Insulin is a hormone that helps control glucose (blood sugar) levels in the blood, which tend to increase after meals. People suffering from type-2 diabetes are resistant to the glucose-lowering effects of insulin. Few medicines can safely reduce this insulin resistance. But new research on mice, just published in the journal Nature, has found a target that might help develop a more effective treatment.
High on sugar
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.