Heredity Strongly Influences Insulin Clearance

Insulin clearance is a highly heritable trait that has now been tracked to specific regions of two chromosomes, a finding that may have important implications for risk assessment in diabetes, polycystic ovary syndrome, and the metabolic syndrome.

Although it has been “virtually neglected” in studies of insulin metabolism, insulin clearance may strongly impact an individual's risk of diabetes and response to the diabetic state, Dr. Mark Goodarzi reported at the Western regional meeting of the American Federation for Medical Research in Carmel, Calif.

In previous work, Dr. Goodarzi and associates had raised the possibility that the metabolic clearance rate of insulin was largely an inherited trait, because of patterns seen in a cohort of 403 Mexican American subjects (Diabetes 2005;54:1222–7).

Their current study of a second cohort of 536 individuals from 162 Hispanic families found that insulin clearance was indeed a highly heritable trait, with an age-, sex-, and body mass index-adjusted heritability rate of 70.5%.

A genome-wide linkage scan applied to samples from the same population identified candidate regions on chromosomes 15 and 20 that may harbor genes influencing insulin clearance, Dr. Goodarzi in an interview.

Insulin clearance is a relatively unknown player in the sequence of events leading to diabetes.

A recent Medline search revealed more than 35,000 references to insulin resistance, more than 16,000 references to insulin secretion, but just 424 references to insulin clearance.

Although underappreciated, insulin clearance may prove to have an important role as a marker of risk or a target for intervention not only for diabetes, but for other disorders characterized by hyperinsulinemia, such as polycystic ovary syndrome.

“It appears that a reduction in insulin clearance may be a compensatory response to the insulin resistant state, acting in concert with increased insulin secretion to increase insulin levels,” Dr. Goodarzi explained.

“If insulin levels increase sufficiently, the insulin resistance may be overcome and blood sugars will be maintained in the normal range. However, if there is a failure to adequately increase insulin levels in the face of insulin resistance (either by failing to increase insulin secretion, or, theoretically, failing to reduce insulin clearance), then diabetes will develop,” said Dr. Goodarzi, associate director of the division of endocrinology at Cedars-Sinai Medical Center, Los Angeles.

To test for heritability, subjects were drawn from the offspring generation within MA-HTN, a Mexican American Hypertension study of 939 subjects from 162 families.

Mexican Americans were chosen for the study because of their high prevalence of insulin resistance and high age-specific prevalence of the metabolic syndrome.

Euglycemic clamps were used to measure insulin sensitivity and clearance, keeping the insulin infusion rate steady for all subjects and obtaining a direct measure of insulin clearance via steady state plasma insulin (SSPI) levels achieved during the clamp study.

Once it was determined that more than 70% of the variation in insulin clearance was due to genetic factors, a genome-wide linkage scan utilizing 388 microsatellites resulted in the discovery of SSPI linkages on chromosomes 15 and 20.

Dr. Joseph M. Vinetz, AFMR western section president, said in a telephone interview that Dr. Goodarzi's study had the potential of “optimizing care in the exploding epidemic of type 2 diabetes,” with “huge ramifications for early prevention throughout society.”

To date, genetic studies of diabetes, insulin resistance, insulin secretion, and insulin clearance “have not yet translated to clinically useful tools,” said Dr. Goodarzi.

However, he predicted that the time is not far off—perhaps 5–10 years—when such a link can be made, perhaps by influencing clinical outcomes by implementing interventions once individuals at risk are identified through genetic testing.

Dr. Goodarzi and his associates did not disclose any conflicts of interest regarding their research.

To date, genetic studies of diabetes and insulin resistance have not yet translated to useful tools. DR. GOODARZI

Insulin clearance is a highly heritable trait that has now been tracked to specific regions of two chromosomes, a finding that may have important implications for risk assessment in diabetes, polycystic ovary syndrome, and the metabolic syndrome.

Although it has been “virtually neglected” in studies of insulin metabolism, insulin clearance may strongly impact an individual's risk of diabetes and response to the diabetic state, Dr. Mark Goodarzi reported at the Western regional meeting of the American Federation for Medical Research in Carmel, Calif.

In previous work, Dr. Goodarzi and associates had raised the possibility that the metabolic clearance rate of insulin was largely an inherited trait, because of patterns seen in a cohort of 403 Mexican American subjects (Diabetes 2005;54:1222–7).

Their current study of a second cohort of 536 individuals from 162 Hispanic families found that insulin clearance was indeed a highly heritable trait, with an age-, sex-, and body mass index-adjusted heritability rate of 70.5%.

A genome-wide linkage scan applied to samples from the same population identified candidate regions on chromosomes 15 and 20 that may harbor genes influencing insulin clearance, Dr. Goodarzi in an interview.

Insulin clearance is a relatively unknown player in the sequence of events leading to diabetes.

A recent Medline search revealed more than 35,000 references to insulin resistance, more than 16,000 references to insulin secretion, but just 424 references to insulin clearance.

Although underappreciated, insulin clearance may prove to have an important role as a marker of risk or a target for intervention not only for diabetes, but for other disorders characterized by hyperinsulinemia, such as polycystic ovary syndrome.

“It appears that a reduction in insulin clearance may be a compensatory response to the insulin resistant state, acting in concert with increased insulin secretion to increase insulin levels,” Dr. Goodarzi explained.

