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Potential therapies based on antidiabetic peptides

https://doi.org/10.1016/j.beem.2007.07.006Get rights and content

Since adipose tissue was shown to be more than a storage organ, the many cytokines it produces have been identified, along with their roles in energy homeostasis, appetite, and insulin resistance. Concurrently, numerous gut hormones with a diversity of effects have been discovered. They include, amongst many others, peptide YY, ghrelin and oxyntomodulin. As these peptides have been investigated, the potential for their use as novel anti-obesity and antidiabetic therapies has been realized. In this chapter we describe the actions of four of the peptides that have been proposed as the basis for promising new therapies for diabetes: leptin, adiponectin, obestatin and peptide YY. They each have an effect on appetite and, directly or indirectly, on glucose metabolism. We synthesize available data for these peptides and consider the therapeutic potential of each.

Section snippets

Leptin

Leptin was the first adipocytokine to be discovered, in 19941, as the product of the OB gene, and it led to the revelation that adipose tissue was an important endocrine organ as well as an energy store.

Leptin is a 167-amino-acid peptide which is structurally similar to several inflammatory cytokines, including interleukin 6 (IL-6), IL-12, and granulocyte colony-stimulating factor. It is primarily produced by adipocytes, but has been shown also to be produced to a lesser extent by a range of

Adiponectin

Adiponectin is an adipocyte-specific secretory protein involved in aspects of energy homeostasis. Adiponectin was originally described by four groups working independently; for this reason it was known by different names: AdipoQ19, adipocyte complement-related protein of 30 kDa (ACRP30)20, adipose most abundant gene transcript 1 (apM1)21, and gelatine binding protein 28 (GBP28).22

A member of the collagen superfamily, adiponectin shares structural homologies with collagens, complement factors,

Obestatin

Gut peptides have received an increasing amount of attention due to their ability to modulate gastrointestinal functions, particularly food intake and digestive motility.61 Obestatin is a recently described gut peptide derived from preproghrelin. It was identified by comparing the preproghrelin gene sequences from 11 mammalian species. A region was found after the known ghrelin-encoding region, flanked by potential cleavage sites. This newly identified region encoded an amidated product of

Peptide tyrosine–tyrosine (PYY)

Named after the tyrosine residues at both ends of the protein, PYY was first described in 1982.73 It is a peptide belonging to a family that includes pancreatic polypeptide and neuropeptide Y. All of these are 36 amino acids in length and are similar in sequence and in tertiary structure.74 PYY is expressed in both neurones and endocrine cells, predominantly the endocrine L cells of the gut epithelium. It is also expressed in the pancreas, primarily by co-expression with glucagon by the α cells

Conclusions

Leptin is still the best-understood adipocytokine, but the much-anticipated therapies based on leptin have yet to materialize. Leptin does have dramatic effects in patients with severe leptin deficiency, but leptin gene mutations are extremely rare. If a way can be found to mitigate leptin resistance in obese subjects, then leptin may yet have a wider role, but as the mechanism is not understood this seems unlikely. Leptin supplements in obese individuals with low normal leptin levels remain a

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