CH 9-pancreatic hormones

panreas

Largest endocrine gland, developed from duodenum

islets of Langerhans: contain endocrine cells, source of pancreatic hormones, secretes insulin and glucagon

acinar cells: exocrine cells, secretes digestive enzymes and buffers

pancreatic hormones

insulin, glucagon, somatostain, panctratic polypeptide

discovered in pancreas of rabbit by Paul Langerhans

pancreas structure

divided into head, body, and tail

Ventral bud (posterior), dorsal bud (anterior), fuse together

Poteior supplief by superior msentriec artery

Anterior supplied by celiac artirfy

Islets of langerhans

contain fenestrated capillaries': faccilated release of pancreatic hormones to circulation

First organ exposed to them: liver

neuro feedback

Parasympathetic
-ACH, muscarinic (M3) receptors, gastrin, VIP
-All 4 hormones released

Sympathetic
-secretion of glucagon and pancreatic polypeptide,
---inhibits insulin and somatostatin
---Nore, nueropeptide Y

Islet cell types

make up 1.5% of pancreas weight

4 islet cells (alpha, beta, delta, F/PP)
•Posterior has mostly F cells, then B cells, then A
•Few F cells in tail
•Anterior has mostly B cells, then a ,thwn D, barely any F
•B cells are in middle oc islests
•F are least abundant, but their volume increases with age and bigger in men


a-20%
b-60%
d-10%
f-1%

hormones

are all Peptides, secreted by islets
A cells=glucagon
•B cells=source of insulin
D cells: somatostatin (SST)
F/PP cells: pancreatic polypeptide
•
Mering and Minkowsksi: showed pancreatic hormones' used for metbaolsim (blood glucose), pancreatomy in dogs lead to diabetes mellitus
•Banting and Best treated diabetic dogs with pancrratic extracr, found treatment had blood glucose lowering effect, discovered insulin
• Structure of insulin, discovered by Sanger

insulin structure

peptide, A,B,C chains, terminal c
Produced In islet B cells
•Peptide bond hydrolyzed by Proprotein Convertase
Has disulfide bond between position 6 and 11
•Cysteine residues at position 7
•Amino acid sequence in insulin is conserved, no big differences between species
•Humans vs pig differ by one amino acid, Bovine vs human differs by 3

Short half life, degraded by insulinase enzyme in liver, kindey, placenta

blood glucose levels

•Normal glucose levels=normoglycemia/euglycemia=90-110
At 40-45 person is lethargic=coma
Below 15=brain damage
80-85=inhibits insulin secretion
At 70=hormones' are secreted to restore noral ststae


At 130=hyperglycemic state, no insulin to break down glucose, causes osmotic diuresis, metabolic acidosis: causes urinary loss of glucose

• Glycosuria:

excess glucose in kidneys that fail to return to blood and is excreted



gluconeogenesis: synthesis of new glucose from noncarbohydrate precursors, provides glucose when dietary intake is insufficient or absen

glucose in kidneys

Glucose in kidneys is reabsorbed using carrier-assisted transport SGLT-1, SGLT-2, glu-t

Glucose Tolerance Ttest (GTT)

Tests body's ability to metabolize amount of glucose
•
Person eats 150 g of carbs 3 days before
Checked at 60 and 130 minuetes

normal results

• fasting blood glucose level - 60 to 100 mg/dL
• One-hour value

impaired: Diabetes Type 1/2

• Fasting blood glucose level - 100 to 125 mg/dL
• Two-hour 140 – 200 mg/dL

Abnormal Results for Diabetes Type 1 or 2

• Fasting blood glucose level - >126 mg/dL or higher
• Two-hour ~ 200 mg/dL or higher

Insulin receptor

Up to 200000 insulin receptors per cell
•
Receptor is dimeric glycoprotein with alpha and B unit, has disulfide bond

Alpha unit: has ligand binding site, causes dimerization of receptor, Has 7 tyrosine residues

