancreatic cancer screening would not be very feasible, and would need to be restricted [in order to make it feasible] to only  those individuals considered “high risk”, (or at least “at risk”), candidates for pancreatic cancer.  Statistically significant scientific and medical data now shows that up to 80% of patients with pancreatic cancer are either hyperglycemic, (presents with a fasting blood-glucose of 100-125 mg (sugar)/dl (100ml/blood)), or are diabetic, (presents with a fasting blood-glucose of greater than 125 mg/dl), and when these patients undergo pancreatic-tumor resection, their diabetic status also improves. [Pancreatic-tumor (cancer) resection refers to tumor removal, Whipple’s procedure, Central Pancreatectomy, etc…and/or other surgical techniques for pancreas preservation.Thus, what this shows is that diabetes [in these patients] appears to be caused by the pancreatic cancer sequelae themselves…and it is becoming clear that there is a strong molecular link between these 2  diseases. 

Because the pancreas plays an integral role in the processes of digestion, absorption, and thusin blood-sugar regulationany loss and/or destruction of pancreatic tissue does indeed increase the risk for the onset of diabetes mellitus, as well as for the cellular/molecular aspects of malabsorption!  Just an Example: During the Whipple procedure,  parts of vital organs, such as those of the pancreas and bile duct, as well as all of the duodenum are removed and “re-sected” (so-to speak). Not to mention the importance of the pancreas, (whole or not), and the bile duct (a given!), besides the duodenum being the integral 1/3 upper sector of the small intestine (for absorption), the duodenum also appears to play an important role in regulating the motility of the stomach and upper G.I.tract.  Motility of the tract, (and it’s regulation), is  vital to proper and life-sustaining digestion, peristaltic movement down the G.I tract, absorption, and excretion. The molecular link/connection is quite transparentand yes, we do have to look at the bigger molecular picture and not limit ourselves to the typical narrow window of thought which we are “trained” to do. Once again“Do not let what you cannot do interfere with what you can do“…comes back into play.  

“Molecular Links”

Using the model presented by Pannala and Basu, et al., from Lancet Oncology, along with “objective” interpretation, we can expound on some of the  “molecular links” between diabetes and pancreatic cancer and their associated connections via their “Mechanisms of Action“.  In order to thoroughly comprehend a system, a disease pathway, and a way to either reverse or change this system or disease modality, its “M-O-A” must be “somewhat” understood. 

If a disease or condition remains localized,  it probably can’t devastate one’s health as long as the disease, condition, injury, etc…originates in a non-vital area of the body.  Just for the sake of clarification, let’s say that a breast tumor, although malignant, would never metastasize, and just stay in the breast tissue (like a cyst). It probably would not ever kill the patient unless it grew to the size of a watermelon.  This is preposterous, but it is just an obvious example to thus understand. Unfortunately, pancreatic cancer, just like malignant breast tumors, not only grow to sometimes incredible sizes, but they do metastasize. When they metastasize to vital, life-sustaining organs and tissues, they eventually can, (and usually do), kill us. Another unfortunate thing about pancreatic cancer is that it really doesn’t have to metastasize, (although it does, and usually to the liver), in order to kill us because it originates in a life-sustaining organ from the start. 

As far as the “M-O-A” correlation of pancreatic cancer and the diabetogenic factors, the high prevalence of diabetics in pancreatic cancer does suggest that β-cell dysfunction, which is also attributed to secretions that are released from the tumor itself,  is another primary or even secondary defect present in pancreatic cancer-associated diabetes. There are both localized and humoral factors that may be attributed to this association. Localized factors are those that affect the pancreas because of the origin of the diseases themselves; i.e., both diseases are affected by β-cell dysfunction. Humoral factors refer to the ones that are found circulating in the bloodstream (i.e., in fluids) that affect other organs and tissues…like hormones do. Thus, what occurs is a destructive combination of both β-cell dysfunction and insulin resistance. With this combination of events occurring simultaneously, there is poor insulin cellular-response which (in-turn) leads to a highly impaired fasting blood-glucose, which then leads to diabetes mellitus.  In many of these cases, the pancreatic tumor may be causing various molecular-mechanical events due to the humoral response, (even at the pre-metastatic stage), thus,  stemming directly from the tumor itself. 

To review some basic physiology; pancreatic production of hormones such as insulin, somatostatin, (which regulates the production and excretion of endocrine hormones by slowing down the production of insulin, glucagon and gastrin), gastrin, (which produces acid by stimulating/inducing acid-producing cells of the stomach to produce HCl), and glucagon all play vital roles in maintaining sugar (glucose) and salt balances, and any compromises in the production and/or regulation of these hormones will  manifest themselves by exhibiting problematic levels in blood-glucose concentrations as well as in plasma-salt imbalances. The pancreas also is one of the organs, (along with the gut and the hypothalamus in the brain), responsible for the release of Vasoactive Intestinal Peptide or VIP.  VIP aids in the control of water-secretion and absorption from the intestinal tract and causes the intestines to secrete water and salts into the intestines to inhibit absorption. Without the proper release of this hormone, water and salts, (i.e., potassium), severe diarrhea and salt imbalances will occur, putting the individual at severe risk of malignant dehydration, nerve dysfunction and heart failure. Thus, one can see that if pancreatic functions are compromised, (as they are with pancreatic cancer), many adverse secondary and tertiary physiological effects will and do occur.  

So what do we know?…Finding the pancreatic tumor at an early stage may allow the patient to gain some time…and this is a positive thing no matter how insidious this tumor may be…but here it is at least localized.

 Here are some thoughts by simply connecting the dots:

Scenario A…If the tumor is discovered before diabetogenic factors become symptomatic… 

If the pancreatic tumor is contained, the chances are it can be [successfully] resected.  

By resection of the tumor, and if the tumor is responsible for the diabetogenic factors, then accordingly it only fits that the diabetic factors should be removed or palliated.

It is also logical that if a patient has had a pancreatic tumor resection, because this is a highly invasive procedure, there will be temporary (but significant) fat loss.

In Type 2 diabetics, any fat loss, especially of some significance, will usually resolve the insulin-resistance factor. 

Resolving the insulin-resistance factor should help to restore β-cell function. 

proper β-cell function should help to palliate or slow “tumor genesis” and improve pancreatic function. 

Scenario B…If diabetes is discovered before a pancreatic problem of any kind arises… 

Follow a proper diabetic diet (under the guidance of a qualified medical professional such as a Registered Dietician (RD).   

Follow an exercise program under the direction of either qualified medical professionals, Certified Trainers, RNs, RDs, or Exercise Physiologists.

Avoid known causes of diabetogenic factors, such as high Glycemic Index foods, diets containing high percentages of low-nutrient density foods, and foods which contain empty calories. Always seek the advice and services of an RD. 

The Bottom Line…Think like Coach Wooden and heed his advise…don’t give up because anything is possible at any given time. Don’t convince yourself you can’t overcome things that just may be possible to overcome!!!! 

If there is incidence of either of these scenarios, hopefully the later one is in your future!!!!   

                                                         -fin- 

A Footnote…                

Ironically…on January 19, 1974, a Notre Dame squad coached by Digger Phelps beat John Wooden’s UCLA team and snapped UCLA’s 88-game winning streak by beating the Bruins,  71-70. This was not supposed to happen because the country and the press said ND could not beat UCLA…ever!  Phelps and ND did not let what they were told they could not do interfere with what they did do!!!! 

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