The tantalizing possibility of an injection to help normalize blood glucose without any of the side effects normally associated with such treatment inched closer today, when a group of academic researchers published novel findings in mice that may one day lead to a "shot" for diabetes in humans.
The scientists discovered an unexpected insulin-sensitizing role for human fibroblast growth factor 1 (FGF-1) when it was injected into a group of a dozen mice that were genetically susceptible to obesity and/or diabetes.
Despite there being a whole family of FGF proteins, "only FGF-1 had this unique ability," explained coauthor Michael Downes, PhD, of the Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California. "This was a surprise for the whole field; it is a novel finding," he told Medscape Medical News.
And what's more, the effects appeared to be independent of the mitogenic activity of FGF-1, and the protein did not cause any of the adverse effects normally associated with glucose-lowering therapies for diabetes, such as hypoglycemia and weight gain. Such a therapy could one day replace currently employed injectable diabetes drugs, such as the glucagonlike peptide-1 (GLP-1) agonists and oral medicines used to treat type 2 diabetes, and may even be used in those with type 1 diabetes to reduce their reliance on exogenous insulin, the researchers postulate.
However, Dr. Downes cautioned that the work in rodents will first require replication in monkey studies before moving on to human trials. "I would say give us a year or two to delivery....This is not ready for use in humans yet; we have to do the proper research first," he observed.
The work is published online July 16 in Nature by Jae Myoung Suh, PhD, also of the Salk Institute for Biological Studies, and colleagues.
rFGF-1 Reduces Glucose With No Hypoglycemia
Dr. Downes and another coauthor Maryam Ahmadian, PhD, also from the Salk Institute for Biological Studies, explained to Medscape Medical News the background behind the experiments they performed.
"We discovered FGF-1 in 2012 when looking at hormones in the gut that are involved during feeding, and we found that FGF-1 is required for fat remodeling," said Dr. Downes. He explained that adipose tissue normally has to expand to store fat from food, so if FGF-1 is lacking, "you don't have the ability to remodel and store fat."
FGF-1 is just one of a number of fibroblast growth factors — so far around 23 members of the FGF family have been identified, he noted. Most of them are noncirculating proteins, including FGF-1, which stays where it is expressed: "It's known not to circulate and has a half-life of less than 5 minutes; it's like molecular Velcro, it stays on the surface of the fat cells."
But despite this property, the researchers discovered that a single subcutaneous injection of 0.5-mg/kg recombinant human FGF-1 in the diabetic mice resulted in blood glucose being normalized, a finding that stunned them.
"The major problem [in type 2 diabetes] is insulin resistance. In diabetes, insulin becomes less potent and so you need more and more insulin to get the same effect, and the glucose levels slowly creep up," Dr. Downes explained.
"Many previous studies that injected FGF-1 showed no effect on healthy mice," he said. "However, when we injected it into a diabetic mouse, we saw a dramatic improvement in glucose."
Also, added Dr. Ahmadian, "When we injected the FGF-1, the mice never became hypoglycemic, so there seemed to be an interaction with the insulin; they seemed to be working together."
For this reason, she is hopeful that if use of FGF-1 in humans pans out, there may be a role for reducing reliance on external insulin in type 1 diabetic patients as well as a place in the treatment of type 2 diabetes.
Nonmitogenic Form of FGF-1 Employed
The team then went on to give serial injections of rFGF-1 with 0.5 mg/kg every other day for 35 days. This chronic treatment did not lead the animals to develop any resistance to rFGF-1, and it led to sustained glucose lowering.
"Chronic pharmacological treatment with rFGF-1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization," they note in their paper.
The resulting sustained glucose lowering and insulin sensitization attributed to rFGF-1 "are not accompanied by the side effects of weight gain, liver steatosis, and bone loss associated with current insulin-sensitizing therapies," they add.
Instead, the injections restored the body's own ability to naturally regulate insulin and blood glucose, appearing to keep it within a safe range — effectively reversing the core symptoms of diabetes, they investigators say.
"With FGF-1, we really haven't seen hypoglycemia or other common side effects," says lead author Dr. Suh in a statement. "It may be that FGF-1 leads to a more 'normal' type of response compared with other drugs because it metabolizes quickly in the body and targets certain cell types."
The mechanism of FGF-1 still isn't fully understood — nor is the mechanism of insulin resistance, the team stresses, but they did discover that the protein's ability to stimulate growth is independent of its effect on glucose.
This is important because of the known mitogenicity of FGF-1 (ie, it promotes cell growth), and there could be concern about potential carcinogenic effects of any resulting therapies that are developed.
For this reason, the version of FGF-1 that they employed was truncated "and had no mitogenic function" anyway, they note, adding that, in theory, this form of FGF-1 should be easy to mass produce as it is already made on a large scale, expressed in bacteria.
The next step in the work will be to conduct experiments in monkey models of diabetes. Pinning down the signaling pathways and receptors that FGF-1 interacts with is one of the first questions the team will address.
"This can be done quickly but we need to raise the funding for our academic lab, which will be in the region of $0.5 to $0.75 million," Dr. Downes concluded.
The researchers report no relevant financial relationships.
Nature. Published online July 16, 2014.