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Monday, September 16, 2019

 

Our brains run on glucose. To keep glu­cose constantly available in the blood re­quires an elaborate system of checks and balances. Insulin tells the cells of the liver, muscles and fat to take glucose away from the blood. The liver also makes and releases glucose, so when we have a meal, insulin also tells it to stop production.

Insulin production is determined not only by the size and composition of a meal but also the sensitivity of the body to insulin’s ac­tions. This means the right amount of insulin is made and released, ensuring that glucose levels fluctuate only slightly, no matter the meal. But when diabetes occurs there is not enough insulin, or not enough insulin-func­tion, to keep glucose levels under control. This can cause glucose levels to end up too high or too low.

Many different factors can contribute to the decline and loss of insulin’s functions. In type-1 diabetes, a person’s immune system inadvertently destroys the insulin-produc­ing beta-cells of the pancreas so they have to have insulin injections.

In type-2 diabetes – the kind that most di­abetes patients have – the capacity for pro­ducing enough insulin to adequately control glucose levels is eroded over many years. At the same time, the body becomes less sensi­tive to the glucose-lowering effects of insu­lin. To compensate for this insulin resistance, more and more insulin must be made and re­leased by the pancreas to keep glucose un­der control. As they do until eventually this system fails.

Type-2 diabetes is treated with diet, in­creased physical activity and medications to not only maintain good glucose levels but also optimal blood pressure, weight and lipid (fatty compounds) levels. However, even with best practice, “normal” glucose levels (similar to those in individuals without diabetes) are seldom achieved. This is partly because the delicate control of insulin production by the pancreas is almost impossible to match with insulin injections or oral medications that stimulate insulin production.

However, if all resistance to insulin’s ef­fects could be safely removed, even a dam­aged pancreas could have enough capacity to bring glucose levels back under control or even back to “normal.”

Taking the resistance head-on

The new study, by Ronald Evans from the Salk Institute for Biological Studies and his colleagues, describes a new regulator of the body’s sensitivity to insulin, and identifies a potential target for the treatment of type-2 diabetes. The team studied a protein called Fibroblast Growth Factor 1 (FGF-1 or acid­ic FGF), which is involved in the regulation of many physiological processes, including wound healing, blood-vessel growth, nerve regeneration and fat cell development. Their work shows that FGF-1 may also play a signifi­cant role in reducing insulin resistance.

They found in earlier experiments that mice which were genetically deficient of FGF- 1 developed severe insulin resistance. But in the new study, elevated glucose levels came down when FGF-1 was injected into mice with genetic or diet-induced forms of type-2 diabetes.

Importantly, this glucose-lowering effect was not seen in mice without diabetes, pre­sumably because there was already enough insulin being made to maintain glucose con­trol (and improvements in insulin sensitivity are normally easily offset by reduced insulin production). Also, FGF-1 did not work in mice that did not produce insulin at all (as in un­treated type 1 diabetes), which suggests that FGF-1 specifically works with and through in­sulin to lower glucose levels in diabetes.

However, the key problem with growth factors like FGF-1 is that, among many other functions, they help things to grow, includ­ing some cancers. It is known, for example, that some cancers express high levels of FGF-1 and many grow faster and more ag­gressively in response to FGF-1.

What is most interesting is that when the growth-enhancing part of FGF-1 was re­moved it still improved glucose levels in diabetic mice. This suggests that FGF-1’s growth effects are independent to its ac­tions on insulin sensitivity. This also rais­es the possibility of selective therapeutics without the alarming risk of enhancing cancer.

Of course, translation from mice to clin­ical practice is a challenging task. But this is a promising a start. Clinical trials are al­ready underway to see if FGF-1 can be used to treat conditions ranging from heart dis­ease to spinal damage. Thanks to this work, it looks like diabetes will be next.

DISCLOSURE STATEMENT

Prof Merlin Thomas receives funding from the Australian NHMRC for his research on diabetic complications. He is author of “Understanding Type 2 Diabetes” and the “Baker IDI CSIRO Diabetes Plan”. He has re­ceived honoraria for educational meetings conducted on behalf of pharmaceutical com­panies relevant to the management of dia­betes including Astra-Zeneca, Servier, Sanofi- Aventis, Abbott, Abvie, Boehringer-Ingelhiem, Lilly, Takeda, Merck Sharpe and Dohme and Bristol Meyers Squibb. Baker IDI receives funding as a Member of The Conversation. bakeridi.edu.au

By Merlin Thomas Adjunct Professor of Preventive Medicineat Baker IDI Heart& DiabetesI nstitute/www.theconversation.com