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Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects.

Swisa A, Granot Z, Tamarina N, Sayers S, Bardeesy N, Philipson L, Hodson DJ, Wikstrom JD, Rutter GA, Leibowitz G, Glaser B, Dor Y - J. Biol. Chem. (2015)

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.

View Article: PubMed Central - PubMed

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.

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Increased insulin secretion despite normal insulin content and β cell mass after LKB1 loss.A, glucose tolerance test in old βLKB mice. Mice were injected with tamoxifen at 1 month of age, and assays were performed 16 months later. n = 4 or 5 per genotype. p value <0.05 by repeated measures analysis of variance. B, plasma insulin levels in old βLKB mice, 15 min after glucose injection. Error bars represent S.D. Mice were injected with tamoxifen at 1 month of age, and assay was performed 1 year later. n = 3 per genotype. C, β cell mass. Graphs represent the percentage of pancreas tissue area stained for insulin (left), the fraction of insulin-stained tissue multiplied by pancreas weight (total β cell mass in mg; center), and total β cell mass per body weight (right). Mice were 4 months old, 3 months after tamoxifen injection. n = 3 mice per group. D, insulin content in pancreata from fed and fasted lox/lox littermate controls and βLKB mice. Insulin content is presented relative to pancreas weight. βLKB mice do not differ in their pancreatic insulin content in either fed or fasted states. n = 4–7 mice per group. E, dynamic insulin secretion assay. Data represent the mean of data from 5 mice per group at age of 6–8 months. For each sample, measured insulin was normalized to total DNA. *, p < 0.05; **, p < 0.01; ***, p < 0.005; ns, p > 0.05.
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Figure 1: Increased insulin secretion despite normal insulin content and β cell mass after LKB1 loss.A, glucose tolerance test in old βLKB mice. Mice were injected with tamoxifen at 1 month of age, and assays were performed 16 months later. n = 4 or 5 per genotype. p value <0.05 by repeated measures analysis of variance. B, plasma insulin levels in old βLKB mice, 15 min after glucose injection. Error bars represent S.D. Mice were injected with tamoxifen at 1 month of age, and assay was performed 1 year later. n = 3 per genotype. C, β cell mass. Graphs represent the percentage of pancreas tissue area stained for insulin (left), the fraction of insulin-stained tissue multiplied by pancreas weight (total β cell mass in mg; center), and total β cell mass per body weight (right). Mice were 4 months old, 3 months after tamoxifen injection. n = 3 mice per group. D, insulin content in pancreata from fed and fasted lox/lox littermate controls and βLKB mice. Insulin content is presented relative to pancreas weight. βLKB mice do not differ in their pancreatic insulin content in either fed or fasted states. n = 4–7 mice per group. E, dynamic insulin secretion assay. Data represent the mean of data from 5 mice per group at age of 6–8 months. For each sample, measured insulin was normalized to total DNA. *, p < 0.05; **, p < 0.01; ***, p < 0.005; ns, p > 0.05.

Mentions: We and others have previously shown that GSIS is enhanced after Cre-mediated deletion of LKB1 in β cells in vivo (23–25, 30). These observations were mostly obtained a short time after deletion of LKB1. To test if hyperfunctionality of β cells in βLKB mice declines with age, as seen in human type 2 diabetes and in some mouse models exhibiting enhanced insulin secretion (39), we measured glucose tolerance and serum insulin levels in βLKB mice up to 16 months after deletion. Injected glucose was cleared faster in mutant mice (Fig. 1A) along with greater insulin secretion (Fig. 1B). Thus deletion of LKB1 in β cells causes a persistent enhancement of β cell function.


Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects.

Swisa A, Granot Z, Tamarina N, Sayers S, Bardeesy N, Philipson L, Hodson DJ, Wikstrom JD, Rutter GA, Leibowitz G, Glaser B, Dor Y - J. Biol. Chem. (2015)

Increased insulin secretion despite normal insulin content and β cell mass after LKB1 loss.A, glucose tolerance test in old βLKB mice. Mice were injected with tamoxifen at 1 month of age, and assays were performed 16 months later. n = 4 or 5 per genotype. p value <0.05 by repeated measures analysis of variance. B, plasma insulin levels in old βLKB mice, 15 min after glucose injection. Error bars represent S.D. Mice were injected with tamoxifen at 1 month of age, and assay was performed 1 year later. n = 3 per genotype. C, β cell mass. Graphs represent the percentage of pancreas tissue area stained for insulin (left), the fraction of insulin-stained tissue multiplied by pancreas weight (total β cell mass in mg; center), and total β cell mass per body weight (right). Mice were 4 months old, 3 months after tamoxifen injection. n = 3 mice per group. D, insulin content in pancreata from fed and fasted lox/lox littermate controls and βLKB mice. Insulin content is presented relative to pancreas weight. βLKB mice do not differ in their pancreatic insulin content in either fed or fasted states. n = 4–7 mice per group. E, dynamic insulin secretion assay. Data represent the mean of data from 5 mice per group at age of 6–8 months. For each sample, measured insulin was normalized to total DNA. *, p < 0.05; **, p < 0.01; ***, p < 0.005; ns, p > 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: Increased insulin secretion despite normal insulin content and β cell mass after LKB1 loss.A, glucose tolerance test in old βLKB mice. Mice were injected with tamoxifen at 1 month of age, and assays were performed 16 months later. n = 4 or 5 per genotype. p value <0.05 by repeated measures analysis of variance. B, plasma insulin levels in old βLKB mice, 15 min after glucose injection. Error bars represent S.D. Mice were injected with tamoxifen at 1 month of age, and assay was performed 1 year later. n = 3 per genotype. C, β cell mass. Graphs represent the percentage of pancreas tissue area stained for insulin (left), the fraction of insulin-stained tissue multiplied by pancreas weight (total β cell mass in mg; center), and total β cell mass per body weight (right). Mice were 4 months old, 3 months after tamoxifen injection. n = 3 mice per group. D, insulin content in pancreata from fed and fasted lox/lox littermate controls and βLKB mice. Insulin content is presented relative to pancreas weight. βLKB mice do not differ in their pancreatic insulin content in either fed or fasted states. n = 4–7 mice per group. E, dynamic insulin secretion assay. Data represent the mean of data from 5 mice per group at age of 6–8 months. For each sample, measured insulin was normalized to total DNA. *, p < 0.05; **, p < 0.01; ***, p < 0.005; ns, p > 0.05.
Mentions: We and others have previously shown that GSIS is enhanced after Cre-mediated deletion of LKB1 in β cells in vivo (23–25, 30). These observations were mostly obtained a short time after deletion of LKB1. To test if hyperfunctionality of β cells in βLKB mice declines with age, as seen in human type 2 diabetes and in some mouse models exhibiting enhanced insulin secretion (39), we measured glucose tolerance and serum insulin levels in βLKB mice up to 16 months after deletion. Injected glucose was cleared faster in mutant mice (Fig. 1A) along with greater insulin secretion (Fig. 1B). Thus deletion of LKB1 in β cells causes a persistent enhancement of β cell function.

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.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus