The kidney and retina's microvascular endothelium, as well as the autonomic nervous system's vasanervosum endothelium, are highly sensitive to hyperglycemia. Prolonged high blood glucose levels lead to elevated glucose levels within these endothelial cells, resulting in structural changes in proteins and lipids, oxidative stress, and altered signaling pathways. These insults, collectively known as glucotoxicity, cause pathological alterations in intracellular and membrane components, as well as secreted molecules that either signal or contribute to the extracellular matrix. Glucotoxicity is responsible for the development of nephropathy, retinopathy, and peripheral neuropathy in poorly controlled diabetes mellitus. Therefore, whole-body metabolism must effectively minimize the magnitude and duration of blood glucose elevation associated with meal ingestion and maintain blood glucose levels below a safe maximum threshold of 100mg/dL at all other times. Fasting blood glucose levels between 100 and 124mg/dL indicate impaired glucose tolerance, while values at 125mg/dL and above indicate diabetes mellitus.

Glucose is continuously consumed by erythrocytes and the brain throughout all metabolic phases. In contrast, hepatocytes, skeletal myocytes, and adipocytes primarily utilize glucose during the digestive phase only. Insulin promotes glycolysis and the entry of pyruvate, the end product of glycolysis, into the TCA cycle and oxidative phosphorylation for ATP production in hepatocytes, skeletal myocytes, and adipocytes.

The GLUT2 isoform of the glucose transporter is expressed in hepatocytes, and its insertion into the cell membrane is not regulated by insulin. Conversely, skeletal myocytes and adipocytes express the GLUT4 isoform. Newly synthesized GLUT4 remains in an intracellular inactive state within GLUT4 storage vesicles. Insulin induces the translocation of GLUT4 to the cell membrane, where it functions as an active glucose transporter.

Hepatocytes convert some of the imported glucose into glycogen, the storage form of glucose, during the digestive phase. Skeletal muscle also converts a portion of glucose into glycogen. However, hepatocytes can only store a limited amount of glucose as glycogen. Additionally, excess glucose in hepatocytes is converted into free fatty acids (FFAs) through 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. The excessive accumulation of intrahepatic TG, known as fatty liver or hepatic steatosis, can lead to insulin resistance, as discussed in insulin signaling.

During the digestive phase, amino acids (AAs) are utilized in various anabolic pathways to regenerate degraded molecules, including other AAs, proteins, nucleotides and nucleic acids, glutathione, and complex lipids.
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.