A collection of patients with inherited insulin resistance disorders started Stephen P. O’Rahilly, MD, down a research path that confirmed the activity of leptin in humans, reimagined type 2 diabetes as a metabolic disease driven largely by overnutrition, and began to unravel the mechanism of action behind metformin.

One Sunday morning, Dr. O’Rahilly delivered the 2019 Banting Medal for Scientific Achievement lecture, “Treasure Your Exceptions—Studying Human Extreme Phenotypes to Illuminate Metabolic Health and Disease.”

The key to success in research is spotting the right set of outliers and following the clues they provide, said Dr. O’Rahilly, Director of the University of Cambridge Metabolic Research Laboratories. For him, those outliers were families with extreme forms of inherited insulin resistance. Genetic disorders of insulin signaling can suppress glucogenesis in the liver, affect glycogen accumulation in the liver and muscle tissue, alter glucose uptake in fat and muscle, and more.

Many of these individuals have symptoms that mimic type 2 diabetes, but do not show the traditional signs of metabolic syndrome, Dr. O’Rahilly said. It took looking into lipodystrophies, primary disorders of adipose issue development and function, before he started to see some answers.

Working with genetic data from nearly 200,000 individuals, Cambridge researchers uncovered 53 single nucleotide polymorphisms for insulin resistance. All had adipose tissue as their site of action.

“The GWAS (genome-wide association study) analysis was hypothesis free,” Dr. O’Rahilly said. “Adipose tissue spoke to us spontaneously. It was not forced by our methods.”

While the SNPs are active in fat, they are associated with lower body fat percentage, Dr. O’Rahilly noted. Many of those genes influence fat-cell differentiation and are associated with waist-hip ratio. Most downregulate activin receptor-like kinase 7 (Alk7).

Impaired adipose tissue, not inflammation, could be the major link between overeating and insulin resistance, Dr. O’Rahilly noted. And inhibiting Alk7 may protect against the metabolic consequences of overnutrition, including type 2 diabetes.

Defects in the conversion of prohormones such as proinsulin and proglucagon also plays a role in obesity. Starting with a single patient with recurrent severe reactive hypoglycemia, Dr. O’Rahilly’s lab identified human leptin deficiency as a genetic cause of obesity. Other genes linked with obesity soon followed. Obesity-related genes are highly expressed in the brain, especially in the hypothalamus.

Leptin is not effective as a weight-loss drug in individuals with normal physiologic levels, Dr. O’Rahilly noted, but there are other targets. Growth/differentiation factor 15 (GDF15) climbs during high levels of stress from some diseases, upon exposure to toxins, during aging, and in other conditions. One notable effect is appetite suppression. GDF15 shows promise as an appetite suppressant for weight loss, and it may play a role in metformin activity.

Metformin is known to reduce body weight, primarily adipose mass. Metformin also disrupts mitochondrial respiration and increases GDF15 expression in the distal intestine and the kidney. With their normal fuel supply disrupted by mitochondrial dysfunction, cells use glucose as a primary energy source, resulting in weight loss and improved insulin sensitivity, Dr. O’Rahilly said.