The main underlying cause of type 2 diabetes mellitus is a decline in the normal function of the insulin producing beta cells in the pancreas. The cause of this beta cell failure is thought to be combination of genetic, environmental, as well as other factors. A widely prevalent inherited variation in the zinc transporter ZnT8 has been shown to be genetic risk factors for developing type 2 diabetes mellitus. ZnT8 is a zinc transporter that plays an important role in the function of insulin producing beta cells. This is thought to be related to the unique roles of zinc and the high zinc content and turnover in beta cells. The investigators and others have previously shown that proper function of ZnT8 is important for a normal function of beta cells. Cadmium has been shown to compete with zinc in several cellular trafficking systems and protein binding sites. Low-level human exposure to environmental cadmium is widely prevalent. It is likely that this low level of exposure is not harmful to most organs. However, studies exploring the effect of chronic exposure of insulin producing beta cells to low levels of environmental cadmium are scarce. The investigators established in current studies that insulin- producing beta cells accumulate cadmium avidly. Consistent with prior clinical evidence for an increased incidence of type 2 diabetes mellitus in persons with a chronic, low level of cadmium exposure, our preliminary data show impaired insulin secretion without inducing global cell toxicity in primary murine islets exposed to low concentrations of cadmium. This interaction between zinc and cadmium in cellular systems lead to our hypothesis that low level environmental cadmium exposure may compound the effects of genetic variations in ZnT8. The investigators hypothesize that this gene-environment interaction may potentiate the risk of diabetes mellitus in carriers of the genetic variation in ZnT8. The goal of this study is to characterize the mechanism by which cadmium impairs beta cell function without inducting global cell toxicity. Furthermore, they will examine the interaction between cadmium exposure and variations in ZnT8 in causing impairment in beta cell function. Public Health Relevance: The main underlying cause of type 2 diabetes mellitus is a decline in the normal function of the insulin producing beta cells in the pancreas. Prior research has shown that an inherited variation in the gene ZnT8 increases the risk for type 2 diabetes by impairing the function of insulin producing beta cells. Our study will examine whether ingestion of trace amounts of the industrial heavy metal cadmium may compound the impairment of the beta cells caused by this genetic variation in ZnT8, thereby increasing the risk for type 2 diabetes significantly in people carrying this genetic variation.

Public Health Relevance

The main underlying cause of type 2 diabetes mellitus is a decline in the normal function of the insulin producing beta cells in the pancreas. Prior research has shown that an inherited variation in the gene ZnT8 increases the risk for type 2 diabetes by impairing the function of insulin producing beta cells. Our study will examine whether ingestion of trace amounts of the industrial heavy metal cadmium may compound the impairment of the beta cells caused by this genetic variation in ZnT8, thereby increasing the risk for type 2 diabetes significantly in people carrying this genetic variation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08ES020880-03
Application #
8608526
Study Section
Special Emphasis Panel (ZES1-LKB-J (K9))
Program Officer
Shreffler, Carol K
Project Start
2012-02-09
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$131,277
Indirect Cost
$9,724
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Wallia, Amisha; Allen, Norrina Bai; Badon, Sylvia et al. (2014) Association between urinary cadmium levels and prediabetes in the NHANES 2005-2010 population. Int J Hyg Environ Health 217:854-60
Vellanki, Priyathama; Lange, Karoline; Elaraj, Dina et al. (2014) Denosumab for management of parathyroid carcinoma-mediated hypercalcemia. J Clin Endocrinol Metab 99:387-90