Michael W. Schwartz, MD

Everything you thought you knew about the causes of diabetes is wrong, according to Michael W. Schwartz, MD. Beta-cell dysfunction and insulin resistance are symptoms, not causes. The real problem is dysfunction in the brain, he said.

“Blood glucose levels are elevated in type 2 diabetes, but they are defended in the same ways as in non-diabetic individuals,” said Dr. Schwartz, the Robert H. Williams Endowed Chair in Medicine and Director of the UW Diabetes Institute at the University of Washington. “It’s a brain-specific defect that contributes to the defense of elevated blood glucose in type 2 diabetes. Brain-directed therapeutic strategies can normalize the defended levels of glycemia rather than simply dropping glucose below its defended level on a day-to-day basis.”

Dr. Schwartz proposed this alternative view of blood glucose control during Sunday morning’s ADA Diabetes Symposium on Emerging Therapeutic Targets and Mechanisms of Action. The session’s three presenters will be featured in an upcoming issue of Diabetes.

Dr. Schwartz’ model of type 2 diabetes as a brain defect stems from observations of the effects of fibroblast growth factor 1 (FGF1). A single injection of FGF1 into diabetic mice and rats didn’t just normalize blood glucose levels for a few minutes or hours, but for 18 months, he said.

This sustained normalization of fasting blood glucose is not secondary to changes in weight, fat, or nutrition, Dr. Schwartz added. FGF1 reduces the set point for blood glucose, giving the body a new, lower target to defend. And unlike other diabetes treatments, FGF1 does not induce hypoglycemia.

“If you have a defect in the brain that defends a too-high set point for blood sugar, the islets will have trouble compensating,” he said. “There’s potential to translate the FGF1 story into humans. That work is ongoing now.”

Matthias H. Tschöp, MD, is taking a different direction. His lab is designing single-molecule combinational therapies to treat obesity and diabetes. The goal is to combine glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon receptor agonism in a single molecule.

“Obesity is a brain disease, therefore a cure requires targeting the brain,” said Dr. Tschöp, Research Director at Helmholtz Zentrum München and Professor and Chair of Metabolic Diseases at the Technische Universität Munchen in Munich, Germany. “Targeting the brain indirectly by modulating endogenous gut-brain signals communicating metabolically relevant information may be safer.”

Several pharmaceutical companies are developing GLP-1/glucagon receptor agonists, Dr. Tschöp noted. His research group is working on a triple GIP, GLP-1, and glucagon receptor agent. This unimolecular tri-agonist has shown unprecedented efficacy against obesity and type 2 diabetes, he said.

Dr. Tschöp’s lab is also working on a unimolecular GIP/GLP-1 receptor agonist informally called “twincretin.” This dual-incretin agent maximizes metabolic benefits in rodents, primates, and humans, he said. A 12-week randomized controlled trial showed significant decreases in A1C, body weight, and total cholesterol with no serious adverse events, he added.

“We don’t know the actual duration of effect,” Dr. Tschöp said. “The improvements were continuing at 12 weeks. We didn’t see a plateau effect by the end of the study.”

Genetic studies offer another approach to finding and evaluating new pathways and targets that could be useful in diabetes.

“Diabetes may be more of a syndrome than a single disease,” suggested Jose C. Florez, MD, PhD, Assistant Professor of Medicine at Mass General Hospital. “Genetic studies can help us understand the differences.”

Clinically relevant findings are already emerging. A genetic variant found in about 17 percent of Inuit genomes mediates insulin resistance in skeletal muscle, Dr. Florez explained. Therefore, clinicians with Inuit patients may want to use an oral glucose tolerance test for diagnosis and insulin sensitizers for therapy, he suggested.

Meanwhile, the Metformin Genetics Consortium has found a variant in the glucose transporter gene associated with glycemic response to metformin. A simple genetic screen could identify patients most likely to respond to the agent, Dr. Florez said.

“Genetic discoveries can help us in a myriad of ways to treat diabetes more effectively and with fewer unintended consequences,” he added.