“If insulin levels increase sufficiently, the insulin resistance may be overcome and blood sugars will be maintained in the normal range. However, if there is a failure to adequately increase insulin levels in the face of insulin resistance (either by failing to increase insulin secretion, or, theoretically, failing to reduce insulin clearance), then diabetes will develop,” said Dr. Goodarzi, associate director of the division of endocrinology at Cedars-Sinai Medical Center, Los Angeles.

To test for heritability, subjects were drawn from the offspring generation within MA-HTN, a Mexican American Hypertension study of 939 subjects from 162 families.

Mexican Americans were chosen for the study because of their high prevalence of insulin resistance and high age-specific prevalence of the metabolic syndrome.

Euglycemic clamps were used to measure insulin sensitivity and clearance, keeping the insulin infusion rate steady for all subjects and obtaining a direct measure of insulin clearance via steady state plasma insulin (SSPI) levels achieved during the clamp study.

Once it was determined that more than 70% of the variation in insulin clearance was due to genetic factors, a genome-wide linkage scan utilizing 388 microsatellites resulted in the discovery of SSPI linkages on chromosomes 15 and 20.

Dr. Joseph M. Vinetz, AFMR western section president, said in a telephone interview that Dr. Goodarzi's study had the potential of “optimizing care in the exploding epidemic of type 2 diabetes,” with “huge ramifications for early prevention throughout society.”

To date, genetic studies of diabetes, insulin resistance, insulin secretion, and insulin clearance “have not yet translated to clinically useful tools,” said Dr. Goodarzi.

However, he predicted that the time is not far off—perhaps 5–10 years—when such a link can be made, perhaps by influencing clinical outcomes by implementing interventions once individuals at risk are identified through genetic testing.

Dr. Goodarzi and his associates did not disclose any conflicts of interest regarding their research.

To date, genetic studies of diabetes and insulin resistance have not yet translated to useful tools. DR. GOODARZI

Insulin clearance is a highly heritable trait that has now been tracked to specific regions of two chromosomes, a finding that may have important implications for risk assessment in diabetes, polycystic ovary syndrome, and the metabolic syndrome.

Although it has been “virtually neglected” in studies of insulin metabolism, insulin clearance may strongly impact an individual's risk of diabetes and response to the diabetic state, Dr. Mark Goodarzi reported at the Western regional meeting of the American Federation for Medical Research in Carmel, Calif.

In previous work, Dr. Goodarzi and associates had raised the possibility that the metabolic clearance rate of insulin was largely an inherited trait, because of patterns seen in a cohort of 403 Mexican American subjects (Diabetes 2005;54:1222–7).

Their current study of a second cohort of 536 individuals from 162 Hispanic families found that insulin clearance was indeed a highly heritable trait, with an age-, sex-, and body mass index-adjusted heritability rate of 70.5%.

A genome-wide linkage scan applied to samples from the same population identified candidate regions on chromosomes 15 and 20 that may harbor genes influencing insulin clearance, Dr. Goodarzi in an interview.

Insulin clearance is a relatively unknown player in the sequence of events leading to diabetes.

A recent Medline search revealed more than 35,000 references to insulin resistance, more than 16,000 references to insulin secretion, but just 424 references to insulin clearance.

Although underappreciated, insulin clearance may prove to have an important role as a marker of risk or a target for intervention not only for diabetes, but for other disorders characterized by hyperinsulinemia, such as polycystic ovary syndrome.

“It appears that a reduction in insulin clearance may be a compensatory response to the insulin resistant state, acting in concert with increased insulin secretion to increase insulin levels,” Dr. Goodarzi explained.

“If insulin levels increase sufficiently, the insulin resistance may be overcome and blood sugars will be maintained in the normal range. However, if there is a failure to adequately increase insulin levels in the face of insulin resistance (either by failing to increase insulin secretion, or, theoretically, failing to reduce insulin clearance), then diabetes will develop,” said Dr. Goodarzi, associate director of the division of endocrinology at Cedars-Sinai Medical Center, Los Angeles.

To test for heritability, subjects were drawn from the offspring generation within MA-HTN, a Mexican American Hypertension study of 939 subjects from 162 families.

Mexican Americans were chosen for the study because of their high prevalence of insulin resistance and high age-specific prevalence of the metabolic syndrome.

Euglycemic clamps were used to measure insulin sensitivity and clearance, keeping the insulin infusion rate steady for all subjects and obtaining a direct measure of insulin clearance via steady state plasma insulin (SSPI) levels achieved during the clamp study.

Once it was determined that more than 70% of the variation in insulin clearance was due to genetic factors, a genome-wide linkage scan utilizing 388 microsatellites resulted in the discovery of SSPI linkages on chromosomes 15 and 20.

Dr. Joseph M. Vinetz, AFMR western section president, said in a telephone interview that Dr. Goodarzi's study had the potential of “optimizing care in the exploding epidemic of type 2 diabetes,” with “huge ramifications for early prevention throughout society.”

To date, genetic studies of diabetes, insulin resistance, insulin secretion, and insulin clearance “have not yet translated to clinically useful tools,” said Dr. Goodarzi.

However, he predicted that the time is not far off—perhaps 5–10 years—when such a link can be made, perhaps by influencing clinical outcomes by implementing interventions once individuals at risk are identified through genetic testing.

Dr. Goodarzi and his associates did not disclose any conflicts of interest regarding their research.

To date, genetic studies of diabetes and insulin resistance have not yet translated to useful tools. DR. GOODARZI