title: LKB1 couples glucose metabolism to insulin secretion in mice.
abstract: OBJECTIVE
  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
  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.
authors: Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, K1H 8L1, Canada.
authors: Accalia
authors: A
authors: Fu
authors: Karine
authors: K
authors: Robitaille
authors: Brandon
authors: B
authors: Faubert
authors: Courtney
authors: C
authors: Reeks
authors: Xiao-Qing
authors: XQ
authors: Dai
authors: Alexandre B
authors: AB
authors: Hardy
authors: Krishana S
authors: KS
authors: Sankar
authors: Svetlana
authors: S
authors: Ogrel
authors: Osama Y
authors: OY
authors: Al-Dirbashi
authors: Jonathan V
authors: JV
authors: Rocheleau
authors: Michael B
authors: MB
authors: Wheeler
authors: Patrick E
authors: PE
authors: MacDonald
authors: Russell
authors: R
authors: Jones
authors: Robert A
authors: RA
authors: Screaton
mesh_terms: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D005973:Glutamine / Q000096:biosynthesis / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics
chemical_list: D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D034741:RNA, Small Interfering; D005973:Glutamine; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D005947:Glucose