FUNCTIONDYSFUNCTION OF ENDOCRINE PANCREAS Pancreas Anatomy Both exocrine

FUNCTION/DYSFUNCTION OF ENDOCRINE PANCREAS

Pancreas Anatomy • Both exocrine, endocrine functions • Exocrine • Release alkaline fluid, enz’s pancreatic duct small intestine – Food breakdown, digestion – Cells = acinar cells

Pancreatic Endocrine Cells • Three endocrine cell types • Regulate carbohydrate, fat, protein metabolism • Secretory products: – Alpha –glucagon – Beta – insulin – Delta – gastrin, somatostatin

Insulin • Synth’d as preproinsulin – Enz cleavage proinsulin, then further cleaved insulin – Biol’ly active hormone released bloodstream = insulin

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Endocrine Pancreas • Synthesize, release hormones circulation – Travel through bloodstream target tissues (especially liver and muscle) – Bind specific receptors cell changes controlling metabolism

Insulin Secr’n Control • Chemically – Beta cells sensitive to concent’s glucose, amino acids in blood • High glu, aa’s, fa’s ins secr’n – When would you expect these chemicals to be in high concentration?

• Hormonally – Beta cells sensitive to circulating hormones • Stim’n insulin release w/ – Cholecystokinin (from intest mucosa w/ eating; incr’d PKC activity) – Gastrointest inhibitory peptide (GIP; released w/ eating; acts through ad cyclase) – ACh from vagus nerve endings • Inhib’n insulin release w/ – a 2 adrenergic agonists – Adrenalin – Somatostatin

• Neurally – Parasymp stim’n insulin secr’d • Insulin secr’n diminished by – Decr’d blood [glucose] – Incr’d blood [insulin] – Sympathetic stim’n

Molecular Mechanism of Insulin Secretion • Blood [glucose] incr • Glu transported b cell through GLUT 2 • Glucokinase/hexokinase Glu-6 -PO 4 • Glycolysis TCA incr’d ATP/ADP

• High ATP/ADP inhib’n K+ channel no K+ out of cell • Depol’n b cell membr • Act’n voltage gated Ca+2 channels – Incr’d Ca into cell AND – Incr’d PKC activity incr’d IP 3 Ca+2 rel’d from ER • Incr’d [Ca+2]intracell • Exocytosis insulin from intracell stores

• Ins release biphasic in healthy indiv’s – Init rapid phase • Reflects release of stored hormone – Slower, delayed phase • Continued release of stored hormone + release newly synth’d hormone

Insulin • Transported through blood to target tissues – Receptor binding at target cells • Target cells have receptors embedded in cell membranes, specific for insulin • When insulin binds its receptor on the target cell: – Acts as biochem signal to inside of the target cell • Overall, cell metabolism is stimulated • increased glucose uptake in the cell, and • regulation of glucose breakdown within the cell, and • regulation of protein and lipid metabolism within cell

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– Overall blood glucose decr’d • Glu signaled to leave blood and enter metabolizing cells (with insulin action) • NOTE: Insulin does NOT – Bind glucose and help excrete it out of the blood – Break down glucose in the blood – Signal increased excretion of glucose • RATHER: Insulin – Goes to target cells and – Signals them to take up glucose from the blood, and – Metabolize the glucose they take up

Disorder ‑ Diabetes mellitus • Group of glucose intolerance disorders • Historical ‑ weight loss and – Excessive urination = polyuria – Excessive thirst = polydipsia – Excessive hunger = polyphagia

• Modern classifications – IDDM ‑ Insulin Dependent Diabetes Mellitus – NIDDM ‑ Non‑Insulin Dependent Diabetes Mellitus – GDM ‑ Gestational Diabetes Mellitus

IDDM (= Type I Diabetes) • 10% of all DM in Western world • Genetic, env assoc’ns – ~10 -15% have parent or sibling with disease – Peak age of diagnosis = 12 years • Genetic/environmental/autoimmune factors destroy beta cells • Believed abrupt onset – Now immunomarkers, preclin symptoms discovered

– Disequilibrium of hormones produced by islets of Lagerhans • Ratio insulin/glucagon controls glu, fat metab – Clinical • Glucose in urine – When insulin not present, glucose not taken up from blood at target cells – Blood glucose very highly incr’d – Incr’d glu filtered, excreted in urine • Weight loss – Patient eats, but nutrients not taken up by cells and/or not metab’d properly • Polyuria, polydipsia, pholyphagia

– Ketoacidosis • Fats metab’d inappropriately accelerated acetyl. Co. A prod’n AND • Decr’d aerobic metab (decr’d glu metab) • Prod’n acetoacetate + b-hydroxybutyrate (acids) + acetone (ketone “body”) prod’d, rel’d to bloodstream • Decreased blood p. H • Compensations for metabolic acidosis – Hypervent’n – Renal compensations • Acetone given off in breath

Treatment • Administer insulin – Animal or human – Cannot be given orally • Protein, so broken down in digestive tract before absorption – Patient must monitor own blood glucose concent and admin insulin with correct timing

• Various insulin formn’s avail – Ins lispro: ins w/ lys/proline switched • More rapid-acting, but avail shorter time • Pts can inject immed before meal – Ins glargine: mod’d ins analog • Forms micropreciptate in subcu tissue prolonged release • Constant basal ins supply – Ins preciptated w/ protamine or zinc slowly absorbed ins – Varied dosing regimens, mixtures slow-, rapid release formulations

• Control diet – Carbohydrates should be ~ 55 -60% of total calories – Fats <30% of total calories – Proteins ~ 15 -20% of total calories • Monitor exercise – Remember: muscles are target tissue; metab much glu – Exercise may irregular blood glu levels • Pancreatic transplant – so far not successful • Experimental therapies – not as successful as hoped

NIDDM (= Type II Diabetes) • More common than IDDM, often undiagnosed • Slow onset • Most common in those > 40 years – More children now diagnosed regularly • May be genetic • Obesity important – Greatest risk factor – Related to increased incidence in children

• Insulin resistance in target cells – See decr’d b cell responsiveness – Decr’d insulin secr’d by b cells – Also abnormal glucagon secreted • May be due to: – Abnormally functioning b cells, OR – Decreased b cell mass, OR – Combination of both, OR – Target cell resistance to insulin • Decr’d # insulin receptors on target cells, OR • Target cells desensitized to insulin

• Clinical – Overweight, hyperlipidemia common (NOTE: these are precursors, not symptoms) – Recurrent infections – Visual changes, others (explained below)

• Treatment – Weight loss – Appropriate diet (see IDDM above) – Exercise – promotes weight loss – Oral hypoglycemics or antihyperglycemics

Oral Hypoglycemics • Sulfonylureas – Stim b cells to incr insulin secretion • Bind subunit of ATP-sensitive K+ channels • Block channels incr’d depol’n of b cell membranes • Incr’d Ca+2 and incr’d insulin released – Work only when b cells are still functioning

• 1 st generation: tolbutamide, tolazamide, acetohexamide, chlorpropamide • 2 nd generation: glyburide, glipizide, glimepiride

• Meglitinides – Also bind ATP sensitive K+ channels BUT at site distinct from sulfonylureas

• Metformin – a biguanide – Mech not completely understood • Act’n c. AMP-dependent kinase incr’d translocation GLUT 4 to cell surface(? ) – Reduces hepatic gluconeogenesis – Reduces LDLs and VLDLs – Increases glu uptake, use in skeletal muscle and fat

Antihyperglycemics • Thiazolindinediones (glitazones) – Max effect only 1 -2 mos treatment – Reduce hepatic glu output, incr glu uptake in muscle • Less insulin needed

– Bind nuclear receptor/transcription factor (PPAR-g) in adipocytes (also muscle, liver) – Incr’d synth of enz’s, prot’s impt to insulin signalling • Lipoprotein lipase • FA transporter prot • Adipocyte fa-binding prot • GLUT 4 • Phosphoenolpyruvate carboxykinase – Used in combination w/ sulfonylureas

• a-Glucosidase Inhibitors – Inhibit enz’s that cleave complex CH’s monosacch’s • Only monosacch’s can be absorbed, so – Delay CH absorption from intestine – Decr’d posprandial incr in blood glucose • BUT gi disturbance side effects – Often used in combination w/ other agents

Gestational Diabetes • Due to incr’d hormone secr’n during pregnancy • Seen if patient has predisposition – If previous or potential glucose intolerance has been noted • Important ‑ incr’d mortality risk for mother, child

Complications of Diabetes Mellitus • Acute – Hypoglycemia • Rapid decrease in plasma glucose • = Insulin shock • Neurogenic responses – Probably due to decr’d glucose to hypothalamus

• Symptoms include: – Tachycardia, palpitations, tremor, pallor – Headache, dizziness, confusion – Visual changes • Treatment – Provide glucose (i. v. or subcu if unconscious) – Observe for relapse

– Ketoacidosis – involves precipitating event (ex: trauma, surgery, infection, stress) • Increased hormones released w/ trauma increased glucose produced by the body’s cells • “Antagonizes” the effects of any glucose present – Incr’d ketones in blood – Acid/base imbalance – Polyuria, dehydration – Electrolyte disturbances – Hyperventilation (Kussmaul’s) – CNS effects – Acetone on breath • Treatment ‑ low dose insulin

• Chronic – Neuropathies • = Nerve dysfunctions • Slowing of nerve conduction • See: – Degeneration of neurons – Sensory, motor deficits – Muscle atrophy, paresthesias – Depression – G. I. problems, as muscle motility decreased – Sexual dysfunction

• Chronic – cont’d – Microvascular disease -- chronic diabetes w/ improper glucose metabolism • Thickening of basement membrane of capillaries – Particularly in eye and the kidney • As the capillary changes – Decr’d tissue perfusion – So ischemia hypoxia

In the retina, weakening of the arterioles and capillaries may result in the characteristic appearance of intraretinal dot and blot hemorrhages, exudates, intraretinal microvascular abnormalities (IRMA) microaneurysms, edema and cotton wool infarcts.

– Microvascular disease – cont’d • In eye – Retina is metabolically active – Hypoxia a big problem (need lots of oxygen at a metabolically active tissue) – See: » Retinal ischemia » Formation of microaneurisms, hemorrhage, tissue infarct, retinal detachment • In kidney – Diabetes is most common cause of end‑stage renal disease – Injured glomeruli (glomerulosclerosis)

– Glomerulus specialized capillary impt to filtr’n – If basement membr thickens, filtration ability changes. Body tries to overcome “clogged filter” over time. See: » Proteinuria (protein excr’d into urine) » Generalized body edema, hypertension » Remember: as body loses protein decreased COP vascular fluids now have even greater relative BHP fluids forced out toward tissues

– Macrovascular disease • Atherosclerosis – Plaque form’n incr’s – Incr’d risk of » Coronary artery disease, so incr’d risk of myocardial infarction » Congestive heart failure » Infections – Stroke – Peripheral vascular disease » Diabetic patients face problems with lower legs, feet; may gangrene and amputation of limbs