Overcoming the obstacles of diagnosing diabetes in Asian Americans

Several years ago both of my parents were identified as being at risk for developing type II diabetes. Diagnosing my parents was an easy call for their doctors to make since both of them exhibited many of the tell-tale signs: moderate obesity, advanced age, high blood pressure, high cholesterol, and a sedentary lifestyle. They are also Asian, which dramatically increases their risk of developing type II diabetes(1). While somewhere around 10% of the Asian American population are diabetic, 90-95% of these cases are type II diabetes. My parents’ doctors primarily recommended lifestyle changes including more exercise and dietary modifications. The latter consisted namely of cutting back on that linchpin of Vietnamese cuisine, white rice, which has been proposed to increase the risk of type II diabetes (2). Unlike my parents’ situation, however, diagnosing diabetes in many Asian Americans turns out to be not so simple.

Diabetes is a complex metabolic disease characterized by the inability to regulate blood glucose levels and is associated with a host of health problems including cardiovascular disease, kidney failure, and retinal damage. Complications from diabetes can lead to ketoacidosis and, more seriously, coma or death. Normally, blood glucose levels are regulated by insulin, a hormone produced by β cells in the pancreas. When blood glucose levels get too high, insulin is released into the blood stream and triggers cells to siphon glucose levels from the blood, thereby restoring normal levels of blood glucose. There are two types of diabetes: type I and type II, both of which negatively affect this balancing act between insulin and glucose. Type I diabetes is characterized by the lack of insulin, which is often due to autoimmunity that destroys the pancreatic β cells that make the hormone. Type II diabetes, on the other hand, presents when cells in the body become resistant to insulin and do not respond properly to the presence insulin. The accurate diagnosis of type I and type II diabetes is important to the health of the individual since treatment can vary.

There is a difficulty in diagnosing diabetes in Asian Americans that stems from the fact that many of the clinical features and risk factors associated with type I and type II diabetes, characterized largely from studies in Caucasian populations, do not apply to Asian Americans. For instance, the genetic variants and autoimmune antibodies typically associated with type I diabetes in Caucasians are uncommon in individuals of Asian descent. Obesity, which is strongly associated with insulin resistance and type II diabetes in Caucasian populations, is an unreliable predictor for Asian Americans since type II diabetes tends to develop in Asian Americans at lower body weights. Furthermore, many Asian Americans with type II diabetes are diagnosed at a younger age and are not overweight–features that are more generally associated with type I diabetes. Importantly, this clinical ambiguity can lead to misdiagnoses between type I and type II diabetes for Asian Americans.

An important feature of type II diabetes is insulin resistance, whereby cells require a higher dose of insulin in order to be coaxed to take up glucose from the blood. Previous studies have indicated that non-diabetics of Asian descent tend to be more insulin resistant than their non-diabetic Caucasian counterparts. This suggests that Asian Americans have a higher predisposition to developing type II diabetes. The degree of insulin resistance might provide a reliable way to differentiate between the type types of diabetes since it is a hallmark of type II diabetes and not type I diabetes.  However, whether type I diabetic Asian Americans are as insulin resistant as those with type II diabetes remains to be tested. All of these concerns, coupled with a rapidly growing Asian American population, represents a significant public health challenge for the Asian American community. It underscores the pressing need to identify reliable criteria and risk factors that define type I and type II diabetes in Asian Americans.

To address these problems, Dr. William Hsu of the Joslin Diabetes Center led a pilot study aimed at characterizing the clinical features that define type I and II diabetes in Asian Americans. The researchers focused on identifying potential biomarkers that would distinguish type I from type II diabetes in Asian Americans as well as determining the level of insulin resistance present in Asian Americans diagnosed with either type I or type II diabetes. The study was conducted on a group of 30 volunteers that consisted of individuals diagnosed with either type I or type II diabetes as well as non-diabetics, all of which were of East Asian descent (Chinese, Korean, and Japanese). The results of the study were published in PLOS One last year (3).

Researchers measured blood levels of various factors associated with metabolism, insulin release, and inflammation in all three groups. They found that levels of the metabolism-associated factors adiponectin and HDL cholesterol were higher in Asian Americans with type I diabetes versus type II diabetes. In contrast, the levels of free fatty acids and C-peptide, a factor associated with insulin release, were lower in Asian Americans with type I diabetes than those with type II diabetes. The presence C-peptide is particularly interesting because it suggests that insulin is still being produced in some type I diabetics, albeit at much lower levels. Insulin is processed from a larger precursor molecule and one of the side products from this processing is C-peptide. These results point to the possibility of using these factors as diagnostics to differentiate type I and type II diabetes specifically in Asian Americans.

Insulin is processed from a larger precursor known as preproinsulin. The first step in processing is the removal of the signal peptide followed by the removal of C-peptide (chain C).

