Transcript Insulin, Glucagon, and Diabetes Mellitus

Insulin, Glucagon,
and Diabetes Mellitus
Prof. dr. Zoran Valić
Department of Physiology
University of Split School of Medicine
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digestive functions
two important hormones: insulin and
glucagon (crucial for normal regulation of
glucose, lipid, and protein metabolism)
other hormones: amylin, somatostatin, and
pancreatic polypeptide
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2)
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acini (secrete digestive juices)
islets of Langerhans (secrete insulin and
glucagon directly into the blood)
1-2 million islets of Langerhans (0.3 mm in
diameter)
three major types of cells: alpha, beta, and
delta cells
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beta cells – 60%, lie mainly in the middle of
each islet, secrete insulin and amylin
alpha cells – 25%, secrete glucagon
delta cells – 10%, secrete somatostatin
PP cells – present in small numbers, secrete
pancreatic polypeptide?
insulin inhibits glucagon secretion, amylin
inhibits insulin secretion, and somatostatin
inhibits secretion of insulin and glucagon
Insulin and Its Metabolic Effects
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Banting and Best (1922) – isolated inzulin
insulin has always been associated with
"blood sugar“, but it has profound effect on
metabolism of fat (acidosis,
arteriosclerosis) and proteins
insulin secretion is associated with energy
abundance
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excess amounts of carbohydrates cause
increase in insulin secretion
insulin stores the excess carbohydrates as
glycogen (liver and muscles)
inzulin stores adipose tissue
inzulin promotes amino acid uptake by cells
and conversion of amino acids into protein
inzulin inhibits the breakdown of proteins
Insulin Chemistry and Synthesis
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small protein (5808)
it is composed of two amino acid chains
connected by disulfide linkages
spliting of the chains – loss of activity
translation of the insulin RNA by ribosomes
 preproinsulin (11500)  in the ER
proinsulin (9000)  in Golgi apparatus
insulin and the C chain peptide
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circulates almost entirely in an unbound
form
plasma half-life averages only about 6 min
cleared from circulation within 10 to 15 min
degraded by the enzyme insulinase mainly
in the liver, to a lesser extent in the kidneys
and muscles
Activation of Target Cell
Receptors and Resulting Effects
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activation of membrane receptor protein
autophosphorylation of beta subunits 
activation of tyrosine kinase 
phosphorylation of multiple other
intracellular enzymes including a group
called insulin-receptor substrates (IRS)
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after few seconds 80% of cells increase their
uptake of glucose (muscle and adipose cells)
cells become more permeable for many
amino acids, potassium and phosphate ions
within 10-15 min change in activity of many
intracellular metabolic enzymes
within few hours or days – rates of
translation and transcription
Inzulin  Muscle Glucose
Uptake and Metabolism
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muscle tissue depends on fatty acids,
resting muscle membrane is only slightly
permeable to glucose
moderate or heavy exercise – fibers more
permeable in absence of insulin
few hours after a meal (BGC is high and
pancreas is secreting large quantities of
insulin)
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if the muscles are not exercising after a
meal, glucose is stored in the form of
muscle glycogen (2-3%)
spurts of anaerobic energy
insulin facilitates glucose transport through
the muscle cell membrane
Insulin  Liver Uptake, Storage,
and Use of Glucose
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storing most of glucose in the form of
glycogen after a meal and its release
between two meals
inactivates liver phosphorylase (glikogen)
increasing the activity of glucokinase
(initial phosphorylation of glucose)
increase activity of glycogen synthase
about 5-6% of the liver mass (100g)
Glucose Release Between Meals
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pancreas decrease its insulin secretion
stopping synthesis of glycogen and
preventing uptake of glucose in the liver
lack of insulin & increase of glucagon
activates phosphorylase (splitting of
glycogen into glucose phosphate)
activation of glucose phosphatase (spliting
of phosphate radical, diffusion of glucose)
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insulin promotes conversion of excess
glucose into fatty acids (lipoproteins – fat)
inzulin inhibits gluconeogenesis (decreasing
the quantities and activities of the liver
enzymes and availability of precursors
required for gluconeogenesis)
Lack of effect of insulin on
glucose uptake and usage by brain
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most of the brain cells are permeable to
glucose and can use glucose without the
intermediation of insulin
only glucose for energy
when the BGC falls too low (1-3 mmol/L) –
hypoglycemic shock (nervous irritability,
fainting, seizures, and even coma)
Effect of Insulin on Fat
Metabolism
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not quite as visible, but equally important
long-term effect of insulin lack – extreme
atherosclerosis (MI, cerebral strokes)
