Treating the Obese Diabetic

Julia Kenkre; Tricia Tan; Stephen Bloom

Disclosures

Expert Rev Clin Pharmacol. 2013;6(2):171-183. 

In This Article

Five-year View

Bariatric surgery offers an instructive paradigm for the future treatment of diabetes and obesity. Much of its effectiveness appears to rest on the elevation of satiety gut hormones, which serve to suppress appetite and to improve glycemia. This implies that pharmacological methods to simulate these gut hormone elevations offer a possible method to reap the benefits of bariatric surgery without the surgery itself: the 'medical bypass.' We therefore anticipate that the therapeutic landscape for 'diabesity' in 5 years time may incorporate gut hormone analogue therapies, including those already presently developed for GLP-1 and newer ones for PYY, pancreatic polypeptide and glucagon. Some promising recent developments are outlined below.

PYY Analogues

PYY3–36 is a satiety gut hormone, secreted after eating, which acts to reduce food intake via central and peripheral pathways. Intravenous infusion of PYY over 90 min can reduce food intake in both lean and obese individuals.[69,104] Early attempts to develop an intranasal preparation of PYY for obesity treatment foundered on the fact that this preparation provoked an acute and excessive rise in circulating PYY levels, leading to the induction of nausea and vomiting.[105] Long-lasting PYY analogues, which provide a smooth and sustained rise in PYY levels suitable for daily or less frequent administration, are in active development as antiobesity treatments. Animal studies suggest that PYY3–36 is capable of increasing insulin sensitivity.[71] However, there are uncertainties surrounding the effect of PYY3–36 on glycemia in humans, and its role in the obese diabetic is yet to be clarified.

Pancreatic Polypeptide Analogues

Pancreatic polypeptide (PP), a peptide hormone secreted by the PP cells of the pancreas postprandially, also acts to suppress food intake.[106,107] As with GLP-1 and PYY, native PP is normally broken down rapidly by peptidases in vivo. Analogues of PP that are resistant to breakdown are therefore currently in development as antiobesity treatments, such as PP 1420.[108]

Combination Gut Hormone Analogue Therapies

The gut hormone elevations seen after bariatric surgery do not occur in isolation. Combinations of gut hormone analogues might therefore be expected to possess enhanced effects on suppression of food intake with a minimized side-effect profile. The authors have previously shown that the combinations of PYY3–36 and GLP-1[70] and of PYY3–36 and oxyntomodulin[109] have additive effects on reduction of food intake. Combinations of PYY, GLP-1 and oxyntomodulin may therefore be of therapeutic value for diabesity, but the development of these combinations is still some way in the future.

As noted above, GLP-1 is able to induce a modest weight loss by its effects on suppression of appetite. However, this weight loss is limited by the dose-limiting side effect of nausea, as well as the fact that GLP-1 has a tendency to reduce energy expenditure.[110] Glucagon has emerged as a possible partner for GLP-1, as both glucagon[111] and GLP-1 inhibit food intake. Importantly, glucagon increases energy expenditure,[112] and the combination of food intake inhibition with increased energy expenditure would be expected to enhance weight loss. Oxyntomodulin, a gut hormone released postprandially, is related to both glucagon and GLP-1 and combines the activity of both hormones. As previously noted it has been shown to induce weight loss via reduction in food intake and increased energy expenditure. Although glucagon alone is known to increase blood glucose by increasing glycogenolysis, the addition of GLP-1 would be expected to counterbalance this deleterious effect by increasing insulin secretion. Animal studies utilizing a GLP-1/glucagon dual agonist peptide have shown that this drug is able to produce an enhanced weight loss and lowers glucose in diet-induced obese mice.[113] A study in human volunteers verified that the combination of glucagon and GLP-1 is able to increase energy expenditure similar to glucagon alone, and that GLP-1 is able to partially ameliorate the hyperglycemic effects of glucagon.[114] Based on these observations, GLP-1/glucagon dual agonists are currently in active development for the treatment of diabetes and obesity.

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