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Diabetes mellitus is a heterogeneous spectrum of metabolic disorders, likely arising from disparate genetic and environmental factors, with a common outcome of impaired glucose homeostasis and hyperglycemia. The pathogenesis, for most persons, involves some combination of insufficient insulin secretion, reduced responsiveness to endogenous or exogenous insulin, increased glucose production, and abnormalities in fat and protein metabolism. The resulting hyperglycemia may lead to both acute symptoms and metabolic abnormalities. A major source of the morbidity of diabetes is chronic end-organ damage that arises from prolonged hyperglycemia and includes retinopathy, neuropathy, nephropathy, and cardiovascular disease. These chronic complications can be mitigated in many patients by sustained control of the blood glucose and treatment of comorbidities such as hypertension and dyslipidemia (Nathan and DCCT/EDIC Research Group, 2013). A wide variety of treatment options for hyperglycemia that target different processes involved in glucose regulation or dysregulation are available (ADA, 2022c).



  • A1c: hemoglobin A1c

  • ADA: American Diabetes Association

  • CGM: continuous glucose monitoring

  • CSII: continuous subcutaneous insulin infusion

  • CVD: cardiovascular disease

  • DPP-4: dipeptidyl peptidase 4

  • GFR: glomerular filtration rate

  • GIP: glucose-dependent insulinotropic polypeptide

  • GK: glucokinase (hexokinase IV)

  • GLP-1: glucagon-like peptide 1

  • GLP-1RA: GLP-1 receptor agonist

  • GLUT: glucose transporter

  • G6P: glucose-6-phosphate

  • GPCR: G protein-coupled receptor

  • Hb: hemoglobin

  • HDL: high-density lipoprotein

  • HGP: hepatic glucose production

  • IAPP: islet amyloid polypeptide

  • IFG: impaired fasting glucose

  • IGT: impaired glucose tolerance

  • IRS: insulin receptor substrate

  • Kir: inward rectifying K+ channel

  • LDL: low-density lipoprotein

  • MODY: maturity-onset diabetes of the young

  • mTOR: mammalian target of rapamycin

  • NPH: neutral protamine Hagedorn

  • PI3K: phosphatidylinositol-3-kinase

  • PPAR: peroxisome proliferator-activated receptor

  • SGLT2: sodium-glucose cotransporter 2

  • SST: somatostatin

  • SUR: sulfonylurea receptor


Regulation of Blood Glucose

The maintenance of glucose homeostasis is a highly developed systemic process involving the integration of several major organs (Figure 51–1). Glucose tolerance refers specifically to tests of this system using standardized oral or intravenous glucose challenges. The actions of insulin are of central importance for glucose homeostasis with webs of interorgan communication via other hormones, nerves, local factors, and substrates also playing vital roles. The pancreatic β cell is essential for normal glucose tolerance, adjusting the amount of insulin secreted very precisely to promote glucose uptake after meals and regulating glucose output from the liver during fasting.

Figure 51–1

Insulin, glucagon, and glucose homeostasis. A. Fasting State—In healthy humans, plasma glucose is maintained in a range from 4.4 to 5 mM and fatty acids near 400 μM. In the absence of nutrient absorption from the GI tract, glucose is supplied primarily from the liver and fatty acids from adipose tissue. During overnight fasting, plasma insulin concentrations decrease, and plasma glucagon rises modestly, contributing to increased hepatic glycogenolysis and gluconeogenesis; low insulin also releases adipocytes from inhibition, permitting increased release of fatty acids into the circulation. Most tissues oxidize ...

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