The Endocrine Pancreas

A triangular gland, which has both exocrine and endocrine cells, located behind the stomach

Strategic location

Acinar cells produce an enzyme-rich juice used for digestion (exocrine product)

Pancreatic islets (islets of Langerhans) produce hormones involved in regulating fuel storage and use.

Pancreas

The Endocrine Pancreas

Islets of Langerhans1 million islets1-2% of the pancreatic massBeta () cells produce insulin Alpha () cells produce glucagon Delta () cells produce somatostatinF cells produce pancreatic polypeptide

Islets of Langerhans

Hormone of nutrient abundance

A protein hormone consisting of two amino acid chains linked by disulfide bonds

Synthesized as part of proinsulin (86 AA) and then excised by enzymes, releasing functional insulin (51 AA) and C peptide (29 AA).

Insulin

1- Large polypeptide 51 AA (MW 6000)

2- Two chains linked by disulfide bonds. A chain : (21 AA) B chain : (30 AA)3 -Disulfide bonds.

Insulin Structure

51 amino acids2 chains linked by disulfide bonds5800 Dalton molecular weight

Insulin Structure

Protein and Polypeptide Synthesis and Release

insulin gene encodes a large precursor of insulin (preproinsulin)

During translation, the signal peptide is cleaved (proinsulin)

During packaging in granules by Golgi, proinsulin is cleaved into insulin and C peptide Insulin Synthesis

DNA (chromosome 11) in cells

mRNA

Preproinsulin (signal peptide, A chain, B chain, and peptide C)

proinsulin insulin Insulin Synthesis

Insulin Synthesis

Synthesis of insulin and role of C-Peptide Inactive Insulin Precursors Preproinsulin and Proinsulin C- peptide Essential for Proper folding Good Indicator of insulin secretion

Insulin synthesis is stimulated by glucose or feeding and decreased by fasting

Threshold of glucose-stimulated insulin secretion is 100 mg/dl.

Glucose rapidly increase the translation of the insulin mRNA and slowly increases transcription of the insulin geneInsulin Synthesis

Glucose is the primary stimulator of insulin secretion

Glucose Dependent Release of Insulin into blood Mediated through rise in Calcium Concentration in - cells Glucose taken into cells is phosphorylated and metabolizedResultant production of ATP ATP sensitive K- Channels closes leading to depolarization Opening of Voltage - gated calcium channels and influx of calcium into the cells Calcium causes vesicles containing insulin to be Exocytosed from cells Drugs like sulfonylureas, oral hypoglycemic agents increase insulin secretion by closing ATP sensitive K Channels

Regulation of Insulin Secretion

No insulin is produced when plasma glucose below 50 mg/dlHalf-maximal insulin response occurs at 150 mg/dlA maximum insulin response occurs at 300 mg/dlInsulin secretion is biphasic:Upon glucose stimulation an initial burst of secretion (5-15 min.)Then a second phase of gradual increment that lasts as long as blood glucose is highRegulation of Insulin Secretion

Insulin secretion is biphasic

Figure 6-10Insulin works through a tyrosine kinase (TK) receptor mechanismInsulin from b cells of the pancreas

Insulin Signaling

Insulin regulation of glucose entry in skeletal muscle*Overall insulin promotes storage of glucose as a fuel and a reduction of blood glucose when elevated

Insulin regulation of glucose metabolism in the liverFigure taken from: http://www.smbs.buffalo.edu/bch/Courses/bch404/GW_Nature_InsulinSig.pdf#search=%22GLUT4%20vesicles%20micrograph%22

Metabolic Effects of InsulinNearly all cells (80%) increase glucose uptake (seconds)Active transportPrimarily affects liver and muscleBrain tissue is exceptedAlters phosphorylation of many key intracellular metabolic enzymes (minutes)Alters protein synthesis and gene transcription (hours)

Insulin Action on Cells: Insulin is the hormone of abundance.The major targets for insulin are:liverSkeletal muscleadipose tissue

The net result is fuel storage as glycogen , TAG & proteins with inhibition of their mobilization

Insulin Action on Carbohydrate Metabolism: Liver:Stimulates glucose oxidationPromotes glucose storage as glycogenInhibits Glycogenolysis Inhibits gluconeogenesis

Muscle:Stimulates glucose uptake (GLUT4)Promotes glucose storage as glycogen

Insulin Action on Carbohydrate Metabolism : Adipose Tissue: Stimulates glucose transport into adipocytes

Promotes the conversion of glucose into triglycerides and fatty acids

Glucose Transport GLUT2 (liver, pancreas) GLUT4, insulin sensitive transporter (muscle, adipose tissue) GLUT3 (brain)

Glycogen SynthesisShort term storage of glucoseActivates glycogen synthase Inhibit glycogen phosphorylaseGlycolysis is also stimulated by insulin

Lipogenic and AntilipolyticInsulin promotes lipogenesis and inhibits lipolysisPromotes formation of -glycerol phosphate and fatty acid synthesisStimulates fatty acid synthase (FAS)Inhibits hormone sensitive lipase (HSL)Activates lipoprotein lipase (LPL)Expression of gene for Lipoprotein Lipase is enhanced

Protein Synthesis Increased and Reduced DegradationInsulin promotes protein accumulation:Stimulates amino acid entry into cells

Increases the activity of protein synthesis by activation of factors required for initiation of translation

Inhibits protein degradation

Action of insulin on Liver:

Action of insulin on Fat:

Action of insulin on Muscle:

Insulin: Summary

Insulin ControlMuscle Glucose uptake Glycogen synthesisLiver Glucose uptake Glycogen synthesis Fatty acid synthesis Glucose synthesisBrainNo effectPancreasBeta cellsGastrointestinalhormonesFeedback amino acids glucose triglyceridesAdipose Glucose uptake Glycerol production Triglyceride breakdown Triglyceride synthesis InsulinMost Cells Protein synthesisAmino acidsBlood glucose

Insulin Affects Tissues Differently: Summary MuscleUptake of glucose and immediate use (exercise) or storage as glycogen (Exercising muscles can take up glucose without insulin)LiverUptake of glucose and storage as glycogenInhibits glycogen phosphorylaseActivates glycogen synthaseInhibits glucose synthesisPromotes excess glucose conversion to fatty acidsAdipose TissuePromotes glucose uptake and conversion to glycerol for fat production

Insulin and Fat MetabolismLiver cells store glycogen only up to 5-6%Remaining glucose metabolized to fatTriglycerides are synthesized and release into bloodAdipose cells store fatInhibits breakdown of triglyceridesStimulates uptake and use of glucose to form glycerolStimulates fatty acid uptake and conversion to triglyceridesLack of insulinFree fatty acids build up in bloodLiver metabolizes to produce phospholipids and cholesterolCan lead to excess acetoacetic acid production and buildup of acetone (acidosis, which can lead to blindness and coma)

Insulin and Protein MetabolismPromotes Transport of amino acidsProtein synthesisGene transcriptionInhibits protein degradationPrevents glucose synthesis in liverPreserves amino acidsLack of insulin causes elimination of protein stores

A 29-amino-acid polypeptide hormone that is a potent hyperglycemic agentProduced by cells in the pancreasIts major target is the liver, where it promotes:Glycogenolysis the breakdown of glycogen to glucoseGluconeogenesis synthesis of glucose from lactic acid and non-carbohydratesRelease of glucose to the blood from liver cellsGlucagon

SYNTHESISDNA in cells

mRNA

Preproglucagon

proglucagon glucagon

Glucagon Signaling

Mechanism of action for glucagonGlucagon from a cells of pancreas

Biological Effects Produced by Glucagon

INCREASED : Glycogenolysis Gluconeogenesis Fatty Acid Oxidation Ketogenesis Uptake of amino acids

DECREASED : Glycogenesis

Factors Affecting Glucagon Secretion:

Glucagon Action on Cells:

Targets of Glucagon ActionActivates 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 gluconeogenesisActivates lipases, breaking down triglycerides.Inhibits acetyl CoA carboxylase, decreasing free fatty acid formation from acetyl CoAResult: more production of glucose and substrates for metabolism

Regulation of Glucagon ReleaseIncreased 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.

Insulin & Glucagon Regulate Metabolism

The Regulation of Blood Glucose Concentrations

A serious disorder of carbohydrate metabolismResults from hyposecretion or hypoactivity of insulinThe three cardinal signs of DM are:Polyuria huge urine outputPolydipsia excessive thirstPolyphagia excessive hunger and food consumptionDiabetes Mellitus (DM)

Diabetes Mellitus Type I Age of onset : Appears during childhood or puberty beta cells destroyed Moderate genetic predisposition Low or No insulin produced chronic fasted state, "melting flesh", Acute complications : ketosis, acidosis, glucosurea, diuresis & coma No response to oral hypoglycemic drugs Treatment only insulin replacement

Frequently occur after the age f 35 gradual appearance of symptomsVery strong genetic predisposition Over 15 million diabetics in USA- 10% type I, 90% type II obesity usually observed Insulin resistance with combined inability of -cells to produce appropriate quantity of insulin Chronic complications: atherosclerosis, renal failure& blindnessAcute complication : hyperosmolar hyperglycemic state

Diabetes Mellitus: Type II --a Group of Diseases

Type II Diabetes MellitusSlow 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

Diabetes Mellitus: Type II a Group of Diseases

GTT

Oral Glucose Tolerance Test Measurement of the ability of b cells to secrete insulin.Ability of insulin to lower blood glucose.Normal persons rise in blood [glucose] after drinking solution is reversed to normal in 2 hrs.Insert fig. 19.8

Symptoms of Diabetes Mellitus

Metabolic Changes in Diabetes Mellitus (DM)

Consequences of Uncorrected Deficiency in Type I Diabetes MellitusInsert fig. 19.11

Treatment in DiabetesChange 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.

HypoglycemiaOver 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 RegulationAnabolic 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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