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The Endocrine Pancreas. Regulation of Carbohydrate Metabolism. Pancreatic Anatomy. Gland with both exocrine and endocrine functions 15-25 cm long 60-100 g Location: retro-peritoneum, 2 nd lumbar vertebral level Extends in an oblique, transverse position

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the endocrine pancreas

The Endocrine Pancreas

Regulation of Carbohydrate Metabolism

pancreatic anatomy
Pancreatic Anatomy

Gland with both exocrine and endocrine functions

15-25 cm long

60-100 g

Location: retro-peritoneum, 2nd lumbar vertebral level

Extends in an oblique, transverse position

Parts of pancreas: head, neck, body and tail

head of pancreas
Head of Pancreas

Includes uncinate process

Flattened structure, 2 – 3 cm thick

Attached to the 2nd and 3rd portions of duodenum on the right

Emerges into neck on the left

Border b/w head and neck is determined by GDA insertion

SPDA and IPDA anastamose between the duodenum and the right lateral border

neck of pancreas
Neck of Pancreas

2.5 cm in length

Straddles SMV and PV

Antero-superior surface supports the pylorus

Superior mesenteric vessels emerge from the inferior border

Posteriorly, SMV and splenic vein confluence to form portal vein

Posteriorly, mostly no branches to pancreas

body of pancreas
Body of Pancreas

Elongated, long structure

Anterior surface, separated from stomach by lesser sac

Posterior surface, related to aorta, lt. adrenal gland, lt. renal vessels and upper 1/3rd of lt. kidney

Splenic vein runs embedded in the post. Surface

Inferior surface is covered by transverse mesocolon

tail of pancreas
Tail of Pancreas

Narrow, short segment

Lies at the level of the 12th thoracic vertebra

Ends within the splenic hilum

Lies in the splenophrenic ligament

Anteriorly, related to splenic flexure of colon

May be injured during splenectomy (fistula)

pancreatic duct
Pancreatic Duct

Main duct (Wirsung) runs the entire length of pancreas

Joins CBD at the ampulla of Vater

2 – 4 mm in diameter, 20 secondary branches

Ductal pressure is 15 – 30 mm Hg (vs. 7 – 17 in CBD) thus preventing damage to panc. duct

Lesser duct (Santorini) drains superior portion of head and empties separately into 2nd portion of duodenum

arterial supply of pancreas
Arterial Supply of Pancreas

Variety of major arterial sources (celiac, SMA and splenic)

Celiac  Common Hepatic Artery  Gastroduodenal Artery  Superior pancreaticoduodenal artery which divides into anterior and posterior branches

SMA  Inferior pancreaticoduodenal artery which divides into anterior and posterior branches

arterial supply of pancreas1
Arterial Supply of Pancreas
  • Anterior collateral arcade between anterosuperior and anteroinferior PDA
  • Posterior collateral arcade between posterosuperior and posteroinferior PDA
  • Body and tail supplied by splenic artery by about 10 branches
  • Three biggest branches are
    • Dorsal pancreatic artery
    • Pancreatica Magna (midportion of body)
    • Caudal pancreatic artery (tail)
venous drainage of pancreas
Venous Drainage of Pancreas
  • Follows arterial supply
  • Anterior and posterior arcades drain head and the body
  • Splenic vein drains the body and tail
  • Major drainage areas are
    • Suprapancreatic PV
    • Retropancreatic PV
    • Splenic vein
    • Infrapancreatic SMV
  • Ultimately, into portal vein
lymphatic drainage
Lymphatic Drainage
  • Rich periacinar network that drain into 5 nodal groups
    • Superior nodes
    • Anterior nodes
    • Inferior nodes
    • Posterior PD nodes
    • Splenic nodes
innervation of pancreas
Innervation of Pancreas

Sympathetic fibers from the splanchnic nerves

Parasympathetic fibers from the vagus

Both give rise to intrapancreatic periacinar plexuses

Parasympathetic fibers stimulate both exocrine and endocrine secretion

Sympathetic fibers have a predominantly inhibitory effect

innervation of pancreas1
Innervation of Pancreas

Peptidergic neurons that secrete amines and peptides (somatostatin, vasoactive intestinal peptide, calcitonin gene-related peptide, and galanin

