Abstract: PO0921
Pathogenic Impact of Altered Leptin in Diabetes Induced by Genetic Deletion of the Canonical Transient Receptor Potential Channel 1 (TRPC1): Role of Insulin, Body Weights, Calcium-Sensing Receptor, and Intracellular Calcium
Session Information
- Diabetic Kidney Disease: Basic Mechanisms
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Eby, Bonnie, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
- Khan, Usman A., The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
- Anwar, Muhammad Mubeen, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
- Lau, Kai, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Background
We recently reported diabetic phenotypes in TRPC1 mutatioon. The role of the elevated serum leptin & reduced adiponectin is unclear. Like CaSR, TRPC1 participates in cell Ca homeostasis & its deficiency impairs Ca entry & induces hyperparathyroidism (JCI Apr 2020). We tested if by raising serum Ca by 4-5 mg%, we would raise cell Ca in adipocytes to lower lepin & elevate adiponectin, based on published in vitro data.
Methods
In age- & sex-matched TRPC1 +/+, +/- & -/- mice, we did metabolic studies, IP glucose toleranace tests, & measured serum cytokines & PTH by ELISA. At 10 m, we injected IP Ca to cause hypercalcemia (~15 mg%) to raise cell Ca enough to lower PTH, & by inference, similar rises in adipocytes & beta cells to alter leptin & insulin. At 16 m, we injected calcimimetic (Parsabiv) IP x 2 wks to evaluate if glucose tolerance is improved by chronically raising cell Ca.
Results
Serum leptin increase in -/- mice vs +/+ by 17% at 4.5 m, 75% (p<0.05) at 6.5 m, & 130% (p<0.001) at 9.5 m. It is directly related to body weight (BW) at 4.5 mon regardless of genotypes or gender (N=80; p<0.05). The relationship holds true at 17 m (p<0.05 for +/+ & p<0.05 for -/-). High fat diet x 3 m stimulates leptin 3 to 5 fold for all 3 genotypes, but linkage to BW holds. Serum leptin after fast (r=0.93) & 30 min post IP glucose (r=0.75) are highly correlated with simultaneous insulin. Leptin rose from 6.6 to 10.6 ng/ml 2 h after IP glucose (p<0.01). With induced hypercalcemia, PTH, elevated in null (288 vs 119 pg/ml), fell 75% (vs. 48% in +/+), but the elevated leptin (15.1 vs. 6.6 ng/ml) did not fall; insulin, similar between +/+ & -/-, fell comparably in both genotypes. GTT did not improve in +/+ or -/- mice after 2 wk of calcimimetics.
Conclusion
1. Leptin is upregulated by anabolism, high fat diet, weight gain, & correlated with body weight & insulin in normal & TRPC1 null mice.
2. It is however increased in TRPC1 deficiency, uncorrected by raising intracellular Ca by hypercalcemia (sufficient to inhibit PTH by 50 to 75%)
3. Like insulin-resistant diabetes in mice with leptin receptor deficiency, we postulate the lack of TRPC1 impairs leptin signaling in neurons inhibiting hyperphagia. The elevated leptin reflects inadequate compensation to combat obesity.
Funding
- NIDDK Support