Dr. Zeenat Hussain Dr. Zeenat Hussain FoundationFoundation

““The ultimate value of life depends The ultimate value of life depends upon awareness and the power of upon awareness and the power of

contemplation rather than upon mere contemplation rather than upon mere survival.”survival.”

AristotleAristotle

Dr. Zeenat Hussain Foundation is Dr. Zeenat Hussain Foundation is working to create awareness against working to create awareness against the diseases among the common the diseases among the common people of Pakistan. This lecture is also a people of Pakistan. This lecture is also a part of this campaign. Your cooperation part of this campaign. Your cooperation and feed back shall be highly and feed back shall be highly appreciated.appreciated.

The Endocrine PancreasThe Endocrine PancreasRegulation of Carbohydrate Regulation of Carbohydrate

MetabolismMetabolism

Presented By:

Nasir Nazeer

Pancreas- Brief HistoryPancreas- Brief History Herophilus, Greek Herophilus, Greek

surgeon first described surgeon first described pancreas.pancreas.

Wirsung discovered the Wirsung discovered the pancreatic duct in 1642.pancreatic duct in 1642.

Pancreas as a secretory Pancreas as a secretory gland was investigated gland was investigated by Graaf in 1671.by Graaf in 1671.

R. Fitz established R. Fitz established pancreatitis as a pancreatitis as a disease in 1889.disease in 1889.

Whipple performed the Whipple performed the first pancreatico-first pancreatico-duodenectomy in 1935 duodenectomy in 1935 and refined it in 1940.and refined it in 1940.

Duct of Wirsung

Duct of Santorini

Pancreatic AnatomyPancreatic Anatomy

Gland with both exocrine and endocrine Gland with both exocrine and endocrine functionsfunctions

15-25 cm long in length15-25 cm long in length 60-100 grams in weight60-100 grams in weight Location: retro-peritoneum, 2Location: retro-peritoneum, 2ndnd lumbar lumbar

vertebral levelvertebral level Extends in an oblique, transverse positionExtends in an oblique, transverse position Parts of pancreas: head, neck, body and Parts of pancreas: head, neck, body and

tailtail

PancreasPancreas

Head of PancreasHead of Pancreas Includes uncinate processIncludes uncinate process Flattened structure, 2 – 3 Flattened structure, 2 – 3

cm thickcm thick Attached to the 2Attached to the 2ndnd and 3 and 3rdrd

portions of duodenum on portions of duodenum on the rightthe right

Emerges into neck on the Emerges into neck on the leftleft

Neck of PancreasNeck of Pancreas 2.5 cm in length2.5 cm in length Straddles SMV and PVStraddles SMV and PV Antero-superior surface supports the Antero-superior surface supports the

pyloruspylorus Superior mesenteric vessels emerge from Superior mesenteric vessels emerge from

the inferior borderthe inferior border Posteriorly, SMV and splenic vein confluence Posteriorly, SMV and splenic vein confluence

to form portal veinto form portal vein Posteriorly, mostly no branches to pancreasPosteriorly, mostly no branches to pancreas

Body of PancreasBody of PancreasElongated, long structureElongated, long structureAnterior surface, separated from Anterior surface, separated from

stomach by lesser sacstomach by lesser sacPosterior surface, related to aorta, Posterior surface, related to aorta,

adrenal gland, renal vessels and upper adrenal gland, renal vessels and upper 1/31/3rdrd of kidney of kidney

Splenic vein runs embedded in the Splenic vein runs embedded in the post. Surfacepost. Surface

Inferior surface is covered by Inferior surface is covered by transverse mesocolontransverse mesocolon

Tail of PancreasTail of PancreasNarrow, short segmentNarrow, short segmentLies at the level of the 12Lies at the level of the 12thth thoracic thoracic

vertebravertebraEnds within the splenic hilumEnds within the splenic hilumLies in the splenophrenic ligamentLies in the splenophrenic ligamentAnteriorly, related to splenic flexure Anteriorly, related to splenic flexure

of colonof colonMay be injured during splenectomy May be injured during splenectomy

