Why is insulin used to treat non-insulin dependent (type-2) diabetes?

| February 17, 2014

This ongoing column is dedicated to sharing with readers the life and experiences of Dr. Edward Mason.

Both intestinal and gastric bypass resolve type 2 diabetes (T2D). These operations expose L cells in the distal bowel to glucose, stimulating secretion of glucagon peptide-1 (GLP-I), which decreases insulin resistance. I have provided references regarding my understanding that T2D is a failure of regulation of digestive tract function.[1] Since the beginning of single cell life the concentration of surrounding fluid has had the concentration (tonicity) of the pre-Cambrian sea. Tonicity control in normal weight people begins with the initial emptying of the stomach, which is usually a gush of highly concentrated nutrients. This gush overflows the duodenum, providing an undiluted sample that is flushed by the upper intestine to the distal bowel.[2] The duodenum has osmoreceptors which regulate post-flush time and quantity of gastric squirts that assure that fluids reaching the upper small bowel have the concentration (tonicity, osmolality) of the pre-Cambrian sea in which life began in single cells. Only changes in the concentration of stomach contents result in repetition of gastric gushes and intestinal flushes (gush/flush). Most gastric emptying is by smaller squirts regulated by duodenal receptors.

Cellular glucose also requires regulation. Two hormones are involved, insulin and GLP-1. Insulin treatment of diabetes began in the early 1920s. I was born and women were allowed to vote for the first time in 1920. Pancreatic beta-cells secrete insulin when plasma glucose is above normal. For T2D GLP-1 is required for decreasing insulin resistance of cells. Evolution provided movement of GLP-1 secreting cells from the salivary glands of early mobile precursors of mammals to the ileum and rectum of mammals. These L cells recognize glucose sweetness and respond by secreting glucagon-like peptide-1 (GLP-1), which decreases insulin resistance of body cells. GLP-1 is also an incretin, stimulating beta cell insulin secretion in the pancreas. Thus insulin secretion is regulated by the concentration of circulating glucose and cellular glucose is regulated by GLP-1, which decreases insulin resistance.

Insulin resistance is normal and provides the mechanism for GLP-1 function in preventing and resolving T2D. Bypass surgery provides the “missing hormone” for T2D. GLP-1 is usually available. It just needs release by glucose or other stimulants. A glucose mimetic that reached distal bowel could be used once approved. It should not be necessary to administer GLP-1 mimetics or medication, which blocks dipeptidyl peptidase-4 (DPP4) destruction of circulating GLP-1. There must be a low level of circulating GLP-1 in patients who respond to DPP4. GLP-1 has a 30-second half-life without DPP4 blockade.

The effective surgical procedures make endogenous GLP-1 available and are, therefore, similar to medical treatment with GLP-1 mimetics. There are a number of advantages of medical treatment with GLP-1 mimetics, DPP4 blocking agents (and glucose mimetics if and when they are approved for use). Dosage can be varied as required between and within patients with oral medications. These agents seldom cause hypoglycemia because the response to GLP-1 only occurs when plasma glucose is above normal. Gastric restriction with gastroplasty and adjustable gastric bands is less direct than gastric bypass and other GLP-1 stimulating operations. Restriction operations only improve T2D by sustained weight reduction. They must restore normal gust/flush and stimulation of L cell secretion.

The importance of all of this to patients, surgeons, pharmaceutical companies and all the rest of us varies depending upon our background, study, and paradigm. A college classmate and I developed diabetes. He died from gangrene of a leg and kidney failure secondary to his diabetes 37 years ago. I discovered my diabetes a few years ago. I have wondered if my classmate died from treatment of T2D with insulin. I have never used insulin. Insulin is above normal in T2D until beta cells are destroyed by over-stimulation. We were both normal weight. Neither of us had bypass operations. GLP-1 stimulating surgery is limited to treatment of less than one percent of candidates by the limited capacity in operating time, obesity surgeons, and financing of medical care. Hundreds of millions of candidates need prevention or treatment of obesity and/or T2D, and the numbers are growing. Surgery revealed the mechanism of Billroth II gastrectomy, and the simpler gastric bypass, in stimulating secretion of GLP-1. Knowing the mechanism revealed the potential for use of glucose mimetics that are poorly absorbed, effective and probably safe in stimulating L cell secretion. Glucose mimetics might be the least expensive choice for treating the T2D epidemic and should assist in reducing excess weight, once approved.

I leave you with a question: Is it safe to treat non-insulin dependent T2D diabetes with insulin? Insulin secretion is stimulated by excessively high concentrations of glucose. As a result, insulin levels are above normal even without insulin treatment. Calle et al have shown that high levels of insulin are carcinogenic.[3] According to Calle insulin is a growth hormone and high concentrations not only cause many types of cancer but accelerate the growth of cancer. Are high plasma insulin levels more important than the high glucose in causing other complications of non-insulin dependent diabetes? Search of the internet for studies of “insulin toxicity” surprisingly revealed nothing. As a retired surgeon I can only search the literature and ask questions. You may be able to provide answers or related questions.

References
1.    Mason EE. Dumping dependent diabetes: Surgical paradigm. Bariatric Times. 2013;10: 12.
2.    Brener W, Hendrix TR, McHugh PR. Regulation of the gastric emptying of glucose. Gastroenterology. 1983;85:76–82.
3.    Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Reviews Cancer. 2004; 4:579–591.

Category: Ed Mason at Large, Past Articles

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