The researchers then sought to determine whether or not there were any differences in insulin resistance between the groups. They used a procedure called a “hyperinsulinemic euglycemic clamp” to measure insulin resistance. To do this, researchers injected a high dose of insulin into the study participants to induce hyperinsulinaemia, a state in which the amount of circulating insulin is in excess of blood glucose levels. This triggers cells to take up glucose and blood glucose levels to drop. A sugar solution is then infused intravenously to restore normal blood glucose levels. Blood glucose levels are monitored continuously while simultaneously measuring the rate of sugar infusion required to maintain normal blood glucose levels. If a person is insulin resistant then their blood glucose levels would drop only slightly due to the initial injection of insulin and, consequently, would only need a low rate of glucose infusion to restore blood glucose to normal levels. A low glucose infusion rate is, therefore, indicative of insulin resistance.

The researchers found that insulin resistance in type II diabetics was significantly higher than in type I diabetics and non-diabetics, while the level of insulin resistance between type I diabetics and non-diabetics were comparable. Since differences in insulin resistance between type I and type II diabetes in Asian Americans were previously unmeasured, this result indicated that insulin resistance might be another criterion for distinguishing between the two types of diabetes. This result also has implications in the treatment of diabetes in Asian Americans. Since type II diabetes is generally associated with obesity, weight loss is often prescribed. Paradoxically, as mentioned earlier, Asian Americans can develop type II diabetes independently of obesity, meaning weight loss for Asian Americans with type II diabetes might prove to be ineffective. This highlights the need for future studies of treatments that specifically focuses on targeting insulin resistance rather than weight management in Asian Americans with type II diabetes.

Lastly, the researchers analyzed the relationship between insulin resistance and the biomarkers measured from participants’ blood. They found a correlation between levels of the protein A-FAPB (adipocyte fatty acid binding protein, a protein involved in fat metabolism and inflammation) and insulin resistance in the control group but not with any of the diabetic groups. In other words, non-diabetics that displayed higher insulin resistance relative to other non-diabetics had higher levels of A-FABP in their blood. A-FAPB is of particular interest as a previous study involving individuals of Chinese descent indicated that levels of A-FAPB predicted the occurrence of type II diabetes in this population (4). Furthermore, in a mouse model, mice deficient for A-FAPB are protected against developing type II diabetes (5). Because insulin resistance is strongly associated with type II diabetes and A-FAPB correlates with insulin resistance only in the non-diabetic control group, the researchers hypothesize that A-FAPB might prove to be a valuable biomarker for identifying Asian American individuals at risk for developing type II diabetes. Their data suggests, however, that A-FAPB could only be used prior to the development of diabetes since the correlation between A-FAPB levels and insulin resistance unravels in both diabetic groups.

While the results of the pilot study reveal some promising leads in establishing reliable criteria for diagnosing type I and type II diabetes in Asian Americans, the researchers  caution that studies involving more participants will be required to confirm their findings. In particular, the A-FAPB results will require a more extensive study whereby individuals with insulin resistance will be studied over time to measure A-FAPB levels and development of type II diabetes. The researchers hypothesize that the correlation between A-FAPB levels and insulin resistance will unravel with the onset of diabetes. Additionally, while the study measured the insulin resistance in type II diabetics, it did not address β cell function (insulin production) in Asian Americans with type II diabetes. One of the treatment strategies for type II diabetes put forth in the paper is to target insulin resistance, but this might be ineffective if β cell function is impaired. Finally, since the study only focused on individuals of East Asian heritage, it remains to be seen if these results are also representative of the South Asian, Southeast Asian, and Pacific Islander communities in the US.
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Calgary Reviews

Beta Cell Biology Consortium

1. Lee JW, Brancati FL, Yeh HC. Trends in the prevalence of type 2 diabetes in Asians versus whites: results from the United States National Health Interview Survey, 1997-2008. Diabetes Care. 2011 Feb;34(2):353-7. Epub 2011 Jan 7. PubMed PMID: 21216863; PubMed Central PMCID: PMC3024348.

2. Hu EA, Pan A, Malik V, Sun Q. White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review. BMJ. 2012 Mar 15;344:e1454. doi: 10.1136/bmj.e1454. Review. PubMed PMID: 22422870; PubMed Central PMCID: PMC3307808.

3. Hsu WC, Okeke E, Cheung S, Keenan H, Tsui T, Cheng K, King GL. A cross-sectional characterization of insulin resistance by phenotype and insulin clamp in East Asian Americans with type 1 and type 2 diabetes. PLoS One. 2011;6(12):e28311. Epub 2011 Dec 2. PubMed PMID: 22164267; PubMed Central PMCID:  PMC3229556.

4. Tso AW, Xu A, Sham PC, Wat NM, Wang Y, Fong CH, Cheung BM, Janus ED, Lam KS. Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort.  Diabetes Care. 2007 Oct;30(10):2667-72. Epub 2007 Jul 9. PubMed PMID: 17620449.

5. Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM. Uncoupling of obesity from insulin resistance through a targeted mutation in  aP2, the adipocyte fatty acid binding protein. Science. 1996 Nov 22;274(5291):1377-9. PubMed PMID: 8910278.


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