Loss of Lkb1 in Adult β Cells Increases β Cell Mass and Enhances Glucose Tolerance in Mice

Fu, Accalia; Ng, Andy Cheuk-Him; Depatie, Chantal; Wijesekara, Nadeeja; He, Ying; Wang, Gensheng; Bardeesy, Nabeel; Scott, Fraser W.; Touyz, Rhian M.; Wheeler, Michael B.; Screaton, Robert A.

doi:10.1016/j.cmet.2009.08.008

Cited by 113 publications

(151 citation statements)

References 66 publications

Supporting

Mentioning

136

Contrasting

Order By: Relevance

“…Loss of LKB1 in mouse beta cells increases insulin granule size and plasma membrane docking We previously reported that islets lacking LKB1 in the beta cell compartment led to a twofold increase in insulin content per cell [19]. As the proximity of insulin granules to the plasma membrane dictates the amplitude of first phase insulin release, we evaluated the size of the RRP in LABKO islets.…”

Section: Resultsmentioning

confidence: 99%

“…GSIS and calcium experiments GSIS and calcium experiments were performed as described previously [19] (ESM Methods).…”

Section: Methodsmentioning

confidence: 99%

“…Animals Control LoxP/LoxP (L/L) and LABKO mice were obtained from mating homozygous Lkb1 floxed mice to Pdx1-CreER tam mice all on an FVB/n background as described previously [19] (electronic supplementary material [ESM] Methods).…”

Section: Methodsmentioning

confidence: 99%

“…We previously demonstrated that Lkb1 adult beta cell knockout (LABKO) mice are resistant to hyperglycaemia induced by a high-fat diet, owing in large part to a doubling of beta cell mass and enhanced insulin stores via mTOR activation [19]. However, targeting liver kinase B1 (LKB1) in the beta cell for the treatment of diabetes would be undesirable as knockout of Lkb1 in adult mice has a deleterious effect on haematopoietic stem cell maturation [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

“…However, targeting liver kinase B1 (LKB1) in the beta cell for the treatment of diabetes would be undesirable as knockout of Lkb1 in adult mice has a deleterious effect on haematopoietic stem cell maturation [20][21][22]. We and others have identified non-overlapping functions in beta cells for LKB1 targets, including MAP/microtubule affinityregulating kinase 2 (MARK2), salt-inducible kinase 2 (SIK2), brain-specific kinase 2 (BRSK2) as well as AMPactivated protein kinase (AMPK) itself [19,[23][24][25][26][27][28], underscoring the potential for identifying the minimal target(s) of LKB1 responsible for enhancing insulin secretion. Here, we systematically interrogated insulin secretion pathway components to identify the signals responsible for enhanced insulin secretion in Lkb1 knockout islets.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

LKB1 couples glucose metabolism to insulin secretion in mice

Robitaille

Faubert

et al. 2015

Diabetologia

Self Cite

View full text Add to dashboard Cite

Aims/hypothesis Precise regulation of insulin secretion by the pancreatic beta cell is essential for the maintenance of glucose homeostasis. Insulin secretory activity is initiated by the stepwise breakdown of ambient glucose to increase cellular ATP via glycolysis and mitochondrial respiration. Knockout of Lkb1, the gene encoding liver kinase B1 (LKB1) from the beta cell in mice enhances insulin secretory activity by an undefined mechanism. Here, we sought to determine the molecular basis for how deletion of Lkb1 promotes insulin secretion. Methods To explore the role of LKB1 on individual steps in the insulin secretion pathway, we used mitochondrial functional analyses, electrophysiology and metabolic tracing coupled with by gas chromatography and mass spectrometry. Results Beta cells lacking LKB1 surprisingly display impaired mitochondrial metabolism and lower ATP levels following glucose stimulation, yet compensate for this by upregulating both uptake and synthesis of glutamine, leading to increased production of citrate. Furthermore, under low glucose conditions, Lkb1 −/− beta cells fail to inhibit acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in lipid synthesis, and consequently accumulate NEFA and display increased membrane excitability. Conclusions/interpretation Taken together, our data show that LKB1 plays a critical role in coupling glucose metabolism to insulin secretion, and factors in addition to ATP act as coupling intermediates between feeding cues and secretion. Our data suggest that beta cells lacking LKB1 could be used as a system to identify additional molecular events that connect metabolism to cellular excitation in the insulin secretion pathway.

show abstract

Section: Resultsmentioning

confidence: 99%

“…GSIS and calcium experiments GSIS and calcium experiments were performed as described previously [19] (ESM Methods).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

LKB1 couples glucose metabolism to insulin secretion in mice

Robitaille

Faubert

et al. 2015

Diabetologia

Self Cite

View full text Add to dashboard Cite

show abstract

Glucose metabolism and pancreatic defects in spinal muscular atrophy

Bowerman

Swoboda

Michalski

et al. 2012

Annals of Neurology

Self Cite

141

164

View full text Add to dashboard Cite

Objective Spinal muscular atrophy (SMA) is the number 1 genetic killer of young children. It is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Although SMA is primarily a motor neuron disease, metabolism abnormalities such as metabolic acidosis, abnormal fatty acid metabolism, hyperlipidemia, and hyperglycemia have been reported in SMA patients. We thus initiated an in-depth analysis of glucose metabolism in SMA. Methods Glucose metabolism and pancreas development were investigated in the Smn2B/− intermediate SMA mouse model and type I SMA patients. Results Here, we demonstrate in an SMA mouse model a dramatic cell fate imbalance within pancreatic islets, with a predominance of glucagon-producing α cells at the expense of insulin-producing β cells. These SMA mice display fasting hyperglycemia, hyperglucagonemia, and glucose resistance. We demonstrate similar abnormalities in pancreatic islets from deceased children with the severe infantile form of SMA in association with supportive evidence of glucose intolerance in at least a subset of such children. Interpretation Our results indicate that defects in glucose metabolism may play an important contributory role in SMA pathogenesis.

show abstract

New Roles of Lkb1 in Regulating Adipose Tissue Development and Thermogenesis

Liu

Shan

2017

Journal Cellular Physiology

View full text Add to dashboard Cite

Adipose tissues regulate energy metabolism and reproduction. There are three types of adipocytes (brown, white, and beige adipocytes) in mammals. White adipocytes store energy and are closely associated with obesity and other metabolic diseases. The beige and brown adipocytes have numerous mitochondria and high levels of UCP1 that dissipates lipid to generate heat and defend against obesity. The global epidemic of obesity and its associated metabolic diseases urge an imperative need for understating the regulation of adipogenesis. Liver kinase B1 (Lkb1), also called STK11, is a master kinase of the AMPK subfamily and plays crucial roles in regulating glucose and energy homeostasis in various metabolic tissues. In this review, we focus on the regulatory roles of Lkb1 in regulating preadipocyte differentiation, adipose tissue development, and thermogenesis. J. Cell. Physiol. 232: 2296-2298, 2017. © 2016 Wiley Periodicals, Inc.

show abstract

Loss of Lkb1 in Adult β Cells Increases β Cell Mass and Enhances Glucose Tolerance in Mice

Cited by 113 publications

References 66 publications

LKB1 couples glucose metabolism to insulin secretion in mice

LKB1 couples glucose metabolism to insulin secretion in mice

Glucose metabolism and pancreatic defects in spinal muscular atrophy

New Roles of Lkb1 in Regulating Adipose Tissue Development and Thermogenesis

Contact Info

Product

Resources

About