The epidemic of type 2 diabetes (T2DM) is widely attributed to rising levels of obesity, which in turn are attributed to lifestyle issues (diet and exercise). So, at best, it’s society’s fault and, at worst, we get to blame each individual patient.
But surely there must be more to it that this? Every practicing clinician has patients with T2DM who are not overweight and, not only are the majority of people with so-called ‘morbid obesity’ non-diabetic, a significant proportion of them have normal insulin sensitivity (i.e. they don’t manifest insulin resistance, which is the way that obesity is meant to drive the increase in T2DM). Furthermore, the inexorable decline in beta-cell function, so clearly demonstrated by the UKPDS, seems to be reversible not only using glucagon-like peptide-1 (GLP-1) injectable therapies but more remarkably by malabsorptive bariatric surgical procedures. This has made various groups question the current thinking around the pathophysiology of T2DM, with a particular focus on the bowel.
It is possible that bariatric surgery manifests its anti-diabetic effects by enhancing the bowel production of the incretins, GLP-1 and gastrointestinal peptide (GIP), but various authors have suggested that the increases seen not are dramatic enough for this to be so. Others have proposed the existence of a pathogenic insulin analogue (PIA), which is absorbed in the proximal gut and which interferes with the insulin binding, preventing the normal function of endogenous insulin. The hypothesis goes on to suggest that the PIA is produced by intestinal micro-organisms in the proximal gut in the presence of food.
The hypothesis is attractive in that it can provide an explanation for the bariatric effect and also the impact of very low calorie diets, which might affect the gut micro-biome. It might also account for the glucose-lowering seen from endoscopic insertion of a duodenal sleeve, which could presumably limit absorption of putative pathogens. Studies in mice support the idea that obesity and related phenotypes can be induced by transplantation of faecal microbiota from obese animals to non-obese ones and more recently, there has been a study in European women, which showed a correlation between the gut meta-genome and various levels of glucose intolerance. Perhaps the hypothesis can also provide an explanation for a recent case report of unintentional rapid weight gain following faecal microbial transplantation in a patient suffering from recurrent Clostridium difficile infection?
It is easy to doubt these novel ideas and certainly teasing out cause and effect will be a challenge. But bear in mind that not so long ago, the idea that a bacterium might be responsible for duodenal ulcers seemed implausible. Also, that the mechanism of metformin has still to be fully elucidated; it certainly does strange things to the bowel and has not been shown to be effective when given intravenously….
Professor Steve Bain