Environmental Factor, January 2010, National Institute of Environmental Health Sciences
Kahn Gives Hans L. Falk Memorial Lecture
By Robin Arnette
Each year scientists from the NIEHS Division of Intramural Research (DIR)(http://www.niehs.nih.gov/research/atniehs/index.cfm) set aside one of the distinguished guest lectureships to honor their first Scientific Director Hans L. Falk, Ph.D. The lecture series features investigators who have made significant contributions to environmental health sciences research. This year's speaker, C. Ronald Kahn, M.D., presented "Genes and Environment in the Epidemic of Diabetes and Obesity." DIR Deputy Scientific Director Bill Schrader, Ph.D., hosted the Dec. 8 event.
Kahn(http://www.joslinresearch.org/LabSites/Kahn/KahnLabHome.asp) noted that the average number of new cases of diabetes in the U.S. increases by one million people each year. The factor that bridges both diabetes and obesity is insulin resistance - a condition in which fat, muscle, and liver cells don't use insulin properly. Insulin resistance is also a problem for a group of disorders collectively known as metabolic syndrome (see text box).
Although he believes that genes play a vital role in these illnesses, Kahn considers the environment to be more of a factor. "While 30,000 genes may be involved, there must be 300,000 or three million environmental impact factors," he maintained. "The environment will interact with these genes in subtle, sometimes overt, ways."
Identifying the relationship between genes and the environment
In a non-diabetic, insulin turns off glucose production in the liver and stimulates glucose uptake in muscle tissue and fat, resulting in lower blood glucose levels. However, in a person with type 2 diabetes or metabolic syndrome, the liver, muscle, and fat are insulin resistant, which means insulin no longer turns off hepatic glucose production, and fails to stimulate glucose uptake in muscle and fat. As a result, glucose levels in the blood increase, and cells have altered metabolism.
To study the interaction between genes and the environment in insulin resistance and metabolic syndrome, Kahn's lab used multiple mouse models, three of which he discussed in the lecture - a tissue specific knockout mouse lacking insulin signaling in the liver, two natural strain variants, and a single normal mouse strain with a modified essential amino acid in its diet.
The liver insulin-resistant knockout (LIRKO) mice constituted the tissue specific knockout model. Because the LIRKO mouse had an inactivated insulin receptor gene in its liver, the liver couldn't sense insulin and behaved like the liver of a diabetic animal. The LIRKO mice exhibited a diabetic glucose tolerance curve, but normal blood cholesterol levels. When Kahn modified the environment by switching the diet of LIRKO mice from low fat to high fat, they developed extensive atherosclerosis and experienced a dramatic increase in serum cholesterol, from 70 to 700 milligrams per deciliter (mg/dl).
In the second group of studies, Kahn investigated the difference between C57Bl/6 mice and 129/Sv mice subjected to a high fat diet or to genetic defects in insulin signaling. In both cases, the C57Bl/6 mice demonstrated more severe insulin resistance and, in the case of the genetic defects, resulted in 90 percent of the C57Bl/6 mice developing diabetes within six months. Only 10 percent of the 129/Sv mice manifested the disease. A Gene Network Analysis determined that one of the most important differences was the inflammatory response genes in the adipose tissue of C57Bl/6 mice, which exhibited increased expression with age or high-fat diet, while the inflammatory genes of 129/Sv mice didn't show an increase. This finding is important because inflammation and the response to inflammation is part of what creates insulin resistance.
To answer whether changing a single nutrient could impact insulin resistance and obesity, Kahn split C57Bl/6 mice into three feeding groups over a 12-week period: low fat, high fat and high fat with double the amount of the amino acid leucine. Mice that ingested the double amount of leucine had improved insulin signaling and glucose tolerance, as well as reduced inflammation and fat.
Kahn concluded, "If one little amino acid can do this much to metabolism, think of what the other three million things in the environment can do regarding signaling and metabolic syndrome."