Diabetes mellitus is a spectrum of metabolic disorders arising from myriad pathogenic mechanisms, all resulting in hyperglycemia. Both genetic and environmental factors contribute to its pathogenesis, which involves insufficient insulin secretion, reduced responsiveness to endogenous or exogenous insulin, increased glucose production, or abnormalities in fat and protein metabolism. The resulting hyperglycemia may lead to both acute symptoms and metabolic abnormalities. Major sources of the morbidity of diabetes are the chronic complications that arise from prolonged hyperglycemia, including 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, 2014; Orchard et al., 2015). There are now a wide variety of treatment options for hyperglycemia that target different processes involved in glucose regulation or dysregulation (Nathan, 2015).
Abbreviations
AC: adenylyl cyclase
A1c: hemoglobin A1c
ADA: American Diabetes Association
BP: blood pressure
CHF: congestive heart failure
CNS: central nervous system
CSII: continuous subcutaneous insulin infusion
CV: cardiovascular
CVD: cardiovascular disease
DPP-4: dipeptidyl peptidase IV
EPI: epinephrine
GDM: gestational diabetes mellitus
GEF: guanine nucleotide exchange factor
GFR: glomerular filtration rate
GIP: glucose-dependent insulinotropic polypeptide
GIRK: G protein–coupled inwardly rectifying K+ channel
GK: glucokinase (hexokinase IV)
GLP: glucagon-like peptide
GLP-1RA: GLP-1 receptor agonist
GLUT: glucose transporter
G6P: glucose-6-phosphate
GPCR: G protein–coupled receptor
GRPP: glicentin-related pancreatic polypeptide
Hb: hemoglobin
HbA1c: hemoglobin A1c
HDL: high-density lipoprotein
HGP: hepatic glucose production
HNF: hepatocyte nuclear transcription factor
IAPP: islet amyloid polypeptide
ICU: intensive care unit
IFG: impaired fasting glucose
IFN: interferon
IGF-1: insulinlike growth factor 1
IGT: impaired glucose tolerance
IL: interleukin
IRS: insulin receptor substrate
Kir: inward rectifying K+ channel
LDL: low-density lipoprotein
MAOI: monoamine oxidase inhibitor
MODY: maturity onset diabetes of the young
mTOR: mammalian target of rapamycin
NE: norepinephrine
NPH: neutral protamine Hagedorn
NSAID: nonsteroidal anti-inflammatory drug
OCT: organic cation transporter
PC: prohormone convertase
PI3K: phosphatidylinositol-3-kinase
PIP3: phosphatidylinositol 3,4,5-trisphosphate
PLC: phospholipase
PPAR: peroxisome proliferator-activated receptor
SGLT2: sodium-glucose cotransporter 2
Shc: Src-homology-2-containing (protein)
SST: somatostatin
SUR: sulfonylurea receptor
TGF: transforming growth factor
TNF: tumor necrosis factor
The maintenance of glucose homeostasis, termed glucose tolerance, is a highly developed systemic process involving the integration of several major organs (Figure 47–1). Although the actions of insulin are of central importance, webs of interorgan communication via other hormones, nerves, local factors, and substrates also play vital roles. The pancreatic β cell is central in this homeostatic process, adjusting the amount of insulin secreted very precisely to promote glucose uptake after meals and to regulate glucose output from the liver during fasting.