Letter to the Editor Re: Sera of Obese Type 2 Diabetic Patients Undergoing Metabolic Surgery Instead of Conventional Treatment Exert Beneficial Effects on Beta Cell Survival and Function: Results of a Randomized Clinical Study

Commentary

We congratulate Alina Constantin and her colleaguesⁱ for their major contribution documenting that cultures of beta cells are adversely affected by serum from obese subjects with type 2 diabetes (T2D) and that these harmful effects are reduced when the cells are exposed to serum from similar, randomized patients who were treated with the laparascopic gastric sleeve operation (LSG). At 6-month follow-up, patients undergoing LSG achieved glycemic control, whereas conventionally treated patients did not. Cells exposed to sera from LSG-treated participants exhibited 1) increased viability and proliferation 2) diminished levels reactive oxygen species and p53; 3) enhanced protein expression of autophagy-related SIRT1 and p62/SQSTM1; 4) significantly decreased transcript levels of endothelial reticulum (ER) stress markers; and 5) augmented insulin expression. Conversely, the 6-month conventional therapy appeared not to impact on circulating redox status. Moreover, 1.1B4 cells exposed to sera from conventionally treated patients experienced mild ER stress.

They concluded that “circulating factors in patients with improved diabetes after metabolic surgery exerted favorable effects on beta cell function and survival”.

We would offer a different conclusion. Based on their excellent data as well as our studiesⁱⁱ it is more likely that the metabolic syndrome is due to toxic signaling from the foregut, stimulated by contact with food. These blood-borne signals limit entry of acetyl CoA into the TCA cycle. Mitochondrial oxidation of substrates is then reduced to a point where ATP production is below that needed to maintain muscle function and a compensatory increase in glycolysis to lactate is required. Lactate produced by muscle causes increased plasma lactate concentration and this drives liver gluconeogenesis by mass action. We have termed this phenomenon the “Vicious Cori Cycle” ⁱⁱⁱ. Thus, in our model, the circulating gut factors are unfavorable and become worse with time.

It is not surprising that this excellent contribution came from the National Institute for Diabetes, Nutrition and Metabolic Diseases in Bucharest, Romania, a leader in diabetes research. The Institute has a fascinating history. It was founded in honor of Nicolae Paulescu who claimed that he discovered insulin before Banting and Best. Following the award, according to Wikipedia, he wrote to the Nobel Prize committee claiming that he had discovered insulin first. However, his claims to priority were soon challenged. Paulescu prepared pancreatic extract in 1916 and tested it in dogs, but Kleiner tested pancreatic extract in dogs in 1915, as did Ludwig Zuelzer in 1906. Zuelzer also wrote to the Nobel Prize committee asserting priority. All of these earlier attempts had produced pancreatic extracts that caused side effects in dogs or humans. The Toronto team had noticed the same side effects with their earlier extracts, but they continued working on the problem until they had purified insulin. However, Ian Murray, professor of physiology at the Anderson College of Medicine in Glasgow, Scotland, vice-president of the British Association of Diabetes, and a founding member of the International Diabetes Federation “Insufficient recognition has been given to Paulesco, the distinguished Roumanian scientist, who at the time when the Toronto team were commencing their research had already succeeded in extracting the antidiabetic hormone of the pancreas and proving its efficacy in reducing the hyperglycaemia in diabetic dogs.” It’s what makes medical history fun.

Again, we congratulate Dr. Constantin and her colleagues on an excellent and timely contribution.