Insulin, Glucagon, and Diabetes Mellitus

Prof. dr. Zoran ValićDepartment of PhysiologyUniversity of Split School of Medicine

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

1) acini (secrete digestive juices)2) 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

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

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

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

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

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

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)

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

muscle tissue depends on fatty acids, resting muscle membrane is only slightly permeable to glucose

1) moderate or heavy exercise – fibers more permeable in absence of insulin

2) few hours after a meal (BGC is high and pancreas is secreting large quantities of insulin)

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

storing most of glucose in the form of glycogen after a meal and its release between two meals

1) inactivates liver phosphorylase (glikogen)2) increasing the activity of glucokinase

(initial phosphorylation of glucose)3) increase activity of glycogen synthase about 5-6% of the liver mass (100g)

Glucose Release Between Meals

1) pancreas decrease its insulin secretion2) stopping synthesis of glycogen and

preventing uptake of glucose in the liver3) lack of insulin & increase of glucagon

activates phosphorylase (splitting of glycogen into glucose phosphate)

4) activation of glucose phosphatase (spliting of phosphate radical, diffusion of glucose)

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

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

not quite as visible, but equally important long-term effect of insulin lack – extreme

atherosclerosis (MI, cerebral strokes) insulin promotes fat synthesis and storage

increases the utilization of glucose (fat sparer)

promotes fatty acid synthesis (in liver):

1) insulin increases transport of glucose into liver cells (glucose pyruvate acetyl-CoA fatty acids)

2) 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

3) 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

1) insulin inhibits the action of hormone-sensitive lipase (hydrolysis of the triglycerides in fat cells)

2) 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

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

1) insulin stimulates transport of many amino acids into the cells (valine, leucine, isoleucine, tyrosine, and phenylalanine)

2) increases translation of mRNA ("turns on" the ribosomal machinery)

3) increases transcription of DNA (enzymes)4) inhibits catabolism of proteins (lysosomes)5) depresses gluconeogenesis (enzymes)

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

response to increased BGC glucose transporters (GLUT 2) in beta cells glucose is phosphorylated to glucose-6-

phosphate by glucokinase “rate limiting step” ATP is formed – inhibits KATP channels

(sulfonylurea) – opening Ca channels – exocytosis of inzulina

Control of Insulin Secretion

formerly, it was believed that insulin secretion was controlled almost entirely by BCG

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

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 (10-25x basal level)

Other Factors That Stimulate Insulin Secretion

1) amino acids (arginine & lysine; little alone, but combined with BGC x2; important)

2) gastrointestinal hormones (gastrin, secretin, cholecystokinin, GIP; amplify the action of glucose; anticipatory effect)

3) other hormones and autonomic nervous system (glucagon, hGH, cortisol, progesterone and estrogen; prolonged secretion – exhaustion of beta cells)

Switching Between Carbohydrate and Lipid Metabolism

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

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

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

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

activation of adipose cell lipase inhibition of storage of triglycerides in liver in high concentrations :

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

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 (4-5x, prevents a decrease in BGC)

Somatostatin Inhibits Glucagon and Insulin Secretion

delta cells, 14 amino acid polypeptide, extremely short half-life, extend the period of absorption, GHIH in hypothalamus

1) locally, depress secretion of both insulin and glucagon

2) decreases the motility of the stomach, duodenum, and gallbladder

3) decreases both secretion and absorption in the gastrointestinal tract

Importance of BGC Regulation

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

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 : type I – insulin-dependent diabetes mellitus

(IDDM) type II – non-insulin-dependent diabetes

mellitus (NIDDM, insulin resistance)

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

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)

increase in BGC to 17-66 mmol/L (300-1200 mg/100 ml :

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)

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

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)

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

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”1) obesity, especially accumulation of abdominal fat2) insulin resistance3) fasting hyperglycemia4) increased blood triglycerides and decreased blood high-

density lipoprotein-cholesterol5) hypertension

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

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

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

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

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