Forgotten players in glucose homeostasis?

It is highly likely that you learned at secondary school that the pancreatic hormones insulin and glucagon are important in the regulation of glucose metabolism. However, it is equally likely that during your further education more attention was given to insulin compared to glucagon, which at best got the role of bystander. Funnily enough both hormones were discovered around the same time (insulin in 1921 and glucagon in 1923) as was their role in glucose homeostasis. Insulin got all attention as new revolutionary medicine, possibly because Insulin Dependent Diabetes Mellitus (Type I DM) was such a lethal disease that could now be properly treated. In contrast, glucagon-deficiency was not recognized as a clinical entity let alone as a disease. This is all very understandable, but it remains enigmatic why insulin-based therapies also dominated the treatment of Non-Insulin Dependent Diabetes Mellitus (Type II DM). Especially in view of the observations in the 1960’s that Type II DM is not a disease of insulin deficiency, but a condition of insulin resistance which cannot be overcome by increased endogenous insulin release. Whatever the explanation for this enigma may be, we are currently witnessing a revival in glucagon-based therapies for the treatment of Type II DM.

At CHDR we have adapted and validated existing techniques to investigate the role of glucagon in glucose homeostasis and to evaluate glucagon-based therapies in humans. The development of these tools with our colleagues in industry and academia was and will be a hallmark of CHDR’s philosophy. This also regards the development of mathematical models that try to capture the complex interplay between insulin, glucagon and glucose. We are proud that all this work is now integral available as PhD thesis, which our colleague Marloes van Dongen will publicly defend on January 7, 2015 in the historical Academiegebouw of Leiden University.

An important role of the specialty of clinical pharmacology is to develop the tools of the drug development trade. We sometimes define new (and untested) medicines as extremely sophisticated technological innovation after evaluation with rather primitive methodology. The ongoing drug innovation wave has to be matched with equally sophisticated methodology to see the potential effects. These techniques have to be developed preferably ahead of a new innovation wave in a certain field[1].

Renewed interest in glucagon as one of the ‘forgotten’ players in glucose homeostasis, of which there are more[2], will lead to a potential wave of new products and devices. We are happy that our work is now available to support this, and make a difference in the attack on the Type II DM epidemic.

Koos Burggraaf

[1] Cohen et al. Annu Rev Pharmacol Toxicol. 2014 Oct 6. [Epub ahead of print]; PMID: 25292425

[2] ‘certain factors produced by the intestinal mucosa in response to nutrient ingestion that are capable of stimulating the release of substances from the endocrine pancreas and thereby reducing blood glucose levels’; see for instance Bayliss WM, Starling EH. Proceedings of the Royal Society of London[Biol] 1902;69:352-353 / Moore B, Edie ES, Abram JH. Biochem J 1906;1:28-38) and La Barre J. Bull Acad R Med Belg 1932;12:620-634.

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