DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1242
SECTION V
Insulin
receptor
α
β
Y-
Shc
-Y
MAP
kinase
Insulin
Gab1
P-Y-
Insulin
IRS proteins
1-4
PI3-kinase
caveola
flotillin Cav
-Y-P APS
CbI CAP
CrkII
GTP
exch C3G
TC10
GDP
PIP 3
(membrane)
PKB
(Akt)
aPKC
PDK1
Translocation
of GLUT 4
GLUT4
Intracellular
vesicle
Glucose
extracellular
intracellular
Glucose
Hexokinase
G-6-P
HORMONES AND HORMONE ANTAGONISTS
Cell growth,
differentiation,
survival
Protein
synthesis
Glycogen
synthesis
Metabolic
pathways
Figure 43–4. Pathways of insulin signaling. The binding of insulin to its plasma membrane receptor activates a cascade of downstream
signaling events. Insulin binding activates the intrinsic tyrosine kinase activity of the receptor dimer, resulting in the tyrosine phosphorylation
(Y-P) of the receptor’s β subunits and a small number of specific substrates (yellow shapes): the Insulin Receptor Substrate
(IRS) proteins, Gab-1 and SHC; within the membrane, a caveolar pool of insulin receptor phosphorylates caveolin (Cav), APS, and
Cbl. These tyrosine-phosphorylated proteins interact with signaling cascades via SH2 and SH3 domains to mediate the effects of
insulin, with specific effects resulting from each pathway. In target tissues such as skeletal muscle and adipocytes, a key event is the
translocation of the Glut4 glucose transporter from intracellular vesicles to the plasma membrane; this translocation is stimulated by
both the caveolar and non-caveolar pathways. In the non-caveolar pathway, the activation of PI3K is crucial, and PKB/Akt (anchored
at the membrane by PIP3) and/or an atypical form of PKC is involved. In the caveolar pathway, caveolar protein flotillin localizes the
signaling complex to the caveola; the signaling pathway involves series of SH2 domain interactions that add the adaptor protein CrkII,
the guanine nucleotide exchange protein C3G, and small GTP-binding protein, TC10. The pathways are inactivated by specific phosphoprotein
phosphatases (eg, PTB1B). In addition to the actions shown, insulin also stimulates the plasma membrane Na + ,K + -ATPase
by a mechanism that is still being elucidated; the result is an increase in pump activity and a net accumulation of K + in the cell.
Abbreviations: APS, adaptor protein with PH and SH2 domains; CAP, Cbl associated protein; CrkII, chicken tumor virus regulator
of kinase II; GLUT4, glucose transporter 4; Gab-1, Grb-2 associated binder; MAP kinase, mitogen-activated protein kinase; PDK,
phosphoinositide-dependent kinase; PI3 kinase, phosphatidylinositol-3-kinase; PIP3, phosphatidylinositol trisphosphate; PKB, protein
kinase B (also called Akt); aPKC, atypical isoform of protein kinase C; Y, tyrosine residue; Y-P, phosphorylated tyrosine residue.
in abundance to the plasma membrane, where it facilitates inward
transport of glucose from the circulation. Insulin signaling also
reduces GLUT4 endocytosis, increasing the residence time of the
protein in the plasma membrane.
Following the facilitated diffusion into cells along a concentration
gradient, glucose is phosphorylated to glucose-6-phosphate
(G-6-P) by a family of hexokinases. Hexokinase II is found in association
with GLUT4 in skeletal and cardiac muscle and in adipose
tissue. Like GLUT4, hexokinase II is regulated transcriptionally
by insulin. G-6-P is a branch-point substrate that can enter several
pathways. G-6-P can be isomerized to G-1-P by phosphoglucomutase,
and then the G-1-P can be stored as glycogen (insulin enhances
the activity of glycogen synthase); G-6-P can enter the glycolytic
pathway (leading to ATP production); G-6-P can also enter the pentose
phosphate pathway.
PATHOPHYSIOLOGY AND DIAGNOSIS
OF DIABETES MELLITUS
Glucose Homeostasis and the Diagnosis
of Diabetes
Broad categories of glucose homeostasis as defined by
the fasting blood glucose or the glucose level following
an oral glucose challenge include:
• Normal glucose homeostasis: Fasting plasma glucose
<5.6 mmol/L (100 mg/dL)
• Impaired fasting glucose (IFG): 5.6-6.9 mmol/L
(100-125 mg/dL)