Hormones

in Metabolism

Ani Retno Prijanti

Biochemistry & Molecular Biology
 Objectives
 Describe the functional anatomy of the pancreas

 List all pancreatic hormones

 Describe the regulation of pancreatic hormone secretions

 Illustrate the mechanisms of action of insulin and glucagon

 Discuss the physiological effects of insulin and glucagon

 Describe the pathophysiology of the different types of

diabetes mellitus
The Major Endocrine Systems and Their Targets
What Hormones Regulate Metabolism?
•Insulin
•Glucagon
•Thyroid hormone
•Cortisol
•Epinephrine

Most regulation occurs in order to maintain

stable blood glucose concentrations for
supplying fuel to the brain!
The Pancreas
 Endocrine Pancreas

• One to two million islets

• Secretion of insulin and glucagon

– Regulate glucose, lipid and protein metabolism

• Others: amylin, somatostatin, pancreatic

polypeptide
 The Endocrine Pancreas (Islets of
Langerhans)
• Alpha (A cells)
– 17-20 % of islet cells
– Glucagon

• Beta (B cells)
– 60-70% of islet cells
– Insulin

• Delta (D cells)
– 7-10% of islet cells
– Somatostatin

• F (PP) cells
– Approx 5% of islet cells
– Pancreatic polypeptide
 Interaction Between the Pancreatic
Hormones
Insulin

Amylin Somatostatin

Glucagon
Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue peptide hormone. It is
cosecreted with insulin from the pancreatic β-cells in the ratio of approximately
100:1
Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting
satiety, thereby preventing post-prandial spikes in blood glucose levels.
Blood Glucose and the Pancreatic
Hormones
Glucose Levels and Insulin Release
from the Beta Cells
Short half life (3-6 min)
 Physiological/Metabolic Effects of
Insulin
• Fat metabolism
– Storage of lipid: TG

• Protein metabolism
– Amino acid uptake by cells
– Conversion of amino acids into proteins
– Inhibits break down of protein

• Carbohydrate metabolism
– Conversion of glucose into glycogen
– Conversion into fat – storage in adipose tissue
 The Insulin Receptor
•Membrane glycoproteins
composed of 2 subunits

•Tyrosine kinase activity

•Sequence of events:
•Insulin binds alpha subunit
•Beta activates itself via
autophosphorylation

•Phosphorylation of IRS-1 and

IRS-2
•Endpoints are:
1. Mitogenic pathway
2. Metabolic pathway
 Metabolic Effects of Insulin
• Energy storage
– Liver
• Promotes anabolism:
– glycogen synthesis and storage
– Inhibits glycogen breakdown
– Promotes glycolysis
– Inhibits gluconeogenesis
– Increases protein, triglyceride and VLDL formation

• Inhibits catabolism
– Decrease hepatic glycogenolysis, ketogenesis and
gluconeogenesis
 Metabolic Effects of Insulin
• Muscle
– Promotes protein synthesis
• Increased amino acid transport
• Stimulating ribosomal protein synthesis

– Promotes glycogen synthesis

• Enhanced by increased glucose transport into cells
• Enhanced activity of glycogen synthase
• Inhibiting activity of glycogen phosphorylase

– Increased glucose transport into muscle cells

 Metabolic Effects of Insulin
• Adipose tissue
– Promotes triglyceride storage

• Increased production of lipoprotein lipase

– Hydrolysis of triglycerides from circulating lipoproteins

• Increasing glucose transport into fat cells

– Increased cellular levels of alpha-glycerol phosphate –
esterification of fatty acids to triglycerides

• Inhibition of intracellular lipolysis (lipase),  inhibit

Hormone sensitive lipase.
Insulin Increases Intracellular Glucose
Insulin and Growth Hormone: Synergy
Kondisi setelah
makan

Insulin
VLDL Menstimulasi LPL  meningkatkan ambilan asam lemak dari kilomikron dan 
Menstimulasi glycolysis  meningkatkan sintesis gliserol fosfate 
 meningkatkan esterifikasi
Meng-inaktivasi HSL 
Efek total: TG storage (menyimpan lemak)
 Kondisi kelaparan atau olah raga

Glucagon, epinephrine

 mengaktifkan adenylate cyclase

 mengaktifkan:
cAMP
protein kinase A
hormone sensitive
lipase/HSL

Efek:
Penguraian TG
Peningkatan asam lemak bebas
 Sintesis/ pembentukan benda Keton di hati

Berlangsung pada saat:

kelaparan , Olah Raga
dalam waktu lama

Menyebabkan:

FFA meningkat
high HSL activity


Benda keton meningkat
 Glucagon
 Counter-regulatory hormone
 Increases blood glucose concentration.
 Effects:
◦ Breakdown of liver glycogen (glycogenolysis)
 Via activation of adenlyl cyclase
 Using an amplification mechanism (i.e. each product is greater
than the one before)
 Can cause blood glucose to double within a few minutes

◦ Increase gluconeogenesis in the liver

 Increased uptake of amino acids which are then used to make
glucose
Glucagon – Mechanism of Action
 Glucagon
Supra-physiological levels

– Activation of adipose cell lipase

– Inhibits storage of triglycerides in the liver

– Increased blood levels of fatty acids

– Enhances heart strength

– Increases blood flow to kidneys
– Enhances bile secretion
– Inhibits gastric acid secretion
 Regulation of Glucagon Secretion
 Blood glucose – most potent regulator

 Increased amino acids in the circulation

– Especially arginine and alanine
– Used to make glucose
 Cathecholamine released
 Gastrointestinal hormones (cholecystokinin, gastrin, GIP).
CCK8 is able to reverse the inhibitory effect of glucose on glucagon secretion, second, CCK8 sensitizes the beta
cell to the insulinotropic effect of glucose, and third, CCK8 enhances the effect of glucose on somatostatin
release. E. J. Verspohl, H. P. T. Ammon

 Glucocorticoids mempengaruhi sekresi glukagon

 Sympathetic and parasympathetic stimulation
 Exercise
– Can increase glucagon 4-5 fold
– Due to increased amino acids?
– Beta-adrenergic stimulation of the islets of Langerhans?
 Somatostatin (GHIH)
Short polypeptide (14 amino acids)
Short half-life (3 min)

Regulation:
– Increased blood glucose
– Increased amino acids
– Increased fatty acids
– Increased GI hormones
– Inhibit cholesterol synthesis

– Cells within pancreatic islets secrete insulin, glucagon and somatostatin. Somatostatin appears to act
primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon. It also has the
effect in suppressing pancreatic exocrine secretions, by inhibiting cholecystokinin-stimulated enzyme
secretion and secretin-stimulated bicarbonate secretion.
 Somatostatin
 Inhibitory effect on both insulin and glucagon
 Decreases motility of stomach, duodenum and
gallbladder
 Decreases secretion and absorption in the
gastrointestinal tract

 End result
1. Extends the period of time during which nutrients are
taken in to the circulation
2. Decreased utilization of absorbed nutrients by tissues
3. Extends the availability of food for longer periods of
time
 Diabetes Mellitus
 Disordered metabolism
 Inappropriate hyperglycemia
o Absolute deficiency of insulin secretion
Type 1 diabetes:
1. Pancreatic beta cell destruction
A. >95% due to autoimmune process
B. <5% idiopathic
2. Prone to ketoacidosis
3. Require insulin replacement therapy

o Reduction in physiological effectiveness of insulin

o Both
 Diabetes Mellitus
• Type 2

– Mostly associated with insulin resistance

– Some impairment in compensatory insulin
secretion
– Heterogenous
– Association with: visceral obesity, hypertension,
hyperinsulinemia, dyslipidemia, coronary heart
disease (syndrome X)
– 80-90% of diabetes cases in the US
 Genetic Defects of Pancreatic B Cell Function

• Late childhood or by age 25 –

– Maturity-onset-Diabetes of the Young (MODY)
• Suggested autosomal dominance transmission
• Defect in glucose-induced insulin release
• Patients:
– Non-obese
– Non-ketosis prone
 Effects of Hyperglycemia
Increased loss of glucose in urine (threshold 180 mg/100ml)
Polyurea
Osmotic diuresis
Cellular dehydration (due to increased osmotic pressure)
Extracellular dehydration
Increased thirst
Tissue injury (chronic)
◦ Heart attacks
◦ Stroke
◦ End-stage kidney diease
◦ Retinopathy
◦ Ischemia/gangrene of limbs
Metabolic acidosis
Fed State
Insulin

stimulates LPL
increased uptake of
FA from chylomicrons
and VLDL

stimulates glycolysis
increased glycerol
phosphate synthesis

increases esterification

induces HSL phosphat-ase

inactivates HSL

net effect: TG storage

 Starved or Exercising State

Glucagon, epinephrine
activates adenylate cyclase
increases cAMP
activates protein
kinase A
activates HSL

net effect:
TG mobilization and
increased FFA
 Summary
 The endocrine pancreas secretes hormones that are
important in maintaining optimal blood glucose levels

 Insulin is secreted during hyperglycemia and lowers blood

glucose by increasing its clearance from the blood and
decreasing its synthesis

 Glucagon is secreted during hypoglycemia and increases

blood glucose (counter-regulatory to insulin)

 Diabetes mellitus is a heterogenous metabolic

disorder(state of hyperglycemia) in which there is either
an inability to secrete insulin, a decrease in the response
to insulin or both
 References
• Greenspan and Gardner, 2004. Basic and
Clinical Endocrinology, 7th edition; Lange.

• Guyton and Hall, 2006. Textbook of Medical

Physiology, 11th edition.

• Lecture: Eeman At-Taras, PhD, etc.

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