GLP-1
A New Potential Target For Obesity and Type II Diabetes
This is one of the topics I will be discussing in my dissertation next month. One of the more recent advances in the treatment of Type II Diabetes and obesity is the use of GLP-I or Glucagon-Like Peptide I as a target for treatment.
GLP-I is a 31 amino acid long peptide secreted in the intestinal tract, by the L-cells of the duodenum, and to a lesser extent by the islets of Langerhans and the central nervous system. Though GLP-I is a potentiator of insulin secretion, and may therefore seem rather unfit for treatment in the aforementioned disorders, it has other benefits that make it very attractive.
It has the potential to reduce appetite, increase insulin sensitivity, slow gastric emptying and digestion and promote glucose expenditure (Ahren et al, 1997; Meneilly et al, 2001). All of which would greatly ameliorate conditions of overweight or insulin insensitivity.
On top of that there is a way to circumvent the insulin secretion problem. While GLP-I is capable of increasing insulin biosynthesis and Beta-cell size on its own (thereby alleviating problems associated diabetes) (Tourrel et al, 2001; Wang et al, 2002), it is dependent on a blood glucose level of 4.3 mmol/l or higher to actually increase insulin secretion. Meaning that in combination with a low-carb diet GLP-I forms a unique and interesting target for the treatment of such disorders.
GLP-I reduces appetite, and with it food and water intake, by functioning as an anorexigenic hormone as well as an inhibitor of orexigenic hormones (Kiefer and Habener, 1999; Drucker, 2003; Turton et al, 1996). The signals promote satiety and create an aversion to further food intake. In both lean and obese subjects, administration of GLP-I lead to decreased food intake.
As an added benefit, GLP-I has neuroprotective benefits (Perry et al, 2003) and may play a role in learning. The method by which GLP-I actually signals the brain to do this is not yet clear.
It may be through direct production in the central nervous system, but more likely via either systemic GLP-I from the L-cells in the digestive tractus, or through peripheral signalling from afferent nerves located there that reach the paraventricular nucleus. A similar case with GLP's effects on slowing gastric emptying, which are likely the result of direct action in the digestive tract and nervous control.
A lot of GLP's effects on the other hand seem to be related to its effects on endocrine function. We already know that GLP produces somatostatin, and if glucose is high enough increases insulin and reduces glucagon secretion, but it also has effects on the release of ACTH (leading to increased cortisol) and LH (leading to increased testosterone).
Leaving us with an irreconcilable problem as to whether GLP-I is anabolic, anti-catabolic, or catabolic. Preliminary studies seem to point towards a more anabolic effect, but if this needs to be judged in light of GLP's effects on insulin, then we need to take care not to extrapolate this to situations of low glucose intake, when it no longer has an effect on insulin release.
Especially since acute stimulation (Kieffer and Habener, 1999) seems to preferentially increase ACTH, and with the extremely short half-life of GLP-I (just a few minutes) it's hard to see any increase as being chronic.
The latter seems to also be the main research-topic when looking at the practical application of this model to treat obesity : coming up with analogues that have a longer half-life. GLP-I is cleared by the reduction of the alanine at the N-terminal by the enzyme DPPIV, while its active part is located at the C-terminal. That leaves a lot of room for alternate amino acid sequences at the N-terminal to avoid destruction by DPPIV without compromising the activity of the peptide.
Of course such manufactured peptides will never make it to the supplement market, so the rest of us have to get by with the promotion of natural GLP-I. GLP-I release is triggered by the intake of glucose, fat or a combination of the two. Obviously taking in glucose is not an option since that would potentiate insulin increase and set us back to square one.
