Exposure to p,p′-dichlorodiphenyldichloroethylene (DDE) induces fasting hyperglycemia without insulin resistance in male C57BL/6H mice

Abstract

Approximately 8.3% of the United States (U.S.) population have either diagnosed or undiagnosed diabetes mellitus. Out of all the cases of diabetes mellitus, approximately 90–95% of these cases are type 2 diabetes mellitus (T2D). Although the exact cause of T2D remains elusive, predisposing factors include age, weight, poor diet, and a sedentary lifestyle. Until recently the association between exposure to environmental contaminants and the occurrence of diabetes had been unexplored. However, recent epidemiological studies have revealed that elevated serum concentrations of certain persistent organic pollutants (POPs), especially organochlorine pesticides, are positively associated with increased prevalence of T2D and insulin resistance. The current study seeks to investigate if this association is causative or coincidental. Male C57BL/6H mice were exposed to DDE (2.0 mg/kg or 0.4 mg/kg) or vehicle (corn oil; 1 ml/kg) for five days via oral gavage; fasting blood glucose, glucose tolerance, and insulin challenge tests were performed following a seven day resting period. Exposure to DDE caused significant hyperglycemia compared to vehicle and this hyperglycemic effect persisted for up to 21 days following cessation of DDE administration. Intraperitoneal glucose tolerance tests and phosphorylation of Akt in the liver, skeletal muscle, and adipose tissue following insulin challenge were comparable between vehicle and DDE treated animals. To determine the direct effect of exposure to DDE on glucose uptake, in vitro glucose uptake assays following DDE exposure were performed in L6 myotubules and 3T3-L1 adipocytes. In summary, subacute exposure to DDE does produce fasting hyperglycemia, but this fasting hyperglycemia does not appear to be mediated by insulin resistance. Thus, the current study reveals that subacute exposure to DDE does alter systemic glucose homeostasis and may be a contributing factor to the development of hyperglycemia associated with diabetes.

Potential contribution of insecticide exposure and development of obesity and type 2 diabetes

“…Exposures to organochlorine insecticides (DDE, HCB, and ɣ-HCH) have led to increased body weight gain in rodents (Table 4) (Chadwick et al, 1988; Howell et al, 2014; Howell et al, 2015; Villeneuve et al, 1977), including a study of parental trans-generational exposure to DDT linked to increased obesity rate in the offspring (Skinner et al, 2013). Similarly, others reported that perinatal exposure to DDT was linked to significant weight gain, but only in female offspring (La Merrill et al, 2014) or reduced weight was reported after dieldrin exposure (Shakoori et al, 1984).…”

Persistent Organic Pollutant Burden, Experimental POP Exposure, and Tissue Properties Affect Metabolic Profiles of Blubber from Gray Seal Pups

“…Adipose tissue synthesises triacylglycerol (TAG) from glucose 67,68 , such that glucose uptake rates can be used to investigate metabolic function of adipose tissue. Glucose uptake is altered by POPs at tissue and the whole animal level in other animals [69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87] . Of glucose taken up by adipose, 20% is stored as TAG, and 70% is used to synthesise lactate 67 .…”

Exposure to an environmentally relevant mixture of organochlorine compounds and polychlorinated biphenyls Promotes hepatic steatosis in male Ob/Ob mice

“…Blood was obtained through cardiac puncture, allowed to clot, and the serum separated by centrifugation. Serum was used to measure fasting insulin levels (Mercodia mouse insulin ELISA), triglyceride (Cayman Chemical), and total cholesterol (Cayman Chemical) levels as previously described (Howell et al, ).…”

“…Digital images were captured at 100× magnification for visual confirmation of macrovesicular steatosis. To quantify the degree of hepatic steatosis, liver triglyceride levels were measured as previously performed and expressed at micromoles of triglyceride (TG) per milligram of protein (Howell et al, ; Howell and Mulligan, ).…”