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23 Cards in this Set
- Front
- Back
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Describe Insulin as Master Metabolic Regulator:
*ANABOLISM: *CATABOLISM: |
*Anabolism: Regulated by Insulin: insulin levels high
Fed-state --> energy storage Growth, maintenance Disposal of Glucose and AA Synthesis: Glycogen (in Liver, Muscle) Fat (in Liver, Adipose tissue) Protein (in Muscle) Insulin ACTIVELY INHIBITS catabolism *Catabolism: Regulated by Glucagon, Stress hormones (SHs=cortisol, GH, epi) Insulin levels low Fasting --> energy utilization Provides energy to tissues Prevents Hypoglycemia Sources: Glycogen (L, M) Fat (A) Protein (M; used for other PRO synthesis & for glucose) |
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How is insulin secreted? What is required to secrete insulin?
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Insulin secretion requires glucose sensing and a complicated pathway.
1) GLUT-2 transport into cell 2) Phosphorylate glucose, glycolysis, etc. 3) Ca influx / ATP K channel 4) Insulin granules are made/secreted |
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Insulin secretion is related to [Glucose]
1) GLUT-2 transport into cell 2) Phosphorylate glucose, glycolysis, etc. 3) Ca influx / ATP K channel 4) Insulin granules are made/secreted K channel structure: inner portion: KIR-6 -Drugs binding here inhibit insulin secretion outer portion: SUR (sulfonyl urea receptor) -Drugs binding here increase insulin secretion |
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Insulin Synthesis:
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*Pancreatic beta cells synthesize prepro-insulin, cleaved to proinsulin
*Maturation occurs in secretory granules to Insulin and C peptide *Insulin is a 51 amino acid protein; ½ life 3-5 min *50% insulin removed by liver during first pass *AMYLIN co-secreted in 1:100 ratio with insulin, acts to SUPPRESS postprandial glucagon and RESTRAIN gastric emptying |
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*Pancreatic beta cells synthesize prepro-insulin, cleaved to proinsulin
*Maturation occurs in secretory granules to Insulin and C peptide *Insulin is a 51 amino acid protein; ½ life 3-5 min *50% insulin removed by liver during first pass *Amylin co-secreted in 1:100 ratio with insulin, acts to suppress postprandial glucagon and restrain gastric emptying |
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*Proinsulin --> 1 Insulin + 1 C-peptide
*Use C peptide as an indirect measurement of how much insulin someone is making. |
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Describe rates of insulin secretion throughout the day:
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Bfast spike just due to high CHO intake at bfast.
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*InsR phosphorylates IRS binding proteins.
*PI3K pathway --> GLUT-4 moves to surface |
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Glucose Transporter Proteins: 4
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*GLUT-1- all tissues; high affinity for glucose, mediates basal uptake esp in BRAIN vasculature
*GLUT-2- “glucose sensor” in BETA CELL; also in LIVER, GI, KIDNEY; lower affinity for glucose *GLUT-3-all tissues; high affinity in NEURONS *GLUT-4- insulin regulated; found in SKELETAL MUSCLE and ADIPOSE tissue |
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Anabolism: Discuss insulin-regulated tissues that store energy:
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*Liver: INHIBITS ketogenesis, gluconeogenesis, stimulates glycogenesis, FA synthesis
*Muscle: STIMULATES glucose uptake via Glut4, glycogenesis; exercise promotes glucose transport via different transporter; INCREASES protein synthesis *Adipose: stimulates glucose uptake via Glut4, FA uptake via activation of lipoprotein lipase for TG storage *Brain: NOT insulin requiring for glucose |
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4 major actions of insulin:
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1) muscle --> PRO (blood sugar decreases)
2) Promotes fat storage 3) Inhibits appetite (insulin receptors in brain) 4) Inhibits glucose production in liver |
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Catabolism: Describe depot Sources of Energy when Insulin is low, counter-reg hormones high:
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*Glucose: from Liver glycogen, then GN
Brain prefers glucose *Fatty Acids: from TG in adipose tissue Hormone-sensitive lipase releases FA FA used by all tissues EXCEPT brain They go to the liver *Ketone bodies: made in Liver from FA Production is reflection of FA delivery to liver Used by all tissues EXCEPT liver |
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ß cell: insulin
alpha cell: glucagon delta cell: SST |
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Describe the effects/actions of Glucagon:
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*Large polypeptide made in islet alpha cells: MAJOR REGULATION is INHIBITION by [GLUCOSE]
*½ life 3-6 minutes, removed by liver, kidneys *Hypoglycemia, catecholamines stimulate release *Actions are largely opposite to Insulin: counter-regulatory *Acts through G-protein coupled receptor to signal via cAMP and downstream kinases *MAJOR EFFECT IS IN LIVER : glycogenolysis (minutes), gluconeogenesis (hours; major substrates are lactate, Alanine, energy-requiring), KETOGENESIS. |
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Yin/Yang b/t insulin and glucagon.
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Glucagon-related peptides:
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*PROGLUCAGON cleaved by prohormone convertase 1/3 into 2 glucagon-like peptides (GLP)-1, -2
*GLP-1 secreted from INTESTINAL L CELLS in response to meals: INCREASES INSULIN, INHIBITS GLUCAGON release -critical partner with insulin in dealing with food *Other targets include stomach, brain (satiety) *Circulating GLP-1 is rapidly INACTIVATED by dipeptidyl peptidase IV (DPP-IV, possible DM intervention?) *GLP-2 secreted with GLP-1, acts on intestine to increase absorption, decrease motility |
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Location/Actions of GLP-1:
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*Intestine
*Effects on brain we are learning about |
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Somatostatin:
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*Synthesized in hypothalamus, pancreatic delta cell, GI tract
*Precursor cleaved into a small (14 amino acids) and large (28 amino acids) peptide *SMS-14 predominates in PANCREAS; SMS-28 predominates in GUT & BRAIN. *SMS-28 > SMS-14 inhibits GH, insulin release *SMS-14 more potent inhibitor of glucagon *Action through family of 5 SMS receptors that are tissue specific |
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Other Counter-regulatory Hormones AKA “Stress Hormones”:
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*Catecholamines (NE,E): stimulate glycogenolysis, GN in liver, lipolysis (HSL)
-Like glucagon, sensitive to [glucose] *Cortisol: proteolysis, GN, INSULIN RESISTANCE Part of “dawn phenomenon”, stress response *GH: lipolysis, INSULIN RESISTANCE Part of “dawn phenomenon”, stress response |
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The point: insulin is an anabolic hormone.
Important growth factor pre-natally. |
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How does hyperglycemia occur?
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How does ketosis occur?
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How does glucose regulate insulin transcription?
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*PI3K pathway activates a transcription factor pathway.
*Genetic mutations in these factors --> MODY *Currently > 6 genes identified that affect insulin secretion. |
