A double knockout for zinc transporter 8 and somatostatin in mice reveals their distinct roles in regulation of insulin secretion and obesity

Authors: YANG, ZHONGYUE - University Of California, Davis; Kirschke, Catherine; CAI, YIMENG - University Of California, Davis; Huang, Liping

Submitted to: Genes and Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/30/2024
Publication Date: 11/20/2024
Citation: Yang, Z., Kirschke-Schneide, C.P., Cai, Y., Huang, L. 2024. A double knockout for zinc transporter 8 and somatostatin in mice reveals their distinct roles in regulation of insulin secretion and obesity. Genes and Nutrition. (2024):19-24. https://doi.org/10.1186/s12263-024-00759-0.
DOI: https://doi.org/10.1186/s12263-024-00759-0

Interpretive Summary: This study investigated the effects of a single knockout of Znt8 or somatostatin (Sst) gene and a double knockout (DKO) of both ZnT8 and Sst simultaneously on glucose metabolism in mice. ZnT8, a zinc transporter that plays a role in insulin crystallization and secretion in the pancreatic beta-cell, was found to be co-expressed in a subset of endocrine D cells where somatostatin was produced and secreted in the mouse gastrointestinal tract. Sst, a peptide hormone, plays crucial roles in the regulation of insulin and glucagon secretion. The absence of ZnT8 expression through targeted deletion of the gene led to increased density of secretory granules in D cells, affecting Sst storage. The DKO mice maintained on a regular laboratory chow diet had reduced body weight compared to the wildtype control. The chow-fed DKO mice also had impaired insulin secretion without alterations in islet morphology or numbers in the pancreas. Furthermore, the DKO mice were susceptible to diet-induced insulin resistance. Additionally, secretion of metabolic-related hormones was dysregulated in high-fat diet challenged DKO mice. We concluded that ZnT8 and Sst coordinated with each other to maintain normal insulin and glucose metabolism and Sst was required for normalizing glucose metabolism in Znt8 knockout mice. These findings shed light on the multifaceted nature of Znt8 and Sst interactions, opening new avenues to understand their roles in controlling glucose metabolism and fat mass.

Technical Abstract: Background Both zinc transporter 8 (ZnT8) and somatostatin (Sst) play crucial roles in the regulation of insulin and glucagon secretion. However, the interaction between them in controlling glucose metabolism was not well understood. The aim of this study was to explore the interactive effects of a double knockout of Znt8 and Sst on insulin and glucose metabolism in mice. Methods Co-expression of ZnT8 with hormones secreted from gastrointestinal endocrine cells of mice was determined using immunofluorescence. Male Znt8 knockout (Znt8KO), Sst knockout (SstKO), double knockout for Sst and Znt8 (DKO), and the wild-type control (WT) were fed a regular chow diet (CD) or a high-fat diet (HFD) at 3 weeks old for 15 weeks. Weights and fasting or fed glucose levels were determined during the study. Glucose and insulin tolerance tests were performed; metabolic-relevant hormone levels including insulin, glucagon, glucagon-like peptide 1, and leptin were measured during the oral glucose tolerance test. Results ZnT8 is co-expressed in a subpopulation of endocrine D cells in the gastrointestinal tract. The absence of ZnT8 expression resulted in an increased density of the dense cores in the secretory granules of the D cell. DKO mice had reduced weight compared to WT when maintained on CD. Compared to Znt8KO and SstKO, DKO mice did not show significant differences in fed or fasting blood glucose level regardless of dietary condition. However, the CD-fed DKO mice had impaired insulin secretion without alterations in islet morphology or numbers. Moreover, DKO mice displayed diet-induced insulin resistance and disrupted metabolic-related hormone secretion during oral glucose chanllenge. Conclusions ZnT8 is co-expressed with Sst in a subpopulation of D cells in the gastrointestinal tract. Znt8-deficiency increased density of the dense cores of the D cell. Somatostatin as well as a normal insulin sensitivity are required for normalizing glucose metabolism in Znt8KO mice. Moreover, ZnT8 may play a role in regulating fat mass and leptin secretion. These findings shed light on the multifaceted nature of Znt8 and Sst interactions, opening new avenues to understand their roles in controlling glucose metabolism and fat mass.