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SEC16B is a novel regulator of glucose homeostasis

ABSTRACT: Genome-wide association studies (GWAS) have so far identified a large number of genetic loci associated with metabolic diseases. SEC16B, an endoplasmic reticulum (ER) export factor, has emerged as a strong candidate associated with obesity in multiple GWAS yet its physiological function on metabolism has not been characterized. Here, by using global Sec16b knockout mice, we show that loss of Sec16b gene causes glucose intolerance without an effect on body weight. At the cellular level, Sec16b loss damages the morphology of the ER and mitochondria in pancreatic β cells. Mechanistically, Sec16b loss impairs insulin secretion via blocking intracellular Ca2+ influx via down-regulating cholinergic synapse signaling in β cells. Moreover, dSec16 loss disrupts glucose homeostasis in Drosophila melanogaster, highlighting a core and evolutionarily conserved role of dSec16 in glucose homeostasis. Taken together, our study has for the first time established SEC16B as a conserved key regulator of metabolic heath across phyla.

ORGANISM(S): Mus musculus

PROVIDER: GSE213919 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.

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SEC16B is a novel regulator of glucose homeostasis

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