Loss of Transcription Factor 19 (Tcf19) Impacts Metabolic Response to Stress

Type 1 and Type 2 diabetes (TID and TIID) differ in etiology, but both have decreased functional pancreatic β-cell mass. Genome-wide association studies identified transcription factor 19 (Tcf19) as a potential causal gene for both TID and TIID. Tcf19 is expressed in both humans and rodents, most highly in the pancreatic islet and upregulated in mouse models of non-diabetic obesity. We showed that TCF19 is necessary for β-cell proliferation and survival in INS1 cells. Thus, we hypothesized that TCF19 regulates β-cell mass developmentally and in adaptive response to stress. A germline whole-body knockout (wbTcf19KO) of Tcf19 mouse model was generated. wbTcf19KO and control (C57BL6/N) mice were fed a chow diet. Lean wbTcf19KO are metabolically similar to controls other than significantly higher body weights. Markers of proliferation (Ki67) and β-cell identity (Pdx1, Nkx6.1, Nkx2.2) were significantly decreased while markers of pro-apoptosis (Chop) and DNA damage response (Bak, Gadd45a, Dtx3l) were significantly increased in islets from wbTcf19KO mice. DNA damage is significantly elevated in wbTcf19KO islets as measured by y-H2AX Western blot. Islet size distribution is significantly altered in wbTcf19KO islets, skewed by many very small islets. wbTcf19KO and control male mice were challenged with high fat diet (HFD; 1-week & 10-week) feeding. These mice failed to appropriately upregulate proliferation markers (Ki67, CyclinD2) in islets after 1-week of HFD. Glucose intolerance and elevated fasting glucose develop in these mice after 10-weeks of HFD. Female mice, less susceptible to diet induced hyperglycemia, were stressed with long-term high fat high sucrose diet (HFHS) feeding to induce insulin resistance. After 8-weeks of HFHS feeding wbTcf19KO females became significantly more glucose intolerant than control HFHS fed female mice. Ongoing studies will examine the impact of Tcf19 knockout on β-cell mass during pregnancy in these HFHS-fed females. Overall, loss of Tcf19 reveals changes in proliferation and DNA damage, which may be critical in stress-induced β-cell mass regulation. © FASEB.