B unit: Tyrosine kinase activity, causes phosphorylation

Up/Down regulation of Insulin receptor

Up regulated=prolonged fasting, glucose is low, insulin is up

Down regulation=high insulin, hyperglycemia

Glucorticoid induced hyperglycemia

cortisol is high, decrease insulin

Type 2 diabetes mellitus

down regulation, high glucose

actions of insulin

Transcriptions pf genes via MAPK=cell growth/differentiation
vascular endothelium=cause vasoconstriction via MAPK
Phosphorlyation of IRS cuases, IP3 production, acivtaes PDK and PKC, uptake of glucose into muscle

actions of insulin 2

Activation of FOXO1 protein=gluconeogenesis
Activation of GS stimulates glycogenesis in skeletal muscle
Activation of eNOS, releases Nop, causes vasodilation

anabolic effects

Glycogenesis: glucose uptake glucose uptake by muscles and adipose tissue,

Lipogensis: synthesis and storage of triglycerides in adipose tissue lipid storage in adipose tissue by the action of lipoprotein lipase

inhibition of lipolysis

ketogenesis by inhibiting hormone-sensitive lipase (which responds to glucagon and epinephrine and causes lipolysis),
•
positive nitrogen balance and uptake of amino acids into the muscles.


Insulin is known to cause leptin release from adipocytes
Glucose Transporters (GluT)

Glucose Transporters (GluT)

• 14 types, uniports

Glut1

Ubiquitous transporter, expressed in erythrocytes, fetal tissues, astrocytes, and is bidirectional.
•

glut2

Bidirectional transporter found islet β cells, hepatocytes, renal tubular cells and enterocytes.
•

GluT3

Bidirectional main glucose transporter expressed in brain, neurons and placenta.

GluT4

bidrectional, Found in adipose tissue and skeletal and cardiac muscles.
•

GLU T5

A fructose transporter in intestine, kidney, testes.

Gly t6

Expressed in spleen, WBCs, brain.

glut7

Transports fructose in testes, ileum and colon.

glut14

Expressed in testes

Sodium Dependent Glucose co transporter (SGLT)

In luminal side in inteniste/kindney

SGLT1

SGLTT-1 in enterocytes in intestine and renal tubes

SGLT2

n PCT, in kidneys, blocked by inhibitors, leading to unrary excretion of glucose and low glucose level

simulating factors of insulin release

• Glucose (up to 30x) via GluT2 trnaspoters, eneters in b cells and closes K channels, ca enters=depolarization
• GIP
• Gastrin, secretin
• Epinperhine via g protein coupled B2 receptors
• GPR40 with calcium via IP3 pathway
• ACH via M3 receptors
• Amino acids
•FFA
GI tract hormones
glucagon
sulfonylureas

inhibit insulin secretion

Somatostatin (SST) via SST-R5 recetor
Epinephrine
Norepinephrine via alpha receptors
Atropine by blocking M3 receptors

Islet Amyloid Polypeptide (IAPP) or Amylin

AA Peptide co-secreted with insulin in B cells in response to glucose
• In stomach, intestine, lung and bran
• Slows down gastric emptying and and inhibition of food intake

glucagon

Encoded by gene on chromosome 2
Single chain Peptide, no disulfide bond
starting from the N-terminus, numbers indicate amino acid residue


Stimulates glycogenolysis's via PKA,
Has hyperglycemic actions


GPCR, acts via cAMP in liver, muscles, adipose tissue


Glycogenolysis

Gluconeogenesis

Lipolysis

Ketogenesis

1--30 Glicentin-related Pancreatic Polypeptide (GRPP

Expressed in both pancreas and intestine,

glucoregulatory potential is largely unknown,

inhibits glucose-stimulated insulin-release.

consists of 30 amino acids.

1-69 Glicentin

Expressed in intestinal L-cells,

69 amino acid long peptide,

stimulates insulin secretion and in the gastrointestinal tract

promotes cell proliferation and gut motility

33-61 Glucagon

Major hormone (29 amino acids) of pancreatic α cells,

also known as hyperglycemic glycogenolytic factor (HGF).

