Is the Gut the “Sweet Spot” for the Treatment of Diabetes?

Abstract

Oskar Minkowski possessed a rare combination of talents: He was an internist with the intuition of a scientist and the dexterity of a surgeon. One day in 1889, he and his colleague Joseph von Mering at the University of Strasbourg performed a total pancreatectomy in a dog to investigate if pancreatic enzymes were necessary to break down fatty acids in the gut. The dog survived the operation but unexpectedly developed polyuria, thirst, hunger, and glycosuria. Minkowski joined the dots to realize the link between the pancreas and diabetes (1).This story is just one example of how surgical manipulations of anatomy can play a major role in advancing knowledge about physiology and disease. Many lessons about the functioning of the central nervous system, the pituitary gland, and the adrenals have been learned through the help of a scalpel (2), and Minkowski's observation provided the fundamental clue that lead to the discovery of insulin by Banting and Best in 1921. More than a century later, surgery may again provide a unique opportunity to improve our understanding of glucose homeostasis, diabetes, and b-cell growth. Readers of Diabetes will know that a number of gastrointestinal (GI) operations used to cause weight loss (bariatric surgery) has also been shown to cause remission of type 2 diabetes (T2D) (3,4) as well as improvement of hypertension and dyslipidemia (5) and reduction of cardiovascular disease and death associated with diabetes and obesity (6). The mechanisms by which these operations control diabetes have become the subject of intense research in recent years, fueled by the experimental evidence that GI bypass surgeries can induce very rapid antidiabetes effects, independent of weight loss (7).The pathophysiology of T2D is complex but the disease is characterized by a combination of insulin resistance and defective insulin secretion that worsens over time (8); treatments of curative intent would need to address both defects. GI bypass procedures can improve insulin sensitivity and production (9,10), suggesting that the GI tract may be a "sweet spot" for diabetes treatment.In particular, Roux-en-Y gastric bypass (RYGB) restores first-phase insulin response (10) and results in hypersecretion of C-peptide and insulin following nutrient ingestion (11), suggesting enhancement of b-cell function (12). Increased b-cell mass has also been hypothesized following controversial reports of nesidioblastosis complicating RYGB (13). Other hints of an effect of GI surgery on b-cell growth derive from observations of increased PDX1 levels (14) and prevention of b-cell loss after experimental duodenal-jejunal bypass in rodents (15), as well as from case reports of heterotopic pancreatic mass after RYGB in humans (16).Lindqvist et al. (17) add support to the hypothesis that RYGB can stimulate b-cell growth. In their study, morphometric analysis revealed a doubling of b-cell mass and islet number in four RYGB-treated pigs, studied 20 days after surgery and compared with pair-fed, sham-operated controls. Extraislet b-c...

Microvascular Outcomes after Metabolic Surgery (MOMS) in patients with type 2 diabetes mellitus and class I obesity: rationale and design for a randomised controlled trial

“…Metabolic surgery additionally improves dyslipidaemia, inflammation and blood pressure 8–10. Mortality was also reduced after surgery, especially in those patients with T2DM,11–15 although baseline body mass index (BMI) did not predict benefit; rather, non-anthropometric parameters such as fasting insulin did predict cardiovascular events and mortality 16–21…”

Diverse mechanisms for endogenous regeneration and repair in mammalian organs

“…One concern is whether the induction of plasticity will ever be therapeutically relevant, given that the proportion of cells in a tissue that exhibit plasticity is often exceptionally rare 37,38 . Time will tell, but it is worth concluding with the observation that gastric bypass surgery in humans enhances pancreatic β-cell function and may also increase β-cell mass 87…”

Metabolic surgery: gastric bypass for the treatment of type 2 diabetes mellitus

“…In the absence of one or more of these feedback mechanisms, these effects would expose to exacerbated insulin hypersecretion and B-cell function and growth, with the concomitant risk of postprandial hyperinsulinemic hypoglycemia and uncontrolled B-cell proliferation. Reduction of nutrient passage and stimuli on the gut by surgical procedures that exclude parts of the foregut and the arrival of them to the handgun could restore appropriate incretin/anti-incretin balance explaining improvement of T2DM (24)(25)(26)(27)(28)(29)(30). Bile acids are now considered to be important regulators of energy balance and metabolism, primarily via de nuclear farnesoid X receptor (FXR) and the G-protein-coupled receptor (TGR5).…”