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Two Studies Shows Lifestyle Can Alter Gene Activity and Diabetes

Posted: Wednesday, July 30, 2008

Researchers found that lifestyle factors, such as lack of exercise, can change the activity of genes involved in insulin resistance. And also that environment contributes more than heredity to the development of insulin resistance.

The finding comes from a study of monozygotic twins in which one of each pair was obese and the other was not, Linda Mustelin, B.Med., of Helsinki University Central Hospital, and colleagues reported.

Because the genetic make-up of the volunteers is identical, the finding suggests that environment contributes more than heredity to the development of insulin resistance in people who are obese, the researchers said.

Their major discovery is that in the obese twins, the transcription of genes involved in mitochondrial oxidative phosphorylation was decreased, they said.

Defects in oxidative phosphorylation in mitochondria have been proposed as a central feature in the pathophysiology of familial insulin resistance, they noted.

At the same time, they said, the obese twins were less physically active than their brothers or sisters and had lower insulin sensitivity.

"These data suggest that physical inactivity may have contributed to the defects in mitochondrial oxidative phosphorylation described in type 2 diabetic patients and prediabetics," the researchers said.

They studied participants in the long-running FinnTwin16 cohort, a population-based, longitudinal study of five consecutive birth cohorts of twins, as well as their siblings and parents. The earliest participants were born in 1975 and the latest in 1979.

In the cohort, they found 14 pairs of twins in which one had a normal body mass index (25, on average) and the other was obese (with an average body mass index of 30). They also studied 10 pairs of twins whose body mass index was not discordant.

The researchers measured whole body insulin sensitivity using the euglycemic hyperinsulinemic clamp technique. They used microarray data from fat biopsies to determine transcription profiles of mitochondrial genes.

They also measured the twins' body composition using dual-energy x-ray absorptiometry (DEXA). Maximal oxygen uptake (VO2max) and working capacity (Wmax) were studied using a bicycle ergometer exercise test with gas exchange analysis.

The researchers found that the obese twins:

Had significantly lower insulin sensitivity than their non-obese counterparts. Their M-value was 6.1 milligrams per kilogram of lean body mass versus 9.2, a difference that was significant at P<0.01.
Had significantly lower (P<0.05) transcription of genes involved in the oxidative phosphorylation pathway in adipose tissue.
Were less fit. They had a VO2max of 50.6 milliliters per kilogram of lean body mass per minute, compared with 54.2 for their non-obese siblings, and a Wmax of 3.9 watts per kilogram of lean body mass versus 4.4. The differences were significant at P<0.05 and P<0.01, respectively.
Were less active, as measured on the Baecke leisure-time physical activity index, where the obese twins scored 2.8 on average, compared with 3.3, which was significant at P<0.01.

The researchers concluded that the changes in gene activity resulted from a cascade of environmental factors, starting with physical inactivity, which led to obesity, lower fitness, and decreased insulin sensitivity.

Practice Pearls:

Explain to interested patients that defects in the expression of some genes are thought to underlie the development of insulin resistance in the obese, but the cause of such defects is not known.
Note that this study suggests that lifestyle factors, such as lack of physical activity, can alter the activity levels of such genes.

Source: Diabetes In Control: Am J Physiol Endocrinol Metab: Mustelin L, et al "Acquired obesity and poor physical fitness impair expression of genes of mitochondrial oxidative phosphorylation in monozygotic twins discordant for obesity" Am J Physiol Endocrinol Metab 2008; DOI: 10.1152/ajpendo.00580.2007.