Term
| What are the 2 types of tissues in the pancreas? |
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Definition
- Acinin cells - Exocrin function, secretes digestive juices into the duodenum. Alkaline fluid w/ digestive enzymes
- Islets of Langerhans - endocrine, secretes insulin and glucagon into the blood. Around the acini. |
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Term
| What are the three types of cells composing Islets of Langerhaans? |
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Definition
- Alpha cells - secrete glucagon into the blood. 25%.
- Beta cells - secrete Insulin and amylin into the blood. 60%. Insulin inhibit Glucagon while amylin inhibits insulin
- delta cells - secrete somatostatin, 10%. Inhibits both glucagon and insulin.
- epsilon cells - secrete ghrelin (regulates feeding behavior) |
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Term
| How are insulin and glucagon regulated? |
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Definition
- Glucagon - secreted when blood sugar is LOW (raise blood sugar) --> gluconeogenesis (new sugar, happens slowly) and glycogenolysis (lysis of glycogen, happens quickly)
- Insulin - released when blood sugar is HIGH - transport of glucose into cells |
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Term
| How does is blood flow distributed in the pancreas? |
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Definition
15% to Islets, from Celiac, Superior mesenteric, and hepatic. Blood leaves the pancreas via Hepatic portal vein to the liver.
Because Beta cells are in the middle, alpha and sigma cells are exposed to insulin |
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Term
| How is the pancreas innervated? |
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Definition
By the vagus nerve: Ach. Increases secretion of Islet hormones.
T5-T8 ganglia: Fight or flight response --> increased glucagon/PP, decreased insulin/SS. NE acts on B2 receptor on alpha cell to release glucagon, and A2 receptor in beta cell to inhibit insulin |
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Term
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Definition
- Insulin antagonized by glucagon
- Stimulated by hypoglycemia
- Inhibited by carb-rich meal. Still get glucagon w/ protein.
- Vagal and SNS stimulation |
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Term
| What are the targets of glucagon? |
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Definition
Liver and adipocytes
- Glycogenolysis - breakdown of glycogen stores in the liver. Inhibits glycolysis
- Lipolysis - liberation of FFAs in adipocytes. Other tissues use FFAs while the brain can use glucose!
- Gluconeogenesis - slow process, makes new glucose
- increase in plasma glucose has a negative feedback on alpha cells |
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Term
| What AAs are gluco- or keto-genic? |
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Definition
- Ketogenic - Leucine and Lysine
- Both - Isoleucine, phenylalanine, tyrosine, trytophan
- All others: glucogenic |
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Term
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Definition
The presence of high blood sugar, especially from excess carbs --> cell depolarizes due to signal from extracellular glucose
- Fat and glucose uptake into cells
- Conversion of AAs into protein |
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Term
| What is the significance of insulin chemistry and synthesis? |
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Definition
2 amino acid chains connected by di-sulfide bonds necessary for activity
Made as a pre-prohormone, cleaved in the golgi and packaged as a pro-insulin hexamer
Exists w/ 2 cleavage sites: C peptide allows for folding then is cleaved off in vesicles.
Rapid removal from circulation by the liver. |
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Term
| What is the function of amylin? |
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Definition
Released along with insulin, increases after a meal. Works w/ insulin to regulate glucose, suppressing post-meal glucagon.
- Low or absent in Type 1 DM
- Impaired before insulin in DM2 |
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Term
| How specifically is insulin secreted from the cell? |
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Definition
- GLUT-1, a glucose transporter, has high affinity for glucose. Uptake into the beta cell --> glucokinase leads to glycolysis followed by the Krebs cycle --> NADP and ATP production
- An ATP-sensitive K+ channel has 2 subunits: Kir6.2 and SUR1. Increased ATP from glycolysis inhibits this channel (Kir6.2) --> increase in calcium and secretion of insulin vesicles |
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Term
| What happens if Kir6.2 and SUR1 are mutated? |
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Definition
- Gain of function - Katp channel open more --> decreased insulin secretion/increased diabetes
- Loss of function - Katp channel closed more, less insulin secretion and hypoglycemia |
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Term
| What are heteroreceptor effects on insulin release? |
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Definition
- Gs - Increased insulin release through GLP1 and GIP (incretins), and GLUCAGON
- Gq - increased insulin release through CKK
- Gi - Decreased insulin release through somatostatin |
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Term
| What happens when the body is fasting? |
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Definition
| Glucose is supplied from the liver and FFAs from adipose - GLUCAGON is high, insulin is low. Brain uses glucose, everything else FFAs. |
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Term
| What happens post-prandially as opposed to fasting? |
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Definition
- Glycogenesis. Lipogenesis
- INSULIN is high. The whole body uses glucose
Liver, muscle and adipose take up glucose. |
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Term
| How is insulin taken up by skeletal muscle, liver, and adipocytes? |
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Definition
Insulin has a receptor, a tyrosine kinase receptor. Binds, becomes autophosphorylated. Recruitment of IRS (insulin response sequence). Activation of kinases --> translocation of GLUT-4, brings in glucose out of the blood.
GLUT-4 acts just like GLUT-1, just in a different place.
Chronic agonism: downregulation of the insulin receptor, increased blood glucose! |
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Term
| What are the differences between carbohydrate, lipid, and protein metabolism? |
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Definition
- Insulin stimulates glucose uptake, FFA uptake, and protein synthesis
- Insulin inhibits glycogenolysis, lipolysis, and protein breakdown
- Too much protein - secretion of glucagon. |
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Term
| What are the functions of incretins? |
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Definition
GI hormones secreted after meals which stimulate insulin release - GLUCOSE DEPENDENT.
Incretin effect - oral glucose effect > infused glucose effect.
- GLP1 - detects food, a drug target. Comes from same peptide as glucagon.
- GIP - detects dietary nutrients, does not stimulate insulin release |
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Term
| What is the function of GLP1? |
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Definition
Chewing --> Vagal stimuli --> GLP1 secretion into the blood by L cells.
Slow nutrient-mediated response
- GLP1 and GLUT-4 response to high glucose to secrete insulin. Also suppresses glucagon, decreases gastric emptying, increases satiety --> weight loss
- Chronic agonism leads to pancreatitis |
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Term
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Definition
| The enzyme that inactivates GLP-1, a drug target |
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Term
| What is insulin resistance? |
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Definition
The failure of normal insulin to produce an expected response
Mutation in the insulin receptor
Decreased glucose utilization, increased lipolysis/glucose production |
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Term
| What is the difference between SQ insulin and pancreatic insulin? |
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Definition
| No rapid rise and fall. Bypasses portal circulation |
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Term
| How is insulin structure important to activity? |
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Definition
Only the monomer can bind to receptors
At high concentrations - dimerizes
At neutral pH/with Zn - hexamer, will take time to dissolve into monomers.
- Stabilization (long acting) by hexamerizing w/ Zn OR by altering amino acids. |
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Term
| What is short-acting regular insulin? |
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Definition
Regular - how our body produced it
hexamers w/ Zn at a neutral pH
Inject 30-45 min pre-prandial |
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Term
| What are short acting insulin analogs? |
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Definition
mono- or dimers --> faster action by alteration of amino acids
Insulin lispro (Lysine and Proline changes)/Humalog - mimics IGF1, very quickly dissociates into monomers. fast acting/short duration
Insulin glulisine (glutamic acid and Lysine)/Apidra - more flexibility
Insulin Aspart/Novolog (Aspartic acid) - dissociates rapidly |
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Term
| What are intermediate-acting insulin analogs (NPH)? |
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Definition
| Mix of monomers and hexamers, dissolves more gradually. Mixed 70:30 w/ regular insulin. |
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Term
| What are long acting insulins? |
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Definition
Alters amino acids at A and B chains:
- Insulin glargine/Lantus - Gly Arg Arg. Slowly dissociates from hexamers, cannot be mixed due to acidic pH. Could promote cancer?
- Insulin determir/Levemir - addition of a sat fatty acid to a lys residue. binds to serum albumin and circulates. BID injection. |
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Term
| What factors affect insulin absorption? |
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Definition
Increased blood flow increases absorption - massage, hot bath, exercise
- Diet and exercise
- site of injection - greatest in abdomen, then arm, butt, thighs
- Normally no immunogenicity |
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Term
| What is the most common AE to insulin? |
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Definition
Hypoglycemia!
Lipoatrophy - dissolving of fat
Lipohypertrophy - too much fat. Why we rotate sites. |
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Term
| What is the MoA of sulfonylureas? |
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Definition
- 1st generation: tolbutamide, acetohexamide, tolazamide, chlorpropamide
- 2nd gen, 100x more potent: glyburide, glipizide, gliclazide, glimepiride. More bulk: pi-pi stack
- MoA: Bind to and block SUR1, inhibiting conductance just like ATP and allowing release of insulin
- Increased insulin response to glucose, but 2ndary failure: insulin levels decline after chronic use. Reduced plasma glucose levels are maintained.
- 99% protein bound: Short half life, long effects --> hypoglycemia and weight gain. Drugs that displace --> more hypoglycemia: ASA/NSAIDs, sulfonamides, ABs, fibrates, EToH, warfarin, MAOIs, BBs
- Weak acids due to negative amine |
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Term
| What agents are non-sulfonylurea channel modulators? |
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Definition
- Repaglinide/Prandin - stimulates insulin release by closing Katp channels on beta cells. 3A4 action, TID dosing. Otherwise mimics sulfonylureas
- Netaglinine - Starlix - Same as others but less hypoglycemia. 2C9 metabolism |
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Term
| What is the MoA of metformin? |
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Definition
Only member of biguanide class
- Activates AMP-kinase (AMPK) on hepatocytes and skeletal muscle cells --> increased glucose uptake and INSULIN SENSITIVITY. Upregulates insulin receptors. Less Lipolysis
- OCT - transport of metformin regulated into cells by OCT. If not OCT, resistant to drug.
- Does NOT work on Beta cells |
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Term
| What is the MoA of 'Glitazones'? |
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Definition
- activate PPAR-gamma, a nuclear receptor. Mostly on adipocytes --> adipocyte differentiation shifts visceral fat to adipose fat.
- Rosiglitazone/Avandia - 14 metabolites. Has an access program
- Pioglitazone/Actos - shifts triglycerides and raises HDL. Increased bladder cancer risk.
- Increase in insulin-mediated glucose uptake by up to 50%
- Lead to CHF, weight gain, and CV risk (Avandia). CHF is a black box warning. |
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Term
| What is the MoA of GLP1 based agents? |
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Definition
- glucose-dependent insulin secretion, inhibits glucagon release
- Exendin-4 homologous to GLP1 and resistant to DPP4
- Exenatide/Byetta - synthetic Exendin-4. BID before meals, metabolized in the kidney and excreted. LARGE insulin response. Higher nausea
- Liraglutide/Victoza - coupled to a fatty acid like levemir. Only have to inject daily. Little renal elimination. A1C lower than SUs, Byetta. May cause thyroid cancers
- AEs: GI, pancreatitis |
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Term
| What is MoA of DPP-4 inhibitors? |
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Definition
Stops DPP4 from cleaving GLP1 --> GLP1 active longer in the bloodstream
- Sitagliptin/Januvia - competitive, excreted renally unchanged
- Saxagliptin/Onglyza - covalent bond b/w nitrile group
ae: may decrease T cells or increase cancer risk. |
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Term
| What is the MoA of alpha-glucosidase inhibitors? |
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Definition
Reduces intestinal absorption of carbs by inhibiting alpha-glucosidase in L-cells. Glucose builds up in the lumen and is excreted.
- Acarbose/Precose - before meals w/ starchy diets. Minimally absorbed
- Miglitol/Glyset
Adjuct therapy, cause GI side effects. |
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Term
| What is the MoA of Symlin/Pramlintide? |
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Definition
| Synthetic amylin, may bind to calcitonin-released receptors --> reduced glucagon, delayed emptying and satiety. Adjunct to insulin |
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