Genetic activation of glucokinase in a minority of pancreatic beta cells causes hypoglycemia in mice

Kevin H. Chen, Nicolai Doliba, Catherine L. May, Jeffrey Roman, Alessandro Ustione, Teguru Tembo, Ariel Negron, Sally Radovick, David W. Piston, Benjamin Glaser, Klaus H. Kaestner, Franz M. Matschinsky

Research output: Contribution to journalArticlepeer-review


Aims: Glucokinase (GK) is expressed in the glucose-sensing cells of the islets of Langerhans and plays a critical role in glucose homeostasis. Here, we tested the hypothesis that genetic activation of GK in a small subset of β-cells is sufficient to change the glucose set-point of the whole islet. Material and methods: Mouse models of cell-type specific GK deficiency (GKKO) and genetic enzyme activation (GKKI) in a subset of β-cells were obtained by crossing the αGSU (gonadotropin alpha subunit)-Cre transgene with the appropriate GK mutant alleles. Metabolic analyses consisted of glucose tolerance tests, perifusion of isolated islets and intracellular calcium measurements. Key findings: The αGSU-Cre transgene produced genetically mosaic islets, as Cre was active in 15 ± 1.2 % of β-cells. While mice deficient for GK in a subset of islet cells were normal, unexpectedly, GKKI mice were chronically hypoglycemic, glucose intolerant, and had a lower threshold for glucose stimulated insulin secretion. GKKI mice exhibited an average fasting blood glucose level of 3.5 mM. GKKI islets responded with intracellular calcium signals that spread through the whole islets at 1 mM and secreted insulin at 3 mM glucose. Significance: Genetic activation of GK in a minority of β-cells is sufficient to change the glucose threshold for insulin secretion in the entire islet and thereby glucose homeostasis in the whole animal. These data support the model in which β-cells with higher GK activity function as ‘hub’ or ‘trigger’ cells and thus control insulin secretion by the β-cell collective within the islet.

Original languageEnglish
Article number120952
JournalLife Sciences
StatePublished - Nov 15 2022


  • Glucokinase
  • Hub cell
  • Islet
  • Trigger cell
  • beta cell


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