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What has the battle against diabetes been like? Man’s battle against diabetes began in the early 1900s with dietary adjustments, abstaining from heavy sugar-laden food. In 1920, Banting and his colleagues discovered insulin; the hormone that regulates blood sugar level. What a relief? Deaths as a result of diabetes reduced drastically. But the ecstasy that followed was short-lived as it was discovered that there is another types of diabetes that is insulin-independent called Type-2 Diabetes. People with this type of diabetes do produce insulin but it is either in insufficient amounts or it is not effectively utilized. About 90% of diabetics today belong to this group. This means that the battle against diabetes rages on.
Over the past 800 years, several strategies for treating Type-2 Diabetes were developed. Some focused on using agents that could stimulate more release of insulin called secretagogues, while others used sensitizers (which reduces the release of glucose from the liver and increases glucose uptake by the muscle) or other agents that slow down digestion of starch. Around the year 2000, the fight against diabetes was taken to another level with the development of injectable peptide analogues such as incretin mimetics which acts like gastro-intestinal hormones GIP and GLP-1. Despite all these, the battle is far from been won. None of these treatment options is without substantial side effects or is able to actually cure diabetes. Sadly enough, lifestyle changes and increased incidence of obesity are causing the number of people suffering from diabetes to increase.
As difficult situations always inspire ingenious solutions, researchers and scientists continue to explore every possible avenue in search for new therapies for diabetes. First was the discovery of exendin-4, a peptide that works like GLP-1 but lasts much longer in the bloodstream, from the saliva of the Gila monster lizard and its development into a new drug called Byetta. But when scientists in the University of Ulster announced the identification of a peptide, Pseudin-2, which stimulates insulin release from a frog’s skin (Pseudis paradoxical) in 2008, it became obvious that the stage is set for a renewed battle against diabetes.
Though James Joyce said “mistakes are the portals of discovery”, research into frogs skins were out of curiosity and necessity than mistakes. It is more like looking at old things with new eyes. As defenceless as amphibians are, nature endowed them with special skin glands that are able to secrete powerful chemicals that act as weapons against their predators and help them cope in the harsh habitats where they are often found. Tachykinins, bradykinin and caerulein were representatives of the first set of peptides to be purified from amphibian secretions in the 1970s while bombinin isolated from the skin secretion of Bombina variegata was the first peptide which antibacterial and hemolytic properties were reported.
The 2008 discovery of Pseudin-2 and its more potent synthetic analogues sparked the beginning of more interesting discoveries from frogs’ skin secretions. From frogs in genus phyllomedusa, rana, bombina and pseudis, researchers have identified peptides with strong insulin-releasing effects. They reported that peptides such as Pipinin-1, Palustrin-1c, Esculentin-1, Esculentin-1B, Brevinin-2EC and Brevinin-1E isolated from frogs in rana genus are able to stimulate up to 3.5-fold insulin release from clonal pancreatic cells. Other peptides such as those in temporin, magainin, and caerulin families have also been found to have insulin releasing effects. Interestingly, many of these peptides are found in more than one species of frog. It does appear that frogs are equipped with more arsenals against Type-2 diabetes than what we have earlier imagined.
What makes these amphibian peptides special candidates for new anti-diabetic drugs? In addition to their insulin-releasing effects, many of them are related to peptides found in human body. For instance, caerulin (isolated from Hyla caerulea) is found to be similar in composition and action to cholecystokinin (the hormone that regulates the digestion of fat and protein). This means that though they are from frogs, they may not be eventually foreign.
Like other peptides that stimulate insulin release, such as GIP and GLP-1 (found in the gut), there is the concern that these peptides may be rapidly degraded from circulation by endogenous enzymes, thereby preventing the realization of their insulinotropic effects. However, peptide modification technology is rapidly becoming popular and scientists are taking advantage of this to prolong their half life. It is hoped that some of the already identified and screened amphibian skin peptides will be subjected to modification using the aforementioned technique even if they have short half-live in vivo.
But where do we go from here? Do diabetics need to start warming up for frog soup or barbeque as a novel therapeutic approach? Well, that won’t happen! Scientists use information from native peptides from frog skins to produce their synthetic forms. The synthetic forms will also be tested for safety and efficacy before their eventual development into drug. Interestingly, remarkable progress has been recorded in this regard. Recent studies have also indicated that many more synthetic forms of amphibian peptides or their analogues are proving to be potent and safe. Apart from Pseudin-2 and its analogues that have been widely publicized, scientists are discovering many more potent synthetic peptides that could serve as potential anti-diabetic drug. Examples of such include peptides in the temporin family, bombesin (isolated from Bombina bombina) and so many more.