Endocrine - Insulin and Glucagon Flashcards
Our metabolic processes _ require energy, but our food intake is _.
Constantly
Inermittent
What is the solution for the constant need of energy but intermittent intake of food?
Ingest more calories than immediately needed and store them
Break down the fuel reservoids for vital organs (brain) when not in a fed state)
Alternating between anabolic (build up) and catabolic (break down) phases
Define
Anabolic phase
Synthesis of the compounds constituting the body’s structure and generally require energy
Protein synthesis and glycogen synthesis
What is the fuction of anabolic hormones? What are some examples?
Build up fuel stores
Insulin, GH
What occurs when caloric intake > demand?
Energy storage
Everything we don’t immediately need is stored for later use
Define
Catabolic Phase
What is it?
Oxidative phosphorylation that release energy
Oxidative phosphorylation/ETC Chain
What is the function of catabolic hormones? What are some examples?
Break down fuel stores
Glucagon, Epi, Cortisol
What happens when demand>caloric intake?
Energy mobilization
When does the anabolic phase begin? How long does it last?
With food ingestion and lasts for several hours
When does the catabolic phase begin?
4-6 hours after food ingestion
Lasts until person eats again
What is the function of pancreatic exocine glands?
Produce digestive enzymes and HCO3-
Secretions for “outside the body”
GI tract is included in “outside the body”
What is the funciton of pancreatic endocrine glands?
Sources of insulin, glucagon, and somatostatin
What are GLP-1 and GIP? What do they do?
Incretins
Cause the secretion of insulin from islets
When insulin levels are higher than glucagon, the patient is in the _ state. What happens to insulin and glucagon in this state?
Fed state
Storage
What are the 4 types of cells in the islets of langerhans?
Pancreatic cell clusters
α cells (on periphery)
β cells (inside islet)
δ cells (sparse throughout islet center)
α cells secrete…
Glucagon
β cells secrete…
Insulin
δ cells secrete…
Somatostatin
Inhibits almost everything
What is the relationship between the pancreatic cells?
α cells - stimulate β cells
β cells - Inhibit α cells
δ cells - Inhibit α cells and β cells
What type of signaling is found between the cells in the pancreas?
Paracrine signaling
Describe the strutcure of insulin:
Protein hormone: 2 chains (A&B) + 2 disulfide bridges
What is the function of the B chains of insulin?
Contain the core of biological activity - binds the receptor
What is the function of the A chains of insulin?
Contains the most species specific sites
High variation between species generally seen between B24 and B25.
Define
Human Insulin
E. coli makes the insulin
Define
Human Analogue Insulin
Go in and change an amino aicd to give different pharmakinics anf pharmadynamics then regular insuin
Acts faster or slower based on need
Describe the synthesis of insulin:
Gene directs synthesis of a preprohormone → signal peptide cleaved (pre removed) → prohormone → cleaved → Insulin + C-peptide
How is the insulin secretory capacity of the pancreas measured? Why?
By measuring C-peptide
It is not removed by the liver and has a significantly longer half life than insulin
Define
C-peptide
Released in a 1:1 ratio with insulin
Indicates β cell function
Has hormone like qualities
Why is the half life of insulin so short?
Cleared by receptor mediated endocytosis, then lysosomal insulinases (Insulin and receptor brought into cell)
~50% of insulin is removed (cleaved/broken down) in a single pass through the liver
What is an issue for diabetics in terms of administering insulin?
Liver normally sees 2x the insulin than the periphery
To administer insulin at the same dosage to maintain regulating liver metabolism, exposes the peripherl tissues to excessive insulin levels
How do insulin levels fluctuate?
Not uncommon for insulin levels to ↓50% during exercise/fasting or ↑10x during food ingestion on a daily basis
How do insulin receptors function?
Binding causes conformational changes which activate Tyrosine Kinase → Insulin autophosphorylates β subunits which amplifies and prolongs the signal → TK phosphorylates cytoplasmic proteins to push insulin deeper into cell
Downregulation of Insulin Receptor Complex:
↓ number of receptors inresponse to chronically high insulin levels
Bring receptors in but do not replace them
Occurs during things like obesity, high CHO intake, insulin resistance
Upregulation of insulin receptors:
Fasting
More receptors are produced to increase insulin
How is the release of insulin regulated?
