How a rare disorder can lead to possible treatments for type 2 diabetes

by Stefan Bröer

A depiction of the molecule that mediates amino acid absorption in the intestine. The transporter is shown as a golden structure. The parts of the molecule that are mutated are shown in green, blue and red indicating different types of atoms.

Hartnup disorder is a rare disorder that is caused by an inability to absorb the breakdown products of protein digestion, namely amino acids. The disorder is named after the first reported case that showed symptoms similar to pellagra, a deficiency of the vitamin Niacin. Similar to Niacin deficiency, the disorder can be treated through good nutrition.

In 2004, Stefan Bröer’s laboratory discovered the gene that is mutated in Hartnup disorder, a so called transporter that mediates the absorption of amino acids in the intestine and kidney. Further research using a mouse model that replicates the disorder led to the discovery that reduced amino acid absorption causes complex changes in body physiology. On the one hand reduced absorption results in less nutrients coming to the liver. On the other hand amino acids derived from food digestion remain in the intestine for extended periods of time. In the liver the reduction of nutrient intake causes release of hormones that prepare the body for calorie restriction. The intestine, by contrast, releases hormones that tell the body to reduce food intake. Together these effects cause better control of blood glucose and improved fat metabolism. Mice lacking this amino acid transporter also gained less weight on a high-fat diet. These improvements are precisely what is needed to treat metabolic disorders, such as type 2 diabetes and obesity.

In fact the metabolic changes are similar to those observed in gastric bypass surgery, a surgery where the stomach size is reduced and the duodenum is bypassed. This surgery is very successful for the treatment of highly obese individuals with type 2 diabetes, but is also quite an invasive procedure that many patients don’t want to undergo.

Stefan Bröer’s group is now trying to identify compounds that block the transporter. Such compounds could become drugs to treat type 2 diabetes and obesity.

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In 2017, we celebrate 50 years of Biology at ANU. This article is one of a set featuring the achievements and memorable occasions of ANU biologists those first 50 years.
Read more at Biology at ANU – the first 50 years.

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