33-69 Oxyntomodulin

Produced in the intestine,

37 amino acid peptide,

suppresses appetite

77-108 Glucagon-like peptide-1 (GLP-1):

Expressed both in the pancreas and intestine,

31 amino acid peptide,

‘incretin’ (promotes glucose utilization), which binds to its receptors on the β cells

stimulates insulin and somatostatin secretion

inhibits glucagon and gastric emptying, and appetite.

promotes β cell proliferation by inhibiting apoptosis.

• 126-158 Glucagon-like peptide-2 (GLP-2

Expressed both in the pancreas and intestine,

33 amino acid peptide

promotes cell growth in GI mucosal tract,

plays a role in short bowl syndrome

malabsorption disorder: due to lack of functional small intestine) Crohn’s syndrome (: inflammatory bowl disease),

both of which cause diarrhea, abdominal pain etc

Stimulators of Glucagon Secretion

stimulated by epinephrine (via β adrenergic receptors)

cholecystokinin (CCK), gastrin, glucocorticoids,
gastrin inhibiting polypeptide (GIP), alanine, and hypoglycemia

inhibitors of glucagon secretion

(GABA)
somatostatin (SST),

epinephrine (via α adrenergic receptors)

and amino acids arginine and leucine

Pancreatic Polypeptide

single chain polypeptide

Expressed in F-cells or pancreatic polypeptide (PP) cells or γ cells in the head of pancreas,

promotes acid secretion by parietal cells and pepsin by chief cells in the gastric mu


Postprandial rise not due to glucose or lipidsDecreases with reduced food intak

not related to diet
antagonistic to CCK and inhibits CCK secretions from the exocrine pancreas

increase in old age, alcohol abuse, diarrhea, chronic renal failure, hypoglycemia or inflammation, and various hormone secreting tumors s

Diabetes Mellitus

First described in 1500 B.C. in Egypt,

due to : hyperglycemia, glucose intolerance, metabolic acidosis and ketosis, suppressed growth and structural damage to the microcirculation in eyes, kidneys and muscles

due to insulin deficiency or insulin insensitivity or both.

(i) insulin-dependent diabetes mellitus (IDDM) and (ii) insulin-independent diabetes mellitus (NIDDM)


use alloxane and streptzocton (destroy B
• T

• Diabetes Mellitus Type 1

juvenile-onset type,
B-cell destruction, no native insulin or its co-secretion, peptide C,

Autoimmune disorder mediated via CD4+ and CD8+

Presence of ketoacidosis, polyuria, polydipsia,

Requires insulin replacement therapy.

diabetes mellitus type 2

Niddm: insulin independent
Adult or maturity-onset type,

defects including hypertension, coronary heart disease, congestive heart failure

insulin resistance, leading to decreased glucose uptake by muscles and other tissues,

Impaired insulin secretion,

Obesity in some subtypes.


The Type 2 diabetes mellitus is seen in 90% of the diabetics in North America.


ype 2 diabetes mellitus: down regulation, high glucose

somatostatin

SST14

SST28

D cells and brain neuron

actions of sst

Effect on GH release (inhibition)

Effects on insulin, glucagon, and pancreatic polypeptide

SST receptors (5 types)S

STR2 (A)

SSTR5 (B

)SST analog

obese type 2

Insensitivity to endogenous insulin

Normal or exaggerated response to glucose
Islet B cell hyperplasia

Insulin Resistance Syndrome (SyndromeX)

Hyperglycemia
Hyperinsulinemia
Hypertension

non-obese type 2

Asians

Deficient insulin release by islet B cells

Maturity-onset diabetes of young (MODY)
Rare monogenic condition

drugs used

Metformin: Reduces hepatic release of glucose.

Glinides: Promote insulin synthesis in th pancreas.

Thiazolidinedione: Glucose uptake/oxidation, FFA into stored fats.

Sulfonylureas: Promote insulin release from intact β cells.

GLP-1 analogs: Incretin, Reduce appetite, slow down gastric emptying

.DPP4 Inhibitors: Inhibit degradation of incretins like GLP-1 and GIP