A 14-year-old boy is brought to the emergency department due to excessive urination and thirst. He has lost 4.5 kg (10 lb) in the last 3 weeks. The patient has no past medical problems. His father has type 1 diabetes mellitus. Physical examination shows dry mucous membranes. Laboratory studies reveal blood glucose of 455 mg/dL, normal anion gap, and hemoglobin A1c of 11.3%. The patient is diagnosed with type 1 diabetes, and treatment with insulin is initiated. In addition to lowering blood glucose, insulin increases glycogen synthesis in hepatocytes. Activation of which of the following molecules most likely promotes this metabolic effect?

Question

A 14-year-old boy is brought to the emergency department due to excessive urination and thirst.  He has lost 4.5 kg (10 lb) in the last 3 weeks.  The patient has no past medical problems.  His father has type 1 diabetes mellitus.  Physical examination shows dry mucous membranes.  Laboratory studies reveal blood glucose of 455 mg/dL, normal anion gap, and hemoglobin A1c of 11.3%.  The patient is diagnosed with type 1 diabetes, and treatment with insulin is initiated.  In addition to lowering blood glucose, insulin increases glycogen synthesis in hepatocytes.  Activation of which of the following molecules most likely promotes this metabolic effect?

Quizplus · Accepted Answer

11ec160b_36c8_2431_9249_13968b05cd09_MD0001_00 Insulin decreases blood glucose levels by increasing glucose uptake into skeletal muscle and adipocytes. In addition to having glucose lowering effects, insulin is an anabolic hormone that promotes synthesis of glycogen, triglycerides, nucleic acids, and proteins. Furthermore, insulin inhibits glycogenolysis and gluconeogenesis. The surface receptor for insulin is a transmembrane protein with intrinsic tyrosine kinase activity in its cytoplasmic domain. Insulin binding activates tyrosine kinase, leading to phosphorylation of insulin receptor substrate 1 (IRS-1). IRS-1 then activates several intracellular pathways that induce the physiologic effects of insulin. Activation of the MAP kinase pathway promotes mitogenic functions such as DNA synthesis and cell growth. In contrast, activation of phosphatidylinositol-3-kinase (PI3K) stimulates metabolic functions such as translocation of GLUT-4 to the cell membrane, glycogen synthesis, and fat synthesis. PI3K promotes glycogen synthesis by activating protein phosphatase, an enzyme that dephosphorylates glycogen synthase, leading to its activation. (Choice A) Janus kinase (JAK) is a component of the second messenger system for various peptide hormones (eg, growth hormone, prolactin) and cytokines (eg, interferon, interleukin). JAK has tyrosine kinase activity; however, it is a cytoplasmic enzyme that is not part of a cell surface receptor (non-receptor tyrosine kinase). (Choice B) Lipoxygenase is an enzyme involved in arachidonic acid metabolism and is responsible for the arm of that pathway that synthesizes leukotrienes. (Choice C) Phospholipase C is activated in the G-protein/inositol triphosphate (IP₃)/calcium second messenger system. Hormone-receptor binding activates a G-protein that in turn activates phospholipase C to degrade phospholipids into IP₃ and diacylglycerol. Both diacylglycerol and the increased intracellular calcium caused by IP₃ lead to protein kinase C activation. (Choice D) Protein kinase A is the primary intracellular effector enzyme in the G-protein/adenylate cyclase second messenger system. Glucagon acts through this pathway to stimulate glycogen breakdown. Protein kinase A activates glycogen phosphorylase via activation of glycogen phosphorylase kinase. Educational objective: Insulin is an anabolic hormone that acts via receptor tyrosine kinase signaling to increase the synthesis of glycogen, proteins, fatty acids, and nucleic acids. Tyrosine kinase/phosphatidylinositol-3-kinase stimulation promotes glycogen synthesis by activating protein phosphatase, an enzyme that dephosphorylates (activates) glycogen synthase. __________ References: Role of phosphatidylinositol 3-kinase activation on insulin action and its alteration in diabetic conditions. (http://www.ncbi.nlm.nih.gov/pubmed/17827708)

A 14-Year-Old Boy Is Brought to the Emergency Department Due