Rich afferent sensory fiber network

Ganglionectomy or celiac ganglion blockade interrupt these somatic fibers (pancreatic pain)

slide18

Production of Pancreatic Hormones by Three Cell Types

  • Alpha cells produce glucagon.
  • Beta cells produce insulin.
  • Delta cellsproduce somatostatin.
islet of langerhans cross section
Islet of Langerhans Cross-section
  • Three cell types are present, A (glucagon secretion), B (Insulin secretion) and D (Somatostatin secretion)
  • A and D cells are located around the perimeter while B cells are located in the interior
  • Venous return containing insulin flows by the A cells on its way out of the islets
pancreatic hormones insulin and glucagon regulate metabolism1
Pancreatic Hormones, Insulin and Glucagon, Regulate Metabolism

Figure 22-8: Metabolism is controlled by insulin and glucagon

structure of insulin
Structure of Insulin
  • Insulin is a polypeptide hormone, composed of two chains (A and B)
  • BOTH chains are derived from proinsulin, a prohormone.
  • The two chains are joined by disulfide bonds.
slide22

Roles of Insulin

  • Acts on tissues (especially liver, skeletal muscle, adipose) to increase uptake of glucose and amino acids.

- without insulin, most tissues do not take in glucose and amino acids well (except brain).

  • Increases glycogen production (glucose storage) in the liver and muscle.
  • Stimulates lipid synthesis from free fatty acids and triglycerides in adipose tissue.
  • Also stimulates potassium uptake by cells (role in potassium homeostasis).
the insulin receptor

phosphorylation of

insulin responsive

substrates (IRS)

RAS

RAF-1

MAP-K

MAP-KK

Final

actions

The Insulin Receptor
  • The insulin receptor is composed of two subunits, and has intrinsic tyrosine kinase activity.
  • Activation of the receptor results in a cascade of phosphorylation events:
specific targets of insulin action carbohydrates
Specific Targets of Insulin Action: Carbohydrates
  • Increased activity of glucose transporters. Moves glucose into cells.
  • Activation of glycogen synthetase. Converts glucose to glycogen.
  • Inhibition of phosphoenolpyruvate carboxykinase. Inhibits gluconeogenesis.
specific targets of insulin action lipids

lipoprotein

lipase

Specific Targets of Insulin Action: Lipids
  • Activation of acetyl CoA carboxylase. Stimulates production of free fatty acids from acetyl CoA.
  • Activation of lipoprotein lipase (increases breakdown of triacylglycerol in the circulation). Fatty acids are then taken up by adipocytes, and triacylglycerol is made and stored in the cell.
regulation of insulin release
Regulation of Insulin Release
  • Major stimulus: increased blood glucose levels

- after a meal, blood glucose increases

- in response to increased glucose, insulin is released

- insulin causes uptake of glucose into tissues, so blood glucose levels decrease.

- insulin levels decline as blood glucose declines

insulin action on cells dominates in fed state metabolism
Insulin Action on Cells: Dominates in Fed State Metabolism
  •  glucose uptake in most cells

(not active muscle)

  •  glucose use and storage
  •  protein synthesis
  •  fat synthesis
other factors regulating insulin release
Other Factors Regulating Insulin Release
  • Amino acids stimulate insulin release (increased uptake into cells, increased protein synthesis).
  • Keto acids stimulate insulin release (increased glucose uptake to prevent lipid and protein utilization).
  • Insulin release is inhibited by stress-induced increase in adrenal epinephrine

- epinephrine binds to alpha adrenergic receptors on beta cells

- maintains blood glucose levels

  • Glucagon stimulates insulin secretion (glucagon has opposite actions).
slide31

Structure and Actions of Glucagon

  • Peptide hormone, 29 amino acids
  • Acts on the liver to cause breakdown of glycogen (glycogenolysis), releasing glucose into the bloodstream.
  • Inhibits glycolysis
  • Increases production of glucose from amino acids (gluconeogenesis).
  • Also increases lipolysis, to free fatty acids for metabolism.
  • Result: maintenance of blood glucose levels during fasting.
mechanism of action of glucagon
Mechanism of Action of Glucagon
  • Main target tissues: liver, muscle, and adipose tissue
  • Binds to a Gs-coupled receptor, resulting in increased cyclic AMP and increased PKA activity.
  • Also activates IP3 pathway (increasing Ca++)
glucagon action on cells dominates in fasting state metabolism
Glucagon Action on Cells: Dominates in Fasting State Metabolism
  • Glucagon prevents hypoglycemia by  cell production of glucose
  • Liver is primary target to maintain blood glucose levels
targets of glucagon action
Targets of Glucagon Action
  • Activates a phosphorylase, which cleaves off a glucose 1-phosphate molecule off of glycogen.
  • Inactivates glycogen synthase by phosphorylation (less glycogen synthesis).
  • Increases phosphoenolpyruvate carboxykinase, stimulating gluconeogenesis
  • Activates lipases, breaking down triglycerides.
  • Inhibits acetyl CoA carboxylase, decreasing free fatty acid formation from acetyl CoA
  • Result: more production of glucose and substrates for metabolism
regulation of glucagon release
Regulation of Glucagon Release
  • Increased blood glucose levels inhibit glucagon release.
  • Amino acids stimulate glucagon release (high protein, low carbohydrate meal).
  • Stress: epinephrine acts on beta-adrenergic receptors on alpha cells, increasing glucagon release (increases availability of glucose for energy).
  • Insulin inhibits glucagon secretion.
other factors regulating glucose homeostasis
Other Factors Regulating Glucose Homeostasis
  • Glucocorticoids (cortisol): stimulate gluconeogenesis and lipolysis, and increase breakdown of proteins.
  • Epinephrine/norepinephrine: stimulates glycogenolysis and lipolysis.
  • Growth hormone: stimulates glycogenolysis and lipolysis.
  • Note that these factors would complement the effects of glucagon, increasing blood glucose levels.
slide38

