Download Insulin and glucose uptake in muscle and adipose tissue

Insulin and glucose uptake in
muscle and adipose tissue
Aleksi Huuha & Iiro Repo
Introduction
• Insulin
• Peptide hormone
• Anabolic, increases the storage of glucose, amino acids and fatty acids
• Glucagon
• Antagonist of insulin
• Peptide hormone
• Catabolic, releases glucose, amino acids and fatty acids from the storages
• Glucose transporters (GLUT)
• Membrane proteins
• Multiple different types
Insulin
• Insulin is a polypeptide
containing two chains of
amino acids linked by disulfide
bridges
• It is synthesized as a part of
larger preprohormone in the
rough ER of the β-cells of
Langerhans islets in pancreas
• Preproinsulin is processed and
proinsulin is formed
• Then proinsulin is cleaved
internally at two sides to yield
insulin and C peptide
(connecting peptide)
• Insulin is transported to the
Golgi apparatus and packaged
into vesicles, which are stored
inside the β-cells
Glucose transporters
• Glucose mostly enters cells by
facilitated diffusion, which is mediated
by glucose transporters (GLUTs)
• GLUTs are transmembrane proteins
that span the cell membrane 12 times
and have their N- and C-terminals
inside the cell
• Insulin stimulates glucose uptake in
muscle, adipose and some other
tissues by increasing the number of
GLUTs in the cell membrane
• GLUT2 is the glucose transporter for
example in β-cells of Langerhans islets
in pancreas
• GLUT4 is the glucose transporter in
muscle and adipose tissue that is
stimulated by insulin
Insulin secretion
Glucose concentration increases in
blood activates secretion of insulin
from β-cells of Langerhans islets in
pancreas
• When the glucose concentration in
blood increases, glucose is
transported into the β-cells through
GLUT2-transporters by facilitated
diffusion
• Glucose is phosphorylated by
glucokinase into glucose-6phosphate, which is then used for
ATP production
• ATP induces the closing of K+channels, which leads to
depolarisation of the cell and
opening of Ca2+-channels
• Ca2+ induces exocytosis of insulin to
the bloodstream
Insulin receptor
• Insulin receptor is a tetramer, which
consists of two α- and two β-subunits
α
α
• It has a molecular weight of
approximately 340 kDa
• Binding of insulin triggers
autophosphorylation of the β-subunits
on tyrosine residues, which in turn
triggers phosphorylations and
dephosphorylations of some cytoplasmic
proteins
• Insulin receptor substrate 1 (IRS-1) is one
of the mediators of the insulin effects in
humans
β
β
Glucose uptake
• When the concentration of
glucose is high and the insulin
receptors are activated by
insulin, GLUT4-transporters
stored in vesicles are
transferred to the cell
membrane which leads to
uptake of glucose
• Glucose is stored in muscles
as glycogen and in adipose
tissue as fat
• ~ 90 % of insulin-stimulated
glucose uptake occurs in
skeletal muscle
• ~ 10% in adipose tissue
Effects of insulin
Insulin resistance
• In insulin resistance the insulin signal
transduction is dysfunctional
• Alterations in receptor expression,
binding, phosphorylation state or kinase
activity
• Overall, it is usually caused by some
genetic defects combined with
environmental stresses
• Ability to remove and process glucose from
bloodstream is defected
→ Constantly high blood glucose
→ Increased chance of type 2 diabetes
References
• Barrett K.E., Barman S.M., Boitano S. & Brooks H.L. (2016) Ganong’s Review of
Medical Physiology. McGraw-Hill Education.
• Chakraborty C. (2006) Biochemical and Molecular Basis of Insulin Resistance.
Current Protein and Peptide Science.
• Figure 1: Dorland's Medical Dictionary for Health Consumers. © 2007 by
Saunders, an imprint of Elsevier, Inc.
• Figure 2: Bryant N.J., Govers R. & James D.E. (2002) Regulated transport of the
glucose transporter GLUT4.
• Figure 3: https://www.studyblue.com/notes/note/n/pancreas/deck/6619458
• Figure 4: Barrett K.E., Barman S.M., Boitano S. & Brooks H.L. (2016) Ganong’s
Review of Medical Physiology. McGraw-Hill Education.
• Figure 5: http://www.proteopedia.org/wiki/index.php/GLUT4
• Figure 6: http://type1diabetes.uk/effects-of-insulin