Glucose tolerance is the ability of an individual to limit the rise in blood glucose levels after a meal. Insulin plays a vital role in promoting glucose tolerance by activating glucose transporters in skeletal muscle. This is achieved by translocating existing GLUT4 transporters to the cell membrane. Insulin also facilitates the storage of glucose as glycogen in muscle and promotes its oxidation through glycolysis. In the absence of insulin during fasting, the number of GLUT4 transporters at the membrane is reduced, leading to lower glucose consumption by the cells. Skeletal muscle fibers with mitochondria switch to using free fatty acids (FFAs) from adipocytes and ketone bodies (KBs) from hepatocytes for energy production. Glucagon receptors are not present in skeletal myocytes. The uptake and oxidation of FFAs and KBs for ATP generation are mainly regulated by intracellular calcium levels and a high AMP:ATP ratio. Exercise, as well as glycogenolysis, also activate these pathways through adrenergic receptor stimulation.

Insulin also promotes the uptake of glucose through GLUT4 transporters and subsequent glycolysis in adipose tissue. This energy derived from glycolysis is utilized by adipose tissue and is also necessary for the esterification of FFAs into triglycerides (TGs) through the generation of glycerol-3-phosphate (G3P). In the absence of insulin during fasting, GLUT4 movement to the cell membrane is blocked.

During the digestive phase, adipocytes synthesize lipoprotein lipase (LPL) and secrete it into the subcapillary space, where it binds to GPI-anchored protein and migrates to the luminal side of the capillary endothelial cell. Lipolysis of chylomicron TGs occurs, releasing free FFAs. The imported FFAs are then activated by transfer to acetyl-CoA to form fatty acyl-CoA. These fatty acyl-CoAs are esterified to G3P, forming TGs. The TG droplets are covered and stabilized by perilipins. Hormone-sensitive lipase (HSL) is dephosphorylated and inactivated, promoting TG storage. During the fasting phase, HSL is phosphorylated and activated, contributing to complete lipolysis of TGs. The final step in TG lipolysis is performed by monoacylglyceride lipase (MGL), releasing FFAs and glycerol.
Fig. 39.15 ). Glucose tolerance refers to the ability of an individual to minimize the increase in blood glucose concentration after a meal. A primary way by which insulin promotes glucose tolerance is activation of glucose transporters in skeletal muscle. Insulin stimulates translocation of preexisting GLUT4 transporters to the cell membrane (reaction 1D). Insulin also promotes storage of glucose in muscle as glycogen (reaction 2D) and promotes oxidation of glucose through glycolysis (reaction 3D). During the fasting phase, low insulin results in a low number of GLUT4 transporters at the membrane (reaction 1F), so these cells consume less glucose (glucose sparing). Skeletal muscle fibers with mitochondria switch to the use of FFAs from adipocytes and KBs from hepatocytes (reaction 3F). Skeletal myocytes do not express glucagon receptors. Uptake of FFAs and KBs and their oxidation for ATP is largely upregulated by intracellular Ca++ levels and a high AMP:ATP ratio. Exercise also activates these pathways, as does glycogenolysis (reaction 2F), through adrenergic receptor stimulation.
2.
(Fig. 39.16A ). Insulin also stimulates GLUT4-dependent uptake of glucose and subsequent glycolysis in adipose tissue (reactions 1D and 2D). Adipose tissue uses glycolysis for energy needs but also for generating G3P (reaction 3D), which is required for esterification of FFAs into TGs (reaction 4D). During the fasting phase, insulin is low, so GLUT4 movement to the cell membrane is blocked (reaction 1F).
2. Adipocytes → FFAs and TG (see
Fig. 39.16B ). Insulin stimulates expression of lipoprotein lipase (LPL) •Fig. 39.15 A, Glucose metabolism in an adipocyte during digestive (“D” reactions) and fasting (“F” reactions) phases. Reactions/pathways:1Dand1F(alsosee
Fig.39.14 legend);2D,glycolysis,pyruvatedehydrogenase/TCAcycle/OxPhos;3D,glycerol-3-phosphatedehydrogenase;4D,esterificationofFFAstoG3Ptoformtriglyceride.B, Lipid metabolism in adipocyte during digestive (“D” reactions) and fasting (“F” reactions) phases. Reactions/pathways:1D,synthesisoflipoproteinlipase(LPL)andLPLsecretionintosubcapillaryspace,bindingtoGPI-anchoredprotein(red box), andmigrationtoluminalsideofcapillaryendothelialcell;2D,lipolysisofchylomicronTGandreleasingfreeFFA(afterdigestion,chylomicronremnantisclearedfromcirculationbyliver);3D,activationofimportedFFAsbytransfertoacetylCoAtoformfattyacylCoA;4D,esterificationoffattyacylCoAstoG3PtoformTG(TGdropletsarecoveredandstabilizedbyperilipins[PL]);5D,dephosphorylationandinactivationofhormone-sensitivelipase(HSL),whichpromotesstorageofTG;1F,phosphorylationandactivationofHSL,whichcontributestocompletelipolysisofTG(ATGL,adipocyteTGlipase;HSL,diacylglyceridelipase;MGL,monoacylglyceridelipase);2F,finalstepinTGlipasebyMGLreleasesFFAandglycerol.