Abstract
Our objective is to identify genes that influence the development of any phenotypes of type 2 diabetes (T2D) or kidney disease in obese animals. We use the reproductively isolated UC Davis fatty Zucker strain rat model in which the defective chromosome 4 leptin receptor (LeprfaSte/faSte) results in fatty obesity. We previously produced a congenic strain with the distal half of chromosome 1 from the Brown Norway strain (BN) on a Zucker (ZUC) background (BN.ZUC-D1Rat183–D1Rat90). Previously published studies in males showed that the BN congenic donor region protects from some phenotypes of renal dysfunction and T2D. We now expand our studies to include females and expand phenotyping to gene expression. We performed diabetes and kidney disease phenotyping in chow-fed females of the BN.ZUC-D1Rat183-D1Rat90 congenic strain to determine the specific characteristics of the UC Davis model. Fatty LeprfaSte/faSte animals of both BN and ZUC genotype in the congenic donor region had prediabetic levels of fasting blood glucose and blood glucose 2 hours after a glucose tolerance test. We observed significant congenic strain chromosome 1 genotype effects of the BN donor region in fatty females that resulted in decreased food intake, urine volume, glucose area under the curve during glucose tolerance test, plasma triglyceride levels, and urine glucose excretion per day. In fatty females, there were significant congenic strain BN genotype effects on non-fasted plasma urea nitrogen, triglyceride, and creatinine. Congenic region genotype effects were observed by quantitative PCR of mRNA from the kidney for six genes, all located in the chromosome 1 BN donor region, with potential effects on T2D or kidney function. The results are consistent with the hypothesis that the BN genotype chromosome 1 congenic region influences traits of both type 2 diabetes and kidney function in fatty UC Davis ZUC females and that there are many positional candidate genes.
Highlights
Type 2 diabetes (T2D) and kidney disease, including end-stage renal disease (ESRD), are correlated with obesity in humans [1, 2]
Our results show that female fatty UC Davis ZUC strain animals have a mild prediabetes phenotype with fasting blood glucose above 100 mg/dL, when using American Diabetes Association (ADA) criteria for prediabetes in humans of >100 mg/dL for fasting plasma glucose [54]
The congenic captures Brown Norway (BN) strain alleles that reduce blood glucose area under the curve (AUC) levels compared with congenic donor genotype ZUC animals during a glucose tolerance test (Table 4) and that reduce urine glucose lost per day (Fig 4)
Summary
Type 2 diabetes (T2D) and kidney disease, including end-stage renal disease (ESRD), are correlated with obesity in humans [1, 2]. Most obese people do not develop T2D or any kidney disease, so obesity itself is not directly causal for these diseases. These three complex traits may share some genes influencing two or more of these diseases such that obesity may increase the risk for T2D or kidney disease in some genetically sensitive people, or these diseases may share some underlying environmental causes. An epidemiological study of approximately 900,000 patients reported that the hazard ratio for death from kidney disease was 1.59 for people with BMIs between 25 and 50. A recent study involving patients with chronic kidney disease reported that increased BMI was correlated with decreased death rates [4]. The effects of weight were independent of diabetes and hypertension [5]
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