Poster 4
Presenter: Melkam Kebede
Thursday, 4:00 – 6:00pm
Melkam Kebede1, Angie Oler1, Kathryn L Schuler1, Mohd Beg2, Brendan J. Floyd1, Jadwiga Marcinkiewicz3, Annik Prat3, Nabil G. Seidah3 and Alan D Attie1 1Department of Biochemistry University of Wisconsin-Madison, Madison, WI, USA; 2University of Wisconsin School of Veterinary Medicine and Public Health, Madison, WI, USA; 3Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109-5680, USA
We positionally cloned SorCS1 as the gene underlying a QTL on mice chromosome 19 that affects fasting insulin levels. Human genome-wide association studies (GWAS) and linkage studies have shown that SORCS1 is associated with human diabetes. The Diabetes Control and Complications Trial conducted a large GWAS and found that SORCS1 was strongly associated with hemoglobinA1c in type 1 diabetic subjects injecting insulin. There was also weak association with diabetes complications; neuropathy, retinopathy, and nephropathy. SorCS1 is expressed in the brain, spinal cord, retina, pancreatic islets and kidneys. To identify the direct role of SorCS1 gene in diabetes susceptibility and complications, we generated a whole-body SorCS1 knockout (KO) mouse on a C57BL/6 background. Female SorCS1 KO mice have increase fasting plasma c-peptide to insulin ratio, suggesting a higher insulin turnover rate. Furthermore, when mice were injected with radiolabelled insulin (125-I-Insulin), it disappeared more rapidly from the circulation in the SorCS1 KO mice. Since SorCS1 is expressed in the kidney and not the liver, we hypothesized that the SorCS1 protein plays a role in renal insulin degradation. In order to test this hypothesis, insulin was coupled with a 'trapped' label: 125I-tyramine-cellobiose (125I-TC) and injected intravenously. As expected, liver uptake of insulin was not different between the genotypes. However, 125I-TC-insulin uptake into the kidney of SorCS1 KO mice increased two-fold. Therefore, our data demonstrate that Sorcs1 plays a role in renal uptake and degradation of insulin. Studies are now underway to investigate the role of SORCS1 in insulin uptake into kidney proximal tubules.