Novel Risk Factors for Type 2 Diabetes

Sleep apnea, second-hand smoking exposure, and fetuin-A
August 2012, Vol 5, No 5, Special Issue ADA 2012 Highlights
Mary Mosley

Several presentations at the 2012 ADA annual meeting focused on new risk factors for diabetes, independent of obesity, that were found in recent studies; these risk factors are obstructive sleep apnea (OSA), exposure to second-hand smoking, and the hepatokines fetuin-A.

Obstructive Sleep Apnea and Diabetes
OSA and type 2 diabetes are major obesity-associated diseases that coexist in the same individuals with insulin resistance. A recent meta-analysis showed a positive relationship between OSA and the risk for diabetes, independent of obesity. Furthermore, OSA was shown to cause diabetes, said Kazuya Fujihara, MD, Department of Internal Medicine, University of Tsukuba Institute of Clinical Medicine, Japan.

Because of the strength of the association between OSA and type 2 diabetes, Dr Fujihara and colleagues conducted a systematic review of cross-sectional and longitudinal studies to investigate whether this association is dependent on obesity. In addition, the causal nature of this relationship was not clear from the available cohort studies.

A total of 41,813 patients were included in the 17 cross-sectional studies identified for this systematic review; of these, 2513 patients had type 2 diabetes and 6524 had OSA. Compared with mild OSA, the patients with severe OSA had a 91% increased risk of type 2 diabetes.

Even after adjusting for obesity, the risk for diabetes in people with OSA remained high (odds ratio [OR], 2.03). When instrumentation rather than questionnaires was used to ascertain OSA, the risk for diabetes was even higher (OR, 2.59 vs 1.56, respectively).

To determine the causal relationship between diabetes and OSA, Dr Fujihara and colleagues examined the data from 11 studies with nearly 38,500 patients. Results showed that severe OSA significantly predicted the risk of developing type 2 diabetes (OR, 1.99). However, having diabetes did not significantly predict the risk of future OSA (OR, 1.03).

Based on these data, said Dr Fujihara, incident diabetes is caused by severe OSA. Conversely, diabetes did not cause OSA. The proposed mechanisms for OSA as causing diabetes include intermittent hypoxia, unhealthy life­styles, or a change in endocrine hormones that contribute to increased insulin resistance, decreased insulin sensitivity, and, ultimately, to a worsening of glycemic control.

All patients with OSA should therefore be screened for diabetes, suggested Dr Fujihara, to facilitate early detection of the disease and initiation of appropriate management.

Second-Hand Smoking and Diabetes
A second study presented at the meeting showed that exposure to second-hand smoking, as measured by serum cotinine levels in never-smokers, is associated with type 2 diabetes in adults in the general population, said Omayma O. Alshaarawy, MBBS, West Virginia University, Morgantown.

Several studies have reported an association between active smoking and diabetes among smokers, but only a few studies have investigated the relationship between environmental tobacco smoking and diabetes in never-smokers. The present study used an objective measure of exposure rather than a self-report as was used in previous studies.

Using data from the National Health and Nutrition Examination Survey (NHANES), Alshaarawy and colleagues studied 8407 participants; of these, 57% were women and 68% were non-Hispanic whites. Their weight was equally distributed across all parts of the spectrum.

NHANES is a nationally representative sample of US adults aged >20 years. The data were adjusted for age, sex, race, and physical activity. The data represented 5 time periods between 1999 and 2008. Persons who were pregnant, had cardiovascular disease, were former or current smokers, or who had missing data on serum cotinine were excluded from the study.

Serum cotinine levels were significantly associated with glycohemo­globin, and the mean change in glycohemoglobin increased with elevations in the cotinine levels.

A significant relationship was found between serum cotinine levels and the development of diabetes; the risk for diabetes increased with elevations in the cotinine levels in the blood.

Cotinine levels in the middle range were associated with a 28% increased risk for diabetes, whereas the highest range of cotinine was associated with a 56% increased risk for diabetes.

The association between second-hand smoke exposure and diabetes risk was stronger in women, non-Hispanic whites, and nonobese persons. Whether this association represents a preventable risk factor requires prospective study.

Fetuin-A, a Hepatokine, and Diabetes
Fetuin-A was identified as a risk factor for diabetes in data from the Nurses’ Health Study in an analysis presented by Qi Sun, MD, SCD, Research Associate, Department of Nutrition, Harvard School of Public Health, Boston.

The liver plays a pivotal role in glucose metabolism. Accumulating evidence shows that the liver produces a group of molecules called hepatokines, including fetuin-A, selenoprotein P, and angiopoietin-like protein 4, which directly regulate glucose sensitivity.

Fetuin-A, also called alpha-2HS-glycoprotein, inhibits insulin receptor activity. A total of 3 previous studies have shown an association between fetuin-A levels and an increased risk of type 2 diabetes, said Dr Sun.

The present study was a prospective, nested, case-control study within the Nurses’ Health Study. The average patient age was 65 years. In 470 women with diabetes, the body mass index was higher at baseline (30 kg/m2), and physical activity was lower than in 470 women without diabetes. The levels of fetuin-A and the liver enzymes alanine aminotransferase (ALT) and gamma-glutamyl peptidase were also elevated in the women with diabetes.

Dr Sun and colleagues found that high plasma fetuin-A levels were significantly associated with an increased risk for developing type 2 diabetes. This association was independent of the established risk factors for diabetes and from the levels of ALT and gamma-glutamyl peptidase.

Overall, the existing data from prospective studies, including the present study, consistently support the hypothesis that fetuin-A is a novel independent risk factor for type 2 diabetes, according to Dr Sun.

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Last modified: September 26, 2012
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