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

Swisa, Avital; Granot, Zvi; Tamarina, Natalia A.; Sayers, Sophie; Bardeesy, Nabeel; Philipson, Louis H.; Hodson, David J.; Wikström, Jakob D.; Rutter, Guy A.; Leibowitz, Gil; Gläser, Benjamin; Dor, Yuval

doi:10.1074/jbc.m115.639237

Cited by 38 publications

(46 citation statements)

References 70 publications

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“…ADP cellular content, which was much higher at basal glucose concentration in metformin-treated cells, reached control values in the presence of stimulatory glucose concentrations; this in turn alters the ATP/ADP ratio that is permissive for K ATP channel closure and enhanced insulin secretion (2), satisfying the set criteria for ADP and the ATP/ADP ratio as candidate MCFs. Considering that Mg 2ϩ -bound ADP activates K ATP channels and prevents ␤-cell depolarization and insulin exocytosis (46), the present data favor the view that ADP acts as an "off" signal and is functionally more relevant for insulin release than ATP (33,(47)(48)(49)(50), at least in the second phase of GIIS.…”

Section: Metabolic Signaling Of Glucose For Insulin Secretionsupporting

confidence: 65%

Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model

Lamontagne

Al‐Mass

Nolan

et al. 2017

Journal of Biological Chemistry

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Metabolic deceleration in pancreatic β-cells is associated with inhibition of glucose-induced insulin secretion (GIIS), but only in the presence of intermediate/submaximal glucose concentrations. Here, we used acute metformin treatment as a tool to induce metabolic deceleration in INS1 (832/13) β-cells, with the goal of identifying key pathways and metabolites involved in GIIS. Metabolites and pathways previously implicated as signals for GIIS were measured in the cells at 2-25 mm glucose, with or without 5 mm metformin. We defined three criteria to identify candidate signals: 1) glucose-responsiveness, 2) sensitivity to metformin-induced inhibition of the glucose effect at intermediate glucose concentrations, and 3) alleviation of metformin inhibition by elevated glucose concentrations. Despite the lack of recovery from metformin-induced impairment of mitochondrial energy metabolism (glucose oxidation, O consumption, and ATP production), insulin secretion was almost completely restored at elevated glucose concentrations. Meeting the criteria for candidates involved in promoting GIIS were the following metabolic indicators and metabolites: cytosolic NAD/NADH ratio (inferred from the dihydroxyacetone phosphate:glycerol-3-phosphate ratio), mitochondrial membrane potential, ADP, Ca, 1-monoacylglycerol, diacylglycerol, malonyl-CoA, and HMG-CoA. On the contrary, most of the purine and nicotinamide nucleotides, acetoacetyl-CoA, HO, reduced glutathione, and 2-monoacylglycerol were not glucose-responsive. Overall these results underscore the significance of mitochondrial energy metabolism-independent signals in GIIS regulation; in particular, the candidate lipid signaling molecules 1-monoacylglycerol, diacylglycerol, and malonyl-CoA; the predominance of K/Ca signaling control by low ADP·Mg rather than by high ATP levels; and a role for a more oxidized state (NAD/NADH) in the cytosol during GIIS that favors high glycolysis rates.

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Section: Metabolic Signaling Of Glucose For Insulin Secretionsupporting

confidence: 65%

Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model

Lamontagne

Al‐Mass

Nolan

et al. 2017

Journal of Biological Chemistry

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“…Correspondingly, recently published transcriptomic data [52], [53] also demonstrate detectable, although low, levels of Elovl2 mRNA in adult human β cells. Interestingly, Elovl2 expression was also up-regulated ∼2-fold in mouse islets in response to deletion of the tumor promoter Liver Kinase B1 (LKB1) [54], a condition in which glucose-stimulated insulin secretion is also enhanced [55]. Interestingly, we also found that over-expression of Elovl2 in β cells potentiated glucose-induced insulin secretion and was associated with an increase of DHA levels.…”

Section: Discussionmentioning

confidence: 60%

Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion

Cruciani-Guglielmacci

Bellini

Denom

et al. 2017

Molecular Metabolism

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ObjectiveIn type 2 diabetes (T2D), pancreatic β cells become progressively dysfunctional, leading to a decline in insulin secretion over time. In this study, we aimed to identify key genes involved in pancreatic beta cell dysfunction by analyzing multiple mouse strains in parallel under metabolic stress.MethodsMale mice from six commonly used non-diabetic mouse strains were fed a high fat or regular chow diet for three months. Pancreatic islets were extracted and phenotypic measurements were recorded at 2 days, 10 days, 30 days, and 90 days to assess diabetes progression. RNA-Seq was performed on islet tissue at each time-point and integrated with the phenotypic data in a network-based analysis.ResultsA module of co-expressed genes was selected for further investigation as it showed the strongest correlation to insulin secretion and oral glucose tolerance phenotypes. One of the predicted network hub genes was Elovl2, encoding Elongase of very long chain fatty acids 2. Elovl2 silencing decreased glucose-stimulated insulin secretion in mouse and human β cell lines.ConclusionOur results suggest a role for Elovl2 in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of β cell failure under metabolic stress.

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“…Skeletal muscle-specific deletion of Lkb1 regulates muscle development, lipid oxidation, glucose homeostasis, and insulin sensitivity13141516. In addition, tissue-specific deletions of Lkb1 in adipose tissue1718, pancreas192021 and brain2223 further demonstrate that Lkb1 plays important roles in these tissues. Moreover, loss of Lkb1 regulates haematopoietic stem cells’ metabolism and survival345, muscle stem cells’ proliferation and differentiation1624, and pancreatic β cells’ polarity20.…”

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confidence: 98%

Deletion of Lkb1 in adult mice results in body weight reduction and lethality

Shan

Xiong

Kuang

2016

Sci Rep

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Liver kinase B1 (Lkb1) plays crucial roles in development, metabolism and survival. As constitutive knockout of Lkb1 in mice leads to embryonic lethality, whether Lkb1 is required for the growth and survival of adult mice is unclear. Here we address this question using a tamoxifen-inducible Lkb1 knockout (KO) mouse model: Rosa26-CreER: Lkb1flox/flox (abbreviated as Rosa-Lkb1). The Rosa-Lkb1 mice exhibited body weight reduction and died within 6 weeks after tamoxifen induction. The body weight reduction was due to reduced weight of various tissues but the brown and white adipose tissues underwent much more pronounced weight reduction relative to the overall body weight reduction. Accordingly, the Rosa-Lkb1 mice had increased blood glucose levels and were intolerant to glucose challenge. Expression levels of adipogenic and lipogenic genes in adipose tissues were also dramatically reduced by Lkb1 deletion. Additionally, Lkb1 deletion reduced lipid deposition and increased expression of mitochondrial (Pgc1a, Cox5b and Cox7a) and hepatic gluconeogenesis related genes (Pepck) in liver. Finally, the Rosa-Lkb1 mice had much reduced oxygen consumption, carbon dioxide production, and energy expenditure. These results demonstrate that Lkb1 plays an important role in maintaining body weight, liver and adipose tissue function, blood glucose homeostasis and survival in adult mice.

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

Cited by 38 publications

References 70 publications

Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model

Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model

Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion

Deletion of Lkb1 in adult mice results in body weight reduction and lethality

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