Module - II
Lecture # 8
Glucose transport
Hormonal control of blood sugar level
Diabetes
BIOT 305
Clinical Biochemistry
Pancreas
Insulin release is triggered by Glucose
The rate-limiting step of glucose metabolism in β
cells is the reaction catalyzed by glucokinase
Glucokinase - β cell’s glucose “sensor”
G6P product is not used to synthesize glycogen,
activity of the pentose phosphate pathway is
minor, lactate dehydrogenase activity is low
G6P produced in β cells is degraded to pyruvate
and then converted to acetyl CoA for oxidation in
the mitochondrion
pancreas responds to increases in the concentration of ATP produced induces an ATP-gated K+ channel in
blood glucose – secreting Insulin the plasma membrane to close
Pancreatic β cells are most sensitive to glucose at Resulting membrane depolarization (the
concentrations of 5.5 to 6.0 mM (normal - 3.6 to 5.8 mM) membrane is normally positive outside) causes a
no evidence for a cell-surface glucose “receptor” voltage gated Ca2+ channel to open
glucose enters β cells via passive transport, and its Ca2+ ion influx triggers the exocytosis of insulin-
metabolism generates the signal for insulin secretion containing secretory granules
level of the β cell’s respiratory activity, which varies with glucose availability, regulates insulin secretion
Insulin stimulates GLUT4 activity
• INSULIN is the primary regulator of blood glucose
concentration - promotes glucose uptake in muscles and
adipose tissue and inhibits hepatic glucose production
• Muscle cells and adipocytes express an insulin-sensitive
glucose transporter known as GLUT4
• accomplished through the appearance of additional
transporter molecules in the plasma membrane
• In absence of insulin, GLUT4 is localized in intracellular
vesicles and tubular structures known as GLUT4 storage
vesicles
• Insulin promotes the fusion of these vesicles to the
plasma membrane. GLUT4 appears on the cell surface
only a few minutes after insulin stimulation
• GLUT4 has a relatively low KM for glucose (2–5 mM) -
cells containing this transporter can rapidly take up
glucose from the blood
• On insulin withdrawal, the glucose transporters are
gradually sequestered through endocytosis
• Brain – constitutively express insulin insensitive
transporter; Liver also lacks GLUT4
Insulin promotes fuel storage in adipocytes & muscles
Inactivates phosphorylase kinase
Promotes glycogen synthesis & decreases the rate
of glycogenolysis
Inhibits transcription of genes encoding the
insulin activates glycogen synthase by promoting dephosphorylation gluconeogenic enzymes while stimulating
Adipocytes - insulin activates the pyruvate dehydrogenase complex, expression of glycolytic genes & lipogenic enzymes
acetyl-CoA carboxylase and increases levels of fatty acid synthase
inhibits lipolysis by inhibiting hormone-sensitive lipase phosphorylase kinase - activates glycogen
phosphorylase and inactivates glycogen synthase
Insulin blocks liver gluconeogenesis & glycogenolysis
Fasted state/stress
glucagon activates a series of intracellular events that lead to glycogenolysis in the liver
Muscle cells, which lack a glucagon receptor and cannot respond directly to the hormone
Glucagon also stimulates fatty acid mobilization from adipose tissue by activating hormone-sensitive lipase
Catecholamines & Glucagon counteract Insulin effect
β-adrenergic receptor - increased intracellular cAMP, which
leads to glycogen breakdown and gluconeogenesis phosphorylase kinase - activates glycogen
α-adrenergic receptor stimulates intracellular [Ca2+], which phosphorylase and inactivates glycogen synthase
reinforces the cells’ response to cAMP is fully active only when phosphorylated and in the
presence of increased [Ca2+]
Hormonal effects on fuel metabolism
Diabetes Mellitus
• Heterogeneous group of multifactorial, polygenic syndrome
• Leading cause of death
• Insulin either is not secreted sufficiently or does not
sufficiently stimulate its target cells
• Elevated blood glucose level – glucose spills over into urine
(diagnostic test); cells still starve as insulin-stimulated glucose
entry is impaired.
• Triacylglycerol hydrolysis, FA oxidation, gluconeogenesis &
ketone body formation accelerated
• Ketoacidosis – H+ excretion accompanied by NH4, Na+, K+, Pi
and H2O excretion – frequent urination and decreased blood
volume
• 2 major forms
1. Insulin-dependent, juvenile onset or
type 1 diabetes
• Insulin absent - Caused by a deficient/defective pancreatic β
cells
• Condition results from an autoimmune response that
selectively destroys β cells
• Symptoms appear abruptly when 80-90% β cells have died
• To survive, patients need - daily insulin injections, balanced
diet & exercise
• Lifespan reduced due to degenerative complications like
kidney failure, nerve impairment and CV disease – imprecise
metabolic control
• Hyperglycemia also leads to blindness through retinal
degeneration and glucosylation of lens proteins, causing
cataracts
Metabolic changes in Type 1 diabetes
2. Non-Insulin-dependent, maturity onset
or type 2 diabetes
• More common (90% diabetes cases), obese individuals
• Individuals have normal or even greatly elevated levels of
insulin but the target cells are not responsive to insulin
• Blood glucose conc much higher than normal
• This hyperglycemia induces pancreatic cells to increase
insulin production
• Small fraction of cases result from mutation in the insulin
receptors – affect insulin-binding ability or tyrosine kinase
activity – however, clear genetic cause not identified
• Many factors – for e.g. increased insulin production from over
eating would suppress the synthesis of insulin receptors.
• 2nd hypothesis: obesity caused elevated blood conc of FFA
decreases insulin signal transduction.
Drugs for treating Type 2 diabetes
Suppressing glucose release Suppressing glucose release, promoting
insulin-stimulated glucose disposal in muscle
• Increases cellular AMP level, which increases AMP to ATP ratio
promotes AMPK phosphorylation & activity
• Increased AMPK activity decreases gluconeogenesis in liver and
increases glucose utilization in muscle
• Metformin may also act by inhibiting glucagon signaling in liver
• TZDs binds and activates the transcription factor PPAR-γ in adipose
tissues. PPAR-γ activation induces synthesis of adiponectin leading
to increased AMPK activity – decrease in lipolysis, FA export. This
decreases the conc of FFA in blood ultimately decreasing insulin
resistance.