insulin promotes fat synthesis and storage
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increases the utilization of glucose (fat
sparer)
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promotes fatty acid synthesis (in liver):
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insulin increases transport of glucose into
liver cells (glucose  pyruvate  acetylCoA  fatty acids)
excess of citrate and isocitrate ions formed
by citric acid cycle when excess amounts of
glucose are being used for energy 
activation of acetyl-CoA carboxylase
formation of triglycerides and release from
liver cells in form of lipoproteins; insulin
activates lipoprotein lipase in adipose tissue
Storage of Fat in Adipose Cells
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insulin inhibits the action of hormonesensitive lipase (hydrolysis of the
triglycerides in fat cells)
insulin promotes glucose transport through
the cell membrane into the fat cells; forms
large quantities of α-glycerol phosphate
(base for glycerol)
Insulin Deficiency Increases Use
of Fat for Energy
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hormone-sensitive lipase in the fat cells
becomes strongly activated (release of fatty
acids and glycerol into circulating blood)
increases plasma cholesterol and
phospholipid concentrations (3x increase in
plasma lipoproteins)
ketosis and acidosis (acetoacetic acid –
acidosis, β-hydroxybutyric acid & acetone)
Effect of Insulin on Protein
Metabolism and on Growth
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insulin stimulates transport of many amino
acids into the cells (valine, leucine,
isoleucine, tyrosine, and phenylalanine)
increases translation of mRNA ("turns on"
the ribosomal machinery)
increases transcription of DNA (enzymes)
inhibits catabolism of proteins (lysosomes)
depresses gluconeogenesis (enzymes)
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insulin and growth hormone interact
synergistically to promote growth
insulin is essential for growth
two hormones function synergistically to
promote growth
each promotes cellular uptake of a different
selection of amino acids, all of which are
required for growth
Mechanisms of Insulin Secretion
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response to increased BGC
glucose transporters (GLUT 2) in beta cells
glucose is phosphorylated to glucose-6phosphate by glucokinase
“rate limiting step”
ATP is formed – inhibits KATP channels
(sulfonylurea) – opening Ca channels –
exocytosis of inzulina
Control of Insulin Secretion
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formerly, it was believed that insulin
secretion was controlled almost entirely by
BCG
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increased BGC stimulates insulin secretion
at BGC 4,5-5,0 mmol/L (80-90 mg/100 ml)
– lučenje 25 ng/min/kg
increase in BGC insulin secretion increases
markedly in two stages
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feedback relation between BGC and insulin
secretion rate
BGC of 20-30 mmol/L (400-600 mg/100
ml) insulin secretion is reaching a peak (1025x basal level)
Other Factors That Stimulate
Insulin Secretion
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amino acids (arginine & lysine; little alone,
but combined with BGC x2; important)
gastrointestinal hormones (gastrin, secretin,
cholecystokinin, GIP; amplify the action of
glucose; anticipatory effect)
other hormones and autonomic nervous
system (glucagon, hGH, cortisol,
progesterone and estrogen; prolonged
secretion – exhaustion of beta cells)
Switching Between Carbohydrate
and Lipid Metabolism
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insulin promotes use of carbohydrates for
energy, depresses the utilization of fats
control – BGC
hGH, cortisol – are secreted in response to
hypoglycemia, inhibit cellular utilization of
glucose while promoting fat utilization
epinephrine – increasing both (BGC and
fatty acids)
Glucagon and Its Functions
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alpha cells of the islets of Langerhans
increase BGC
large polypeptide (3485); composed of a
chain of 29 amino acids
hyperglycemic effect/hyperglycemic
hormone
Effects on Glucose Metabolism
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breakdown of liver glycogen
(glycogenolysis; adenylyl cyclase  cAMP
 protein kinase  phosphorylase b 
phosphorylase a  degradation of glycogen
into glucose-1-phosphate 
dephosphorylation  BGC; amplifying
mechanism)
Effects on Glucose Metabolism
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increased gluconeogenesis in the liver
(increase in the rate of amino acid uptake
by the liver cells and then the conversion of
many of the amino acids to glucose by
gluconeogenesis (pyruvate 
phosphoenolpyruvate))
Other Effects of Glucagon
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activation of adipose cell lipase
inhibition of storage of triglycerides in liver
in high concentrations :
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enhances the strength of the heart,
increases blood flow in some tissues,
especially the kidneys, enhances bile
secretion, inhibits gastric acid secretion
Regulation of Glucagon Secretion
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increased BGC inhibits glucagon secretion
(exactly opposite from effect of insulin)
increased blood amino acids stimulate
glucagon secretion (same as insulin; alanine
and arginine)
exercise stimulates glucagon secretion (45x, prevents a decrease in BGC)
Somatostatin Inhibits Glucagon
and Insulin Secretion
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delta cells, 14 amino acid polypeptide,
extremely short half-life, extend the period
of absorption, GHIH in hypothalamus
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locally, depress secretion of both insulin and
glucagon
decreases the motility of the stomach,
duodenum, and gallbladder
decreases both secretion and absorption in the
gastrointestinal tract
Importance of BGC Regulation
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glucose is the only nutrient used by brain,
retina, and germinal epithelium of gonads
most of the glucose between meals is used
in the brain
glucose can exert high osmotic pressure
(cellular dehydration), loss of glucose in
urine, osmotic diuresis by the kidneys (loss
of fluids and electrolytes), damage to many
tissues, especially to blood vessels
Diabetes Mellitus
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syndrome of impaired carbohydrate, fat,
and protein metabolism, caused by either
lack of insulin secretion or decreased
sensitivity of the tissues to insulin
two general types :
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type I – insulin-dependent diabetes mellitus
(IDDM)
type II – non-insulin-dependent diabetes
mellitus (NIDDM, insulin resistance)
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metabolism of all main foodstuffs is altered
prevent the efficient uptake and utilization
of glucose by most cells of the body
increase in BGC
cell utilization of glucose falls increasingly
lower, and utilization of fats and proteins
increases
Type I Diabetes
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injury to beta cells or diseases that impair
insulin production (viral infections or
autoimmune disorders, heredity)
usual onset of type I diabetes occurs at
about 14 years of age – juvenile diabetes
mellitus
may develop abruptly (few days or weeks)
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increase in BGC to 17-66 mmol/L (3001200 mg/100 ml :
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loss of glucose in urine (BCG > 10 mmol/L)
cell dehydration (osmotic transfer of water out
of the cells; osmotic diuresis  extracellular
dehydration)
chronic increase – tissue injury(MI, stroke,
kidney failure, retinopathy ,blindness, and
ischemia and gangrene of the limbs, peripheral
neuropathy, autonomic nervous system
dysfunction)
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severe metabolic acidosis (excess keto
acids) + dehydration = severe acidosis 
diabetic coma  death
physiological compensations: rapid and
deep breathing, decrease in bicarbonate
depletion of body's proteins (asthenia (lack
of energy) despite eating large amounts of
food (polyphagia))
Type II Diabetes
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diminished sensitivity of target tissues to
the metabolic effects of insulin – insulin
resistance
far more common (90-95%)
occurs after age of 30 – adult-onset diabetes
in recent years – younger individuals
(increasing prevalence of obesity)
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increased plasma insulin concentration
(hyperinsulinemia)
compensatory response by the pancreatic
beta cells
in the early stages of the disease – moderate
hyperglycemia; in the later stages – beta
cells become "exhausted" or damaged –
more severe hyperglycemia
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gradual process, beginning with excess
weight gain and obesity (fewer insulin
receptors or abnormalities of the signaling
pathways)
in some individuals pancreas is “used up”
in the beginning – limitation of food intake,
decrease in body weight
“metabolic syndrome”
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obesity, especially accumulation of abdominal fat
insulin resistance
fasting hyperglycemia
increased blood triglycerides and decreased blood highdensity lipoprotein-cholesterol
hypertension
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drugs that increase insulin sensitivity –
thiazolidinediones
drugs that suppress liver glucose production
– metformin
drugs that cause additional release of insulin
by the pancreas – sulfonylureas
in the later stages of type II diabetes, insulin
administration is usually required
Physiology of Diagnosis of DM
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urinary glucose (qualitative & quantitative
tests)
BGC (4,5-5,0 mmol/L – normala, 6,0
mmol/L gornja granica) & insulin levels
oral glucose tolerance test (OGTT) – 1 g
glucose / kg body mass
acetone breath
Treatment of Diabetes
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insulin is available in several forms
(regular, longer-acting insulins)
individualized pattern of treatment
dieting and exercise
animal / recombinant DNA
lipid-lowering drugs to control high level of
blood cholesterol
Insulinoma – Hyperinsulinism
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excessive insulin production from an
adenoma of an islet of Langerhans
much rarer than diabetes
10-15% of these adenomas are malignant –
tremendous production of insulin
more than 1 kg of glucose have had to be
administered every 24 hours
Insulin Shock and Hypoglycemia
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insulin-secreting tumors or administration
of too much insulin
BGC: 3-4 mmol/L – CNS becomes
excitable, hallucinations, extreme
nervousness, trembling, sweating
BGC: 1-3 mmol/L – clonic seizures and
loss of consciousness
state of coma, permanent damage