(fistula)(fistula)

Pancreatic DuctPancreatic Duct Main duct (Wirsung) runs the entire length Main duct (Wirsung) runs the entire length

of pancreasof pancreas 2 – 4 mm in diameter, 20 secondary 2 – 4 mm in diameter, 20 secondary

branchesbranches Ductal pressure is 15 – 30 mm Hg thus Ductal pressure is 15 – 30 mm Hg thus

preventing damage to pancreatic ductpreventing damage to pancreatic duct Lesser duct (Santorini) drains superior Lesser duct (Santorini) drains superior

portion of head and empties separately portion of head and empties separately into 2into 2ndnd portion of duodenum portion of duodenum

Arterial Supply of Arterial Supply of PancreasPancreas

VVariety of major arterial sources (celiac, ariety of major arterial sources (celiac, SMA and splenic)SMA and splenic)

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

SMA (Superior mesentric artery) SMA (Superior mesentric artery) Inferior Inferior pancreaticoduodenal artery which divides pancreaticoduodenal artery which divides into anterior and posterior branchesinto anterior and posterior branches

Pancreatic Arterial SupplyPancreatic Arterial Supply

Venous Drainage of Venous Drainage of PancreasPancreas

Follows arterial supplyFollows arterial supply Anterior and posterior arcades drain Anterior and posterior arcades drain

head and the bodyhead and the body Splenic vein drains the body and tailSplenic vein drains the body and tail Major drainage areas areMajor drainage areas are

Suprapancreatic PVSuprapancreatic PVRetropancreatic PVRetropancreatic PVSplenic veinSplenic vein Infrapancreatic SMVInfrapancreatic SMV

Ultimately, into portal veinUltimately, into portal vein

Venous Drainage of the PancreasVenous Drainage of the Pancreas

Lymphatic DrainageLymphatic DrainageRich periacinar network that drain Rich periacinar network that drain

into 5 nodal groupsinto 5 nodal groupsSuperior nodesSuperior nodesAnterior nodesAnterior nodesInferior nodesInferior nodesPosterior nodesPosterior nodesSplenic nodesSplenic nodes

Pancreatic Hormones, Insulin and Pancreatic Hormones, Insulin and Glucagon, Regulate MetabolismGlucagon, Regulate Metabolism

Production of Pancreatic Hormones by Three Cell Types

Alpha cells produce glucagon. Beta cells produce insulin. Delta cells produce somatostatin.

Islet of Langerhans Cross-Islet of Langerhans Cross-sectionsection

Three cell types are Three cell types are present, A (glucagon present, A (glucagon secretion), B (Insulin secretion), B (Insulin secretion) and D secretion) and D (Somatostatin secretion)(Somatostatin secretion)

A and D cells are located A and D cells are located around the perimeter around the perimeter while B cells are located while B cells are located in the interiorin the interior

Venous return Venous return containing insulin flows containing insulin flows by the A cells on its way by the A cells on its way out of the islets out of the islets

Pancreatic Hormones, Insulin and Pancreatic Hormones, Insulin and Glucagon, Regulate MetabolismGlucagon, Regulate Metabolism

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

Structure of InsulinStructure of Insulin

Insulin is a Insulin is a polypeptide polypeptide hormone, composed hormone, composed of two chains (A and of two chains (A and B)B)

BOTH chains are BOTH chains are derived from derived from proinsulin, a proinsulin, a prohormone.prohormone.

The two chains are The two chains are joined by disulfide joined by disulfide bonds.bonds.

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 ReceptorThe Insulin Receptor

The insulin receptor is composed of two The insulin receptor is composed of two subunits, and has intrinsic tyrosine kinase subunits, and has intrinsic tyrosine kinase activity.activity.

Activation of the receptor results in a Activation of the receptor results in a cascade of phosphorylation events:cascade of phosphorylation events:

phosphorylation ofinsulin responsive substrates (IRS) RAS

RAF-1

MAP-KMAP-KK Final

actions

Specific Targets of Insulin Specific Targets of Insulin Action: CarbohydratesAction: Carbohydrates

Activation of glycogen synthetaseActivation of glycogen synthetase. . Converts glucose to glycogen.Converts glucose to glycogen.

Inhibition of Inhibition of phosphoenolpyruvate phosphoenolpyruvate carboxykinasecarboxykinase. Inhibits . Inhibits gluconeogenesis.gluconeogenesis.

Increased activity of glucose transporters. Moves glucose into cells.

Specific Targets of Insulin Specific Targets of Insulin Action: LipidsAction: Lipids

Activation of acetyl CoA carboxylaseActivation of acetyl CoA carboxylase. . Stimulates production of free fatty acids Stimulates production of free fatty acids from acetyl CoA.from acetyl CoA.

Activation of lipoprotein lipaseActivation of lipoprotein lipase (increases (increases breakdown of triacylglycerol in the breakdown of triacylglycerol in the circulation). Fatty acids are then taken circulation). Fatty acids are then taken up by adipocytes, and triacylglycerol is up by adipocytes, and triacylglycerol is made and stored in the cell.made and stored in the cell.

Regulation of Insulin ReleaseRegulation of Insulin Release Major stimulus: increased blood glucose Major stimulus: increased blood glucose

levelslevels- after a meal, blood glucose increases- after a meal, blood glucose increases

- in response to increased glucose, - in response to increased glucose, insulin is releasedinsulin is released

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

Insulin Action on Cells: Insulin Action on Cells: Dominates in Fed State MetabolismDominates in Fed State Metabolism

glucose uptake in most cellsglucose uptake in most cells

(not active muscle)(not active muscle) glucose use and storageglucose use and storage protein synthesisprotein synthesis fat synthesisfat synthesis

Insulin Action on Cells: Insulin Action on Cells: Dominates in Fed State MetabolismDominates in Fed State Metabolism

Insulin: Summary and Control Insulin: Summary and Control Reflex LoopReflex Loop

Other Factors Regulating Insulin Other Factors Regulating Insulin ReleaseRelease

Amino acidsAmino acids stimulate insulin release (increased stimulate insulin release (increased uptake into cells, increased protein synthesis).uptake into cells, increased protein synthesis).

Keto acidsKeto acids stimulate insulin release (increased stimulate insulin release (increased glucose uptake to prevent lipid and protein glucose uptake to prevent lipid and protein utilization).utilization).

Insulin release is inhibited by stress-induced Insulin release is inhibited by stress-induced increase in adrenal epinephrineincrease in adrenal epinephrine- epinephrine binds to alpha adrenergic receptors - epinephrine binds to alpha adrenergic receptors on beta cellson beta cells

- maintains blood glucose levels- maintains blood glucose levels Glucagon Glucagon stimulatesstimulates insulin secretion (glucagon insulin secretion (glucagon

has opposite actions).has opposite actions).

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 Mechanism of Action of GlucagonGlucagon

Main target tissues: liver, muscle, and Main target tissues: liver, muscle, and adipose tissueadipose tissue

Binds to a Gs-coupled receptor, resulting Binds to a Gs-coupled receptor, resulting in increased in increased cyclic AMPcyclic AMP and increased and increased PKA activity.PKA activity.

Also activatesAlso activates IP3 pathway IP3 pathway (increasing (increasing CaCa++++))

Glucagon prevents hypoglycemia by Glucagon prevents hypoglycemia by cell cell production of glucoseproduction of glucose

Liver is primary target to maintain blood Liver is primary target to maintain blood glucose levelsglucose levels

Glucagon Action on Cells: Glucagon Action on Cells: Dominates in Fasting State Dominates in Fasting State

MetabolismMetabolism

Glucagon Action on Cells: Dominates Glucagon Action on Cells: Dominates in Fasting State Metabolismin Fasting State Metabolism

Targets of Glucagon ActionTargets of Glucagon Action Activates a Activates a phosphorylasephosphorylase, which cleaves off a , which cleaves off a

glucose 1-phosphate molecule off of glycogen.glucose 1-phosphate molecule off of glycogen. Inactivates Inactivates glycogen synthaseglycogen synthase by by

phosphorylation (less glycogen synthesis).phosphorylation (less glycogen synthesis). Increases Increases phosphoenolpyruvate phosphoenolpyruvate

carboxykinasecarboxykinase, stimulating gluconeogenesis, stimulating gluconeogenesis Activates Activates lipaseslipases, breaking down triglycerides., breaking down triglycerides. Inhibits Inhibits acetyl CoA carboxylaseacetyl CoA carboxylase, decreasing , decreasing

free fatty acid formation from acetyl CoAfree fatty acid formation from acetyl CoA Result:Result: more production of glucose and more production of glucose and

substrates for metabolismsubstrates for metabolism

Regulation of Glucagon ReleaseRegulation of Glucagon Release

Increased blood glucoseIncreased blood glucose levels inhibit levels inhibit glucagon release.glucagon release.

Amino acidsAmino acids stimulate glucagon release stimulate glucagon release (high protein, low carbohydrate meal).(high protein, low carbohydrate meal).

Stress:Stress: epinephrine acts on beta- epinephrine acts on beta-adrenergic receptors on alpha cells, adrenergic receptors on alpha cells, increasing glucagon release (increases increasing glucagon release (increases availability of glucose for energy).availability of glucose for energy).

Insulin Insulin inhibitsinhibits glucagon secretion. glucagon secretion.

Other Factors Regulating Other Factors Regulating Glucose HomeostasisGlucose Homeostasis

GlucocorticoidsGlucocorticoids (cortisol): stimulate (cortisol): stimulate gluconeogenesis and lipolysis, and gluconeogenesis and lipolysis, and increase breakdown of proteins.increase breakdown of proteins.

Epinephrine/norepinephrineEpinephrine/norepinephrine: stimulates : stimulates glycogenolysis and lipolysis.glycogenolysis and lipolysis.

Growth hormoneGrowth hormone: stimulates : stimulates glycogenolysis and lipolysis.glycogenolysis and lipolysis.

Note that these factors would Note that these factors would complement the effects of glucagon, complement the effects of glucagon, increasing blood glucose levels.increasing blood glucose levels.

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.

A few 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

Hormonal Regulation of Nutrients

Regulation of Energy MetabolismRegulation of Energy Metabolism Energy reserves:Energy reserves:

Molecules that Molecules that can be oxidized for can be oxidized for energy are derived energy are derived from storage from storage molecules molecules (glycogen, protein, (glycogen, protein, and fat).and fat).

Circulating Circulating substrates:substrates: Molecules Molecules

absorbed through absorbed through small intestine and small intestine and carried to the cell carried to the cell for use in cell for use in cell respiration.respiration.

Insert fig. 19.2

Pancreatic Islets (Islets of Pancreatic Islets (Islets of Langerhans)Langerhans)

Alpha cells secrete glucagon.Alpha cells secrete glucagon. Stimulus is decrease in Stimulus is decrease in

blood [glucose].blood [glucose]. Stimulates glycogenolysis Stimulates glycogenolysis

and lipolysis.and lipolysis. Stimulates conversion of Stimulates conversion of

fatty acids to ketonesfatty acids to ketones.. Beta cells secrete insulin.Beta cells secrete insulin.

Stimulus is increase in blood Stimulus is increase in blood [glucose].[glucose].

Promotes entry of glucose Promotes entry of glucose into cells.into cells.

Converts glucose to Converts glucose to glycogen and fat.glycogen and fat.

Aids entry of amino acids Aids entry of amino acids into cells.into cells.

Glucose homeostasis – Putting it all Glucose homeostasis – Putting it all togethertogether

Figure 26.8

Insulin

Beta cellsof pancreas stimulatedto release insulin intothe blood

Bodycellstake up moreglucose

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

Liver takesup glucoseand stores it asglycogen

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)

Alphacells ofpancreas stimulatedto release glucagoninto the blood

GlucagonLiverbreaks downglycogen and releases glucoseto the blood

Blood glucose levelrises to set point;stimulus for glucagonrelease diminishes