50% is released basally to help hold onto stores (not break them down - ↓lipolysis, ↓proteolysis, ↓glycogenolysis)
50% is released during mealtime to ↓ blood glucose
What is the relationship between glucose and insulin?
Direct
↑Glucose ↑Insulin
What occurs during the early phase of insulin secretion at meal time?
An initial burst of insulin in the first 10 minutes after a meal (fusion of docked granules)
What occurs during the late phase of insulin secretion during mealtime?
A slower rise of insulin is released
Mobilization from a reserve pool
Which phase of insulin secretion is lost in Type II Diabetes?
Early Phase → Takes longer to ↓ blood glucose and ↑ Insulin
What effect do incretins havr on insulin secretion?
They amplify glucose-induced insulin release
What causes the difference between mealtime insulin response and IV glucose insulin response?
Mealtime insulin response > IV glucose insulin response
Mealtime insulin goes through the GI tract → incretins active and induce/amplify insulin secretion → lot of insulin
IV Induced response goes through vasculature → passes by the intestines → Insulin secretion from GI tract is not triggered → less insulin around
What is the major function of insulin?
Promote storage of ingested mutrients and inhibit their release (breakdown)
Synthesize proteins, CHO, lipids, nucleic acids
Where are the major sites of action for insulin? Why?
Liver, Muscle, Adipose Tissue
3 major tissues specialized for storage
Blood glucose is a reflection of…
glucose coming into the bloodstream and glucose disappearing from the blood
Glucose is removed from the blood by…
Muscles (when excess)
Fat
Brain/CNS
Glucose enters the blood from..
Liver glucose production
Intestine glucose absorption
What affet does insulin secretion have on tgeh liver and muscle?
Inhits liver glucose production
Stimulates muscle insulin uptake
Glucose transporters: Function
GLUT 1 & 3
Describe. What does it do?
Ubiquitous
Mediates basal glucose transport
Very high affinity for glucose
Can transport at low [glucose]
Glucose transporters: Function
GLUT 2
Low affinity for glucose
Transports only when glucose is high (postprandially)
Found in Pancreatic β cells and hepatic cells → signal insulin secretion
Bidirectional transport depending on [glucose]
Glucose transporters: Function
GLUT 4
Found in skeletal muscle, heart, and adipose tissue
Regulated by insulin
Transporters are sequestered intracellularly
Require signal for them to come to cell surface
Insulin/exercise transport them to cell surface → help ↓ glucose levels
Glucose transporters: Function
GLUT 5
On the brush border of SI Cells
transport fructose
Describe the GLUT 2 pathway:
Glucose enters cell → K+ channels close →membrane depolarizes →Calcium channel opens → influx of calcium → exocytosis of insulin → insulin secretion
Describe the GLUT4 pathway:
Exercise → stimulates AMPK, Ca2+, ROS, NO → stimulates detachment of GLUT4 from endosome → translocation to cell surface
Insulin can also stimulate translocation of GLUT4
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How does the muscle get glucose in absence of insulin/exercise?
GLUT1 on cell surface
Overall function of insulin in charbohydrate metabolism:
Insulin stimulates glucose utilization by enhancing its storage as glycogen or by glycolysis (Stimulates glucose uptake to get it out of the blood)
Inhibits hepatic glucose production (Fed state, don’t need liver glucose)
Charbohydrate Metabolism:
Function of insulin on the liver:
↑ glucose uptake by conversion of glucose to glucose 6-P via glucokinase - glucose utilization
↑glycogen synthesis (storage of glucose) - glucose utilization
↓glycogen breakdown - inhibit hepatic glucose production
↓GNEO - inhibit hepatic glucoe production
Charbohydrate Metabolism:
Function of insulin on the Muscle:
↑Glucose uptake (uses GLUT4)
↑Glycogen synthesis
↑Glycolysis
Glucose is made into glycogen or broken down
Charbohydrate Metabolism:
Function of insulin on the Adipose Tissue:
↑Glucose uptake (GLUT4)
↑Glycogen synthesis
Protein metabolism
Function of insulin on muscle:
↑Protein synthesis
Overall function of insulin in fat metabolism?