Hormonal Regulation of Nutrients

  • Right after a meal (resting):
  • - blood glucose elevated
  • - glucagon, cortisol, GH, epinephrine low
  • - insulin increases (due to increased glucose)
  • - Cells uptake glucose, amino acids.
  • - Glucose converted to glycogen, amino acids into protein, lipids stored as triacylglycerol.
  • - Blood glucose maintained at moderate levels.
slide39

Hormonal Regulation of Nutrients

  • Afew hours after a meal (active):
  • - blood glucose levels decrease
  • - insulin secretion decreases
  • - increased secretion of glucagon, cortisol, GH, epinephrine
  • - glucose is released from glycogen stores (glycogenolysis)
  • - increased lipolysis (beta oxidation)
  • - glucose production from amino acids increases (oxidative deamination; gluconeogenesis)
  • - decreased uptake of glucose by tissues
  • - blood glucose levels maintained
turnover rate
Turnover Rate
  • Rate at which a molecule is broken down and resynthesized.
  • Average daily turnover for carbohydrates is 250 g/day.
    • Some glucose is reused to form glycogen.
      • Only need about 150 g/day.
  • Average daily turnover for protein is 150 g/day.
    • Some protein may be reused for protein synthesis.
      • Only need 35 g/day.
        • 9 essential amino acids.
  • Average daily turnover for fats is 100 g/day.
    • Little is actually required in the diet.
      • Fat can be produced from excess carbohydrates.
        • Essential fatty acids:
          • Linoleic and linolenic acids.
regulation of energy metabolism
Regulation of Energy Metabolism
  • Energy reserves:
    • Molecules that can be oxidized for energy are derived from storage molecules (glycogen, protein, and fat).
  • Circulating substrates:
    • Molecules absorbed through small intestine and carried to the cell for use in cell respiration.

Insert fig. 19.2

pancreatic islets islets of langerhans
Pancreatic Islets (Islets of Langerhans)
  • Alpha cells secrete glucagon.
    • Stimulus is decrease in blood [glucose].
    • Stimulates glycogenolysis and lipolysis.
    • Stimulates conversion of fatty acids to ketones.
  • Beta cells secrete insulin.
    • Stimulus is increase in blood [glucose].
    • Promotes entry of glucose into cells.
    • Converts glucose to glycogen and fat.
    • Aids entry of amino acids into cells.
energy regulation of pancreas
Energy Regulation of Pancreas
  • Islets of Langerhans contain 3 distinct cell types:
    • a cells:
      • Secreteglucagon.
    • b cells:
      • Secreteinsulin.
    • D cells:
      • Secrete somatostatin.
regulation of insulin and glucagon
Regulation of Insulin and Glucagon
  • Mainly regulated by blood [glucose].
  • Lesser effect: blood [amino acid].
    • Regulated by negative feedback.
  • Glucose enters the brain by facilitated diffusion.
  • Normal fasting [glucose] is 65–105 mg/dl.
regulation of insulin and glucagon continued
Regulation of Insulin and Glucagon (continued)
  • When blood [glucose] increases:
    • Glucose binds to GLUT2 receptor protein in b cells, stimulating the production and release of insulin.
  • Insulin:
    • Stimulates skeletal muscle cells and adipocytes to incorporate GLUT4 (glucose facilitated diffusion carrier) into plasma membranes.
      • Promotes anabolism.
oral glucose tolerance test
Oral Glucose Tolerance Test
  • Measurement of the ability of b cells to secrete insulin.
  • Ability of insulin to lower blood glucose.
  • Normal person’s rise in blood [glucose] after drinking solution is reversed to normal in 2 hrs.

Insert fig. 19.8

regulation of insulin and glucagon1
Regulation of Insulin and Glucagon
  • Parasympathetic nervous system:
    • Stimulates insulin secretion.
  • Sympathetic nervous system:
    • Stimulates glucagon secretion.
  • GIP:
    • Stimulates insulin secretion.
  • GLP-1:
    • Stimulates insulin secretion.
  • CCK:
    • Stimulates insulin secretion.
slide49

Bodycellstake up moreglucose

Insulin

Beta cellsof pancreas stimulatedto release insulin intothe blood

  • Glucose homeostasis – Putting it all together

Liver takesup glucoseand stores it asglycogen

Blood glucose leveldeclines to a set point;stimulus for insulinrelease diminishes

High bloodglucose level

STIMULUS:Rising blood glucoselevel (e.g., after eatinga carbohydrate-richmeal)

Homeostasis: Normal blood glucose level(about 90 mg/100 mL)

STIMULUS:Declining bloodglucose level(e.g., afterskipping a meal)

Blood glucose levelrises to set point;stimulus for glucagonrelease diminishes

Alphacells ofpancreas stimulatedto release glucagoninto the blood

Liverbreaks downglycogen and releases glucoseto the blood

Glucagon

Figure 26.8

hormonal regulation of metabolism
Hormonal Regulation of Metabolism
  • Absorptive state:
    • Absorption of energy.
    • 4 hour period after eating.
    • Increase in insulin secretion.
  • Postabsorptive state:
    • Fasting state.
    • At least 4 hours after the meal.
    • Increase in glucagon secretion.
absorptive state
Absorptive State
  • Insulin is the major hormone that promotes anabolism in the body.
  • When blood [insulin] increases:
    • Promotes cellular uptake of glucose.
    • Stimulates glycogen storage in the liver and muscles.
    • Stimulates triglyceride storage in adipose cells.
    • Promotes cellular uptake of amino acids and synthesis of proteins.
postabsorptive state
Postabsorptive State
  • Maintains blood glucose concentration.
  • When blood [glucagon] increased:
    • Stimulates glycogenolysis in the liver (glucose-6-phosphatase).
    • Stimulates gluconeogenesis.
    • Skeletal muscle, heart, liver, and kidneys use fatty acids as major source of fuel (hormone-sensitive lipase).
    • Stimulates lipolysis and ketogenesis.
diabetes mellitus
Diabetes Mellitus
  • Chronic high blood [glucose].
  • 2 forms of diabetes mellitus:
    • Type I: insulin dependent diabetes (IDDM).
    • Type II: non-insulin dependent diabetes (NIDDM).
type i diabetes mellitus
Type I Diabetes Mellitus
  • b cells of the islets of Langerhans are destroyed by autoimmune attack which may be provoked by environmental agent.
    • Killer T cells target glutamate decarboxylase in the b cells.
  • Glucose cannot enter the adipose cells.
    • Rate of fat synthesis lags behind the rate of lipolysis.
      • Fatty acids converted to ketone bodies, producing ketoacidosis.
  • Increased blood [glucagon].
    • Stimulates glycogenolysis in liver.
type ii diabetes mellitus
Type II Diabetes Mellitus
  • Slow to develop.
  • Genetic factors are significant.
  • Occurs most often in people who are overweight.
  • Decreased sensitivity to insulin or an insulin resistance.
    • Obesity.
  • Do not usually develop ketoacidosis.
  • May have high blood [insulin] or normal [insulin].

Insert fig. 19.12

treatment in diabetes
Treatment in Diabetes
  • Change in lifestyle:
    • Increase exercise:
      • Increases the amount of membrane GLUT-4 carriers in the skeletal muscle cells.
    • Weight reduction.
    • Increased fiber in diet.
    • Reduce saturated fat.
hypoglycemia
Hypoglycemia
  • Over secretion of insulin.
  • Reactive hypoglycemia:
    • Caused by an exaggerated response to a rise in blood glucose.
    • Occurs in people who are genetically predisposed to type II diabetes.

Insert fig. 19.13

metabolic regulation
Metabolic Regulation
  • Anabolic effects of insulin are antagonized by the hormones of the adrenals, thyroid, and anterior pituitary.
    • Insulin, T3, and GH can act synergistically to stimulate protein synthesis.
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