This web page was produced as an assignment for an undergraduate course at Davidson College.
ARNT - The Type II Diabetes Gene?
permission pending from (http://health.howstuffworks.com/diabetes1.htm)
Popular Press Article - "New Diabetes Gene Discovered" (link)
As with most news articles, readers of this August 14th article from Health24.com should be wary of taking this title at face value. The gene described in this article, ARNT, is by no means new. Suzenne Reisz-Porszasz and collegues characterized the quaternary structure of ARNT over 10 years ago (1994). Not to mention, ARNT certainly has been shown to function in natural response to oxygen deprivation and at least one copy of ARNT is necessary for survival past 10 days in mice (Maltepe et al., 1997). So, this gene is not newly discovered or unifunctional. Fortunately, the content of this article is much more responsibly written than the title implies.
The first line of the article puts the discovery in its proper context. The author states “Scientists have discovered a gene that plays a role in the most common type of type 2 diabetes” (2005). The discovery only exhibited that ARNT is expressed abnormally in the beta cells of people with type 2 diabetes. The same gene, when defective in mice, disrupts insulin secretion. Filled with quotes, this article presents little other than the pure scientific findings and a few ambitious implications.
To its credit, this article goes into more detail about the actual studies conducted than most popular releases. It even highlights the use of a model organism experiment in this study without exaggerating the parallels that can be drawn from results in mice. However, there are a few lines that could give readers false hope for more effective diabetes treatment in the immediate future. The author mentions the possibility of a cure and suggests that scientists could boost the expression of ARNT. No scientist or doctor can reliably predict how far away a cure for type 2 diabetes lies. Boosting the expression of a single gene in only specific cell types is much simpler in theory than application. Such optimistic conclusions probably encourage the average reader, but are not completely realistic.
Scholarly Journal Publication – “Loss of ARNT/HIF1beta Mediates Altered Gene Expression and Pancreatic-Islet Dysfunction in Human Type 2 Diabetes" (link)
The ARNT study was run by Dr. Ronald Kahn of the Harvard Medical School and Joslin Diabetes Center. Dr. Kahn and associates performed their study in two phases. The first phase utilized microarrays to look at the differences in gene expression levels between normal human and type diabetes patient pancreas islet cells. These cells control insulin production. Therefore, scientists suspect that disruptions in the normal islet genome may be responsible for many type 2 diabetes cases. The microarrays showed many genes had decreased expression levels in human diabetic islet cells. Specifically, ARNT expression was decreased by 18% from control levels with a significant p value of 0.000012 (Gunton et al., 2005). This p value showed that the likelihood that these results stemmed from a true difference between diabetic and normal islet cells was over 99%.
In the second phase of the study, the researchers performed experiments on “knockout” mice. These mice were genetically engineered to be completely deficient of functional ARNT. This allowed scientists to characterize ARNT’s function in vivo, or in a living organism. ARNT knockout mice were tested for their response to glucose and insulin secretion levels. The differences between normal and ARNT knockout mice were greater in females than males. Female mice showed significantly decreased serum insulin levels and significantly higher glucose levels after glucose treatment. Male mice of the same genotype showed a similar, though less drastic, difference in glucose tolerance, but exhibited no change in serum insulin levels. Upon extraction and inspection of deficient mice islet cells, however, insulin release in response to increasing glucose concentration was severely and significantly decreased (2005).
The authors of this publication conclude that the ARNT is clearly essential for normal islet cell function. Since many genes showed altered expression patterns, but none more than ARNT, the writers suggest that the protein may be a regulator of other genes affected in type 2 diabetes patients.
This study showed both the recently discovered power of genomics techniques and the continued usefulness of model organism experiments. While this study does not conclusively prove that ARNT defects cause type 2 diabetes, it has paved the way for future research of this disease. Scientists long suspected that problems in pancreatic islet cells are responsible for the development of type 2 diabetes. However, there are many environmental factors associated with the disease, making it difficult to determine the relative roles of nature and nurture in this case.
The Islets of Langerhans are a group of endocrine cells that consititute 1-2% of the human pancreas. They are responsible for the release of insulin and glycogen in response to increases and decreases in blood glucose levels, respectively. Beta cells, specifically, release insulin (WikipediaB, 2005). So, scientists looked at human expression patterns of every known gene in these cells. Genomics microarray techniques made such a powerful comparison relatively simple to conduct. However, the lowered expression levels of ARNT could have been either a cause or an effect of the diabetes condition. Therefore, the more traditional method of model organism study had to be used to test the effect of ARNT inactivation. The ARNT knockout mice experiment showed that loss of the gene has a functional effect on insulin release in response to glucose levels.
Taken together, these two experiments should direct future type 2 diabetes research. Gunton and associates have been effectively shown that deficient ARNT expression can cause the symptoms of type 2 diabetes and that the gene is indeed affected in many people diagnosed with the condition. Functional analysis of ARNT in humans could lead to a better understanding of the condition in humans and perhaps pave the way for future treatment options.
August 2005. Health 24. New Diabetes Gene Discovered. <http://www.health24.com/news/Diabetes/1-904,32845.asp>. Accessed 2005 Sep 12.
Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, Tseng Y, Roberson RS, Ricordi C, O’Connell PJ, Gonzalez FJ, Kahn CR. 2005. Loss of ARNT/HIF1b Mediates Altered Gene Expression and Pancreatic-Islet Dysfunction in Human Type 2 Diabetes. Cell 122:337-349. <http://www.cell.com/content/article/abstract?uid=PIIS0092867405005416>. Accessed 2005 Sep 12.
Maltepe E, Schmidt JV, Baunoch D, Bradfield CA, Simon MC. 1997 Mar. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT [abstract]. In Nature 396(6623):403-7. PubMed MEDLINE. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9121557&query_hl=5>. Acessed 2005 Sep 13.
Reisz-Porszsz S, Probst MR, Fukunaga BN, Hankinson O. 1994. Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT). Molecular Cell Biology 14(9):6075-6086. <http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=8065341>.
Accessed 2005 Sep 13.
Wikipedia A. 2005 Aug 15. Diabetes mellitus type 2. <http://en.wikipedia.org/wiki/Type_2_diabetes>. Accessed 2005 Sep 13.
Wikipedia B. 2005 Sep 8. Pancreas. <http://en.wikipedia.org/wiki/Pancreas>. Accessed 2005 Sep 13.
© 2005 Department of Biology, Davidson College, Davidson, NC 28036
Please direct comments, criticisms and questions to andrysdale "at" davidson.edu