With Alan R. Saltiel, MD, Elif Oral, MD, and commentary by Caroline Apovian, MD
Growing evidence points to an inflammatory link between obesity and type 2 diabetes (T2D), but the underlying molecular events responsible for this interaction remain unclear.1-3 Obesity produces a state of low-grade inflammation, particularly in the liver and in adipose cells.
Building on earlier findings that local inflammation is a key step in the evolution of insulin resistance, researchers sought to discover whether amlexanox, a little known anti-inflammatory drug indicated for allergy and asthma, could improve insulin resistance in people with diabetes.4
In an animal model, amlexanox was identified as a potential metabolic therapy by Saltiel laboratory, demonstrating that this drug was a selective inhibitor of two kinases that were over-expressed in obese rodents.1
Researchers led by Alan R. Saltiel, MD, professor of medicine at the University of California at San Diego School of Medicine, showed that amlexanox induced a statistically significant reduction in hemoglobin A1c (HbA1c) and fructosamine, another measure of blood glucose over time, in a subset of obese individuals with T2D and nonalcoholic fatty liver disease.4 These responders also showed improvements both in insulin sensitivity and hepatic steatosis.
In this proof-of-concept study,4 the findings from 42 obese patients with T2D who were followed for 12 weeks was published in Cell Metabolism. Half the patients were randomized to receive amlexanox, while the other half received a placebo. Blood sugar, insulin sensitivity, weight, and liver fat were measured and a biopsy of adipose cells from each patient’s midsection was taken before and after the trial to ascertain whether any changes in gene expression occurred.
“Interestingly, not everyone responded to amlexanox to the same degree,” Elif Oral, MD, associate professor of medicine at the University of Michigan Medical School in Ann Arbor, told EndocrineWeb.
“About 35% of patients had a remarkable response in a short timeframe of 12 weeks, in our placebo- controlled study.4 We saw that these patients had more inflammation in the fat tissue and also had higher C-reactive protein (CRP) levels at baseline,” Dr. Oral said.
These levels correlated with the reduction in HbA1c at the end of the amlexanox treatment, while there was no similar response in placebo-treated patients,4 according to the authors. Baseline CRP was also positively correlated with BMI, percent of adiposity, and percent of liver fat, supporting the connection between serum CRP and obesity-related inflammation.
Using next generation RNA-sequencing analysis, the researchers compared gene expression in the fat cells of responders and nonresponders prior to drug treatment to identify a molecular signature of responders.
We found that responders’ cells were characterized by a distinct inflammatory gene expression signature, which indicated a potential difference in the inflammatory state of the subcutaneous fat cells prior to treatment, said Dr. Saitiel, After treatment with amlexanox, nonresponders showed virtually no gene changes, but the responders showed a unique pattern of changes in the expression of more than 1,000 genes
“It may be that some patients who have higher inflammation may activate their relevant pathway more, and therefore are better responders. If we can show that in a prospective manner, this will be very exciting,” Dr. Oral told EndocrineWeb. Amlexanox is an inhibitor of the inflammatory kinases IKKε and TBK1.
As evidenced by elevated levels of CRP at baseline,4 the group who responded most had increased inflammation in adipose tissue, which resulted in overexpression of these counter-inflammatory kinases, which were produced in response to inflammation but worsened the patient’s insulin resistance, Dr. Saltiel said.
“We now postulate that for the first time, we can identify potential responders by selecting those that have a higher CRP level at baseline or by evaluating the inflammation in adipose tissue. This would be another way of personalizing diabetes therapy,” said Dr. Oral, The subgroup also showed that amlexanox appeared to “rev up energy expenditure genes in the fat tissue. We think if we use other drugs in combination with amlexanox that activate the adrenergic system in adipose tissue, we can increase the weight loss effect of the drug.”
“This is a landmark study,” commented Caroline Apovian, MD, director of the Nutrition and Weight Management Center at Boston Medical Center, and professor of medicine at Boston University School of Medicine, to EndocrineWeb, “because it will help obesity medicine specialists and endocrinologists identify obese patients who are most likely respond to this drug using subcutaneous fat biopsies.”
Biopsied adipose tissue at baseline showed a pattern of gene expression indicative of inflammation and changes in gene expression in response to amlexanox that are consistent with increased energy expenditure.4 The study findings suggest that inhibitors of inflammatory kinases offer promise as effective therapies for metabolic disease in a subset of patients who are obese.
Patients with a BMI over 30 and significant visceral obesity would be the primary target for early intervention, said Dr. Apovian, and amlexanox could help prevent diabetes and fatty liver disease in these patients.
“While using amlexanox in patients is not yet ready for prime time, these results show that subcutaneous fat biopsies have great predictive value,” Dr. Apovian.
"As far as I know, [next generation sequencing] has never been done before in an early clinical trial, and represents the future of personalized medicine approaches," said Dr. Saitel, "We continue to pour over this sequencing data, and are still identifying interesting new clusters of gene changes that are likely to reveal further insights into these molecular targets, and about the heterogeneity of type 2 diabetes."