Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects.
Bottom Line: However, the full spectrum of LKB1 effects and the mechanisms involved in the secretory phenotype remain incompletely understood.Surprisingly, enhanced GSIS is seen despite profound defects in mitochondrial structure and function in LKB1-deficient β cells, expected to greatly diminish insulin secretion via the classic triggering pathway.This study shows that β cells can be manipulated to enhance GSIS to supra-normal levels even in the face of defective mitochondria and without deterioration over months.
Affiliation: From the Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.Show MeSH
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Mentions: To understand the basis for the functional defect in mitochondria of βLKB β cells, we examined mitochondrial structure at high resolution using transmission electron microscopy. Islets of control islets presented with a typical pattern of mitochondria, including the fine structure of cristae (Fig. 5A). Islets of βLKB mice, examined 3–10 months after deletion of LKB1, revealed a strikingly different pattern of mitochondria. Mitochondria in mutant β cells were swollen and absent of cristae. The effect was specific to β cells, as adjacent α cells in the same sections had the normal appearance of mitochondria (Fig. 5B). The latter observation also rules out artifacts related to fixation and processing of tissue. The mitochondrial defect was found in 60% of β cells in βLKB islets (n = 6 mice, 15–20 cells examined per mouse) compared with ∼12% of mitochondria that had such appearance in wild type islets (Fig. 5C). In affected β cells, all mitochondria were apparently disrupted. This suggests a cell autonomous, all or none effect, occurring in the LKB1-deleted β cells and sparing cells that have escaped cre-mediated deletion. We have not observed other ultra-structural alterations in βLKB islets beyond the previously reported distended endoplasmic reticulum (42). In particular, we tested whether LKB1-deficient islets had more insulin granules docked at the plasma membrane (up to 200 nm from the membrane) as a potential indication for enhancement in distal release but found no difference between wild type and mutant islets (data not shown).
Affiliation: From the Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.