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Pories: excessive insulin is the key to T2DM

Insulin resistance is a defensive mechanism against an oversupply of fuel
Future drug development should address excessive insulin secretion rather than increasing insulin sensitivity or secretion

It is more likely that type 2 diabetes is caused by excessive levels of insulin, rather than insulin resistance, according to Dr Walter J Pories, professor of surgery at East Carolina University. Speaking at the Minimally Invasive Surgery Symposium, in Cleveland, Ohio, he explained that for years the medical community has been concentrating on sugar – rather than the real culprit, insulin.

“If the problem with type 2 diabetes is hyperinsulinemia, should we be treating it with insulin?” said Pories.

The treatment of type 2 diabetes has aklways been "glucocentric". Throughout history physicians have thought of sugar as the source of diabetes. As far back as 400BC, the Indian physician Sushruta described the sugary taste of a diabetic’s urine, and for hundreds of years this was the foundation of diagnosis.

Pories said that even today, physicians use glucose to guide diagnosis and treatment of diabetes, measuring fasting blood sugar, Hb1Ac, postprandial blood sugar, glucose tolerance test and glucose clamp.

The first breakthrough came in 1921, when Frederick Banting and Charles Best discovered insulin. The discovery was made when Banting tied a ligature around the pancreatic duct and found that several weeks later, the pancreatic digestive cells had died and been absorbed by the immune system, leaving thousands of islets. They then isolated an extract from these islets, producing what they called isletin, now known as insulin, and successfully tested this extract on a pancreatectomised dog.

Over the next few years insulin was found to correct high sugar levels in children, and later adults.

Diabetes 1 & 2

For 15 years, physicians did not distinguish between diabetes types 1 and 2, and insulin was adopted as the only effective treatment for both diseases, despite their fundamental differences. It was not until January 1936, when Sir Harold Percival Himsworth published his paper on the two types of diabetes, that a distinction was made between type 1 and type 2 diabetes, based on insulin sensitivity.

“To this day, type 1 and 2 diabetes is still defined as the body’s inability to produce insulin type 1, or enough insulin to overcome ‘insulin resistance’,” said Pories.

Pories cited his team’s own research that demonstrated type 2 diabetes patients are very hyperinsulinemic, sometimes as 900% of normal in advanced cases, and that while maximum basal (or fasting) insulin secretion falls as type 2 diabetes progresses, it remains higher than insulin secretion in a normal person.

“Yet, our treatment of type 2 diabetes aims to overcome the lack of insulin,” he said. “Despite advances in treatment, type 2 diabetes remains the primary cause of blindness, kidney failure and dialysis, amputation, and a major cause of heart attacks, strokes and early deaths. Diabetes is our most costly disease and these costs have doubled in the last decade. Medical treatment has not been as successful as we would like it to be.”

Pories also cited a study by Reed et al that showed basal insulin levels after a mid-level caloric meal challenge were twice the normal level. However, within a week after bariatric surgery the normal insulin levels and response were corrected and stay corrected three months after surgery.

“These findings suggest that the central lesion in type 2 diabetes is not insulin resistance but, instead, an excess of insulin production and that insulin resistance is a defensive mechanism against an oversupply of fuel,” said Pories. “This is demonstrated by the fact that type 2 diabetes clears and insulin levels return to normal in a few days after bypass surgery. However, insulin resistance improves but does not return to normal levels even after three months.”

Returning to the thousands of islets first discovered by Banting and Best, he said that bariatric surgery is directly related to the decrease in contact between food and the gut, and that this excess of food causes excess secretion of insulin.

“Insulin resistance is most likely the cells’ defensive response and the metabolic error in type 2 diabetes lies between the gut and the islets,” he said. “But current bariatric surgeries are all focused on the post-islet mechanisms.”

Pories questioned whether it was correct to treat type 2 diabetes with insulin if hyperinsulinemia is the problem, particularly if research has shown that low and high mean HbA1c values are associated with increased all-cause mortality and cardiac events.

He said that bariatric surgery has shown that type 2 diabetes is no longer an irreversible disease and can be cured by a reduction in food intake and/or exclusion of parts of the gastrointestinal tract with the reduction of excessive fuel to the cells.

“It is more likely that type 2 diabetes is due to hyperinsulinemia rather than insulin resistance,” said Pories. “And future drug development should address excessive insulin secretion rather than increasing insulin secretion, reducing insulin resistance and insulin administration.”

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