Stimulates TG synthesis and inhibits TG breakdown
Fat Metabolism
Function of Insulin in Liver:
↑TG synthesis
Fat metabolism
Function of insulin in adipose tissue:
↓Lipolysis (breakdown lipids in absence of insulin causing ketoacidosis)
↑TG synthesis
↑Fatty acid synthesis
Ketoacidosis
occus when virtually no insulin is available
Develop ketone bodies to supplent lack of insulin
Without insulin, acetyl CoA is converted into ketone bodies
What happens to fatty acids in liver when insulin is present?
FFA in liver → VLDL and trigylcerides
What happens to fatty acids in the liver when insulin is absent?
FFA in liver → ketone bodies
DKA is triggered by..
Lack of insulin
↑ in counterregulatory hormones due to stress
Diabetes mellitus is characterized by…
Hyposecreton of insulin
An absolute relative deficiency of insulin/ecess of glucagon
Hyperglycemia and the 3 polys (Polyuria, Polydipsia, Polyphagia)
What is the relationship between insulin and glucagon?
indirect
↑Insulin ↓Glucagon
Low I/G Ratio
What does it mean?
↓glucose uptake and utilization
↑hepatic glucose production
Causes hyperglycemia
Define
Hyperglycemia
↑glucose
Define
Polyuria
Excessive urine production
Excess glucose > glucose renal tbular maximum → acts as osmotic diuretic
Define
Polydipsia
Increased thirst
Dehydration from osmotic diuresis
Define
Polyphagia
Excessive eating
Insulin inhibits feeding, lack of insulin could ↑ appetite
Intracellular glucose is low (despite high blood glucose) signals starvation
What is the age of onset for diabetes?
Type 1: usually during childhood (90% of cases begin between 10-14) but may occur at any age
Type 2: Usually occurs during adulthood but may occur in children and adolescents
What type of onset does diabetes have?
Type 1: usually abrupt (sudden)
Type 2: Gradual
Precipitating factors of type one diabetes?
Autoimmune response
Possible exposure to viral agent, toxin, or random immunologic event
What are the precipitating factors of type II diabetes?
Obesity; nutrition, age, inactivity
Steps in the pathogensis of Type I diabetes:
- Genetic susceptibility
- environmental event (virus or β-casein) (Coxsackie B4, mumps and rubella)
- Insulitis - infiltration of activiated T lymphocytes and macrophages
- Activiation of autoimmunity - β cells have gone from self to nonself
- Immune attack on β cells (antibodies and cell mediated)
- development of frank diabetes - most β cells are destroyed
What are the autoantibodies and what do they do?
Insulin, Glutamic acid decaroxylase, Islet antige-2
↑risk of developing diabetes if you have one of these → risk ↑s further if you have multiple
Generalized steps of Type 1 diabetes development in a patient with Genetic predisposition
Genetic predisposition → Triggering event →overt immunologic abnormalities, normal insulin release →progressive loss of insulin release, glucose normal → overt diabetes, C-peptide present → No c-peptide
How is insulin effected in Type 1 Diabetes?
Release is minimal or absent
Exogenous source required
How is insulin effected in Type 2 Diabetes?
High insulin levels (hyperinsulinemia) due to poor tissue response (insulin resistance)
Diabetic response sensitivity to insulin:
Type 1: Sensitive
Type 2: Relatively resistance (tissues don’t respond to insulin)
What is the response to diet alone in diabetic patients?
Type 1: Negligible → diet changes won’t help
Type 2: present to some degree → diet changes can help decreases diabetic symptoms
Does type 1 diabetes respond to sulfonylurea agents and metformin?
No
Does type 2 diabetes respond to sulfonylurea agents and metformin?
Yes
Define
Sulfonyleurea Agents
What do they do?
↑production of insulin by β cells in pancreas
Define
Metformin
What does it do?
Makes tissues more sensitive to insulin
Symptoms of type 1 diabetes:
Polyuria
Polydipsia
Weight loss
Symptoms of type 2 diabetes:
Mild to none (might drink and urinate more)
Fatigue, sores that don’t heal, numbness
Classic symptoms of Diabetic Ketoacidosis (DKA):
Abdominal pain
Nausea
Vomiting
What 4 challenges ↑ the risk of type 2 diabetes?
↓AMPk
↑POPs
↑Cortisol
How does ↓AMPk ↑ the risk of Type 2 diabetes?
Influences glucose/lipose pathways
Activation of AMPK switches off ATP-consuming processes (i.e. GNEO) while switching on catabolic processes that generate ATP (i.e. lipid oxidation)
Metformin increases
How do ↑POPs ↑ the risk of Type 2 diabetes?
Persistany Organic Polutants
Obesity did not increase the risk of type 2 if those people had very low levels of POPs in their bodies
How do ↑Cortisol ↑ the risk of Type 2 diabetes?
Stress
↑cortisol → ↑GNEO → hyperglycemia → ↑insulin seceretion → ↑fat synthesis (centripetal obesity, hyperlipidemia)
↑cortisol → ↑protein breakdown → glucogenogenic amino acids → ↑GNEO
↑cortisol → ↑protein breakdown → ketogenic amino acids → ↑fat synthesis (centripetal obesity, hyperlipidemia)
What is the suspected link between Obesity and insulin resistance?
Cytokines TNF-α (AT) and IL-6 (from AT macrophages)
When cells get overfat, they release inflamatory proteins → interfere with IRS-associated insulin signaling
How does type II diabetes progress?
Normal → IR → IGT → Diabetic
Progression of Type II Diabetes
What happens during the Insulin Resistance phase?
↑Insulin secretion
No change in glucose
Pre-diabetic
Progression of Type II Diabetes
What happens during the Impaired glucose tolerance phase?
↑Insulin secretion but not enough to ↓blood glucose
↑glucose
Pre-diabetic
Progression of Type II Diabetes
What happens during the Diabetic phase?
High blood glucose but little insulin produced
Pancreatic β cells break down because they cannot keep up with the blood glucose levels
Low insulin
What are causes of insulin resistance?
Abnormal β-cell secretory product
Circulating insulin antagonists
Target tissue defects
What is the major cause of insulin resistance?
Target tissue defects → post receptor defects →biggets cause is between signalling pathway and receptors
What does an OGTT show in a patient with Diabetes mellitus?
Blood glucose is above renal threshold
↑length of time to ↓blood glucose and remains high
What was they result determined by the Diabetes Prevention Progams study?
After 3 years, lifestyle intervention cut risk of diabetes in half
Key to prevention: weight loss
Small weight loss = tremendous bang for the buck
What are the long-term complications exclusive to Type II Diabetes?
Begins with hyperglycemia
Microvascular Disease → Damage to small vessels → retinopathy, nephropathy, neuropathy
What are the long-term complications not exclusive to Type II diabetes?
Macrovascular Disease → Damage to medium and large blood vessels → cornary arter disease, cerebrovascular disease, peripheral vascular disease
What causes the long-term complications of type 2 diabetes?
Occur when tissues that are freely permeable to glucose are exposed to hyperglycemia
↑blood glucose for long periods of time
What can be done to prevent long-term complications of Type II Diabetes?
Monitoring Hemaglobin A1c
↑Hemaglobin A1c → ↑risk for micro diseases
Decreas the risk of long-term complications by lowering Hemaglobin A1c to 7% or less
Why is hypoglycemia not considered a complication of diabetes?
It is a complication of treatment of diabetes due to an imblance between diabetes meds and food intake/activity
The more hypoglycemic episodes a patient experiences, the more likely they are to have another
During hypoglycemia, how do Counterregulatory Hormones work?
They have a powerful and coordinated response that acts on the liver to ↑ glucose
What are the Counterregulatory Hormones that counteract hypoglycemia? Where do they come from?
GH - brain
NE - Hypothalamus/SNS
Epi - Adrenal Medulla
Cortisol - Adrenal Gland
Glucagon - Pancreas
What are the actions of Glucagon?
Mobilization of glucose (glycogenolysis and GNEO)
Lipolysis in liver (small stores) and AT
Ketoenesis (directs FFA to β-oxidation not Tg synthesis)
What is the I/G ratio?
It determines the net physiological response of the liver
Fasting: I/G = 2
Fed: I/G = 30
Synthesis of Glucagon:
Pancreatic islet α - cells synthesis preproglucagon → proglucagon → glucagon
Intestinal cells: alternative processing of proglucagon → GLP-1
Major regulator of glucagon secretion
Hypoglycemia
Stimulates glucagon secretion
Minor reglators of glucagon:
AA, Epi, SNS, Cortisol, GH, Stress
Normal Basal levels of glucagon and insulin:
Glucagon → Liver → produces glucose → Taken up by