Theendotheliumofthemicrovasculatureofthekidneyandretina,aswellastheendotheliumofthevasanervosumoftheautonomicnervoussystem,areparticularlysensitivetohyperglycemia.Chronicallyhighbloodglucoseresultsinpathologicallyhighintracellularlevelsofglucoseintheseendothelialcells,resultinginalteredproteinandlipidstructure,oxidativestress,andalteredsignalingpathways.Theseinsults,collectivelyreferredtoasglucotoxicity, causepathologicalchangesinintracellularandmembranecomponentsaswellasinsecretedmoleculesthateithersignaland/ormakeuptheextracellularmatrix.Indeed,glucotoxicityistherootcauseofthenephropathy, retinopathy, and peripheral neuropathy thatoccurinpoorlycontrolleddiabetesmellitus.Thereforewhole-bodymetabolismduringallmetabolicphasesmustmeetthechallengeofminimizingthemagnitudeanddurationoftheriseinbloodglucoseassociatedwithingestionofamealandmustmaintainbloodglucosebelowasafemaximalthresholdof100mg/dLduringallothertimes.Fastingbloodglucosebetween100and124mg/dLisindicativeofimpaired glucose tolerance, andvaluesat125mg/dLandaboveareevidenceofdiabetes mellitus.
Glucose is consumed by erythrocytes and the brain continually throughout all metabolic phases. In contrast, hepatocytes, skeletal myocytes, and adipocytes primarily use glucose during the digestive phase only. Insulin stimulates glycolysis and entry of pyruvate (end product of glycolysis) into the TCA cycle and oxidative phosphorylation for ATP production in hepatocytes, skeletal myocytes, and adipocytes (see
Table 39.1).
Hepatocytes express the GLUT2 isoform of the glucose transporter, which is not regulated by insulin for its insertion into the cell membrane. In contrast, skeletal myocytes and adipocytes express the GLUT4 isoform. Newly synthesized GLUT4 exists in an intracellular inactive state with GLUT4 storage vesicles (G4-i in
Fig. 39.3B ). Insulin induces translocation of GLUT4 to the cell membrane, where it can function as an active glucose transporter (G4-m in
Fig. 39.3A).
After its phosphorylation to G6P by glucokinase, hepatocytes convert some of the imported glucose into the storage form, glycogen, during the digestive phase (see
Fig.
39.3A ). Similarly, skeletal muscle converts some of the G6P from imported glucose into glycogen. Hepatocytes can only store a finite amount of glucose as glycogen. Hepatocytes also convert excess glucose into FFAs through the process of de novo lipogenesis (DNL). These FFAs are typically esterified to glycerol-3-phosphate (G3P) to form triglyceride (TG), which accumulates as intrahepatic TG during the digestive phase (see
Fig. 39.3A ). As discussed later for insulin signaling, an excessive accumulation of intrahepatic TG (i.e., fatty liver, hepatic steatosis) can result in insulin resistance.
During the digestive phase, AAs are used in multiple anabolic pathways to regenerate degraded molecules, including other AAs, proteins, nucleotides and nucleic acids, glutathione, and complex lipids.