++
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).
++
Abbreviations
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
+++
PHYSIOLOGY OF GLUCOSE HOMEOSTASIS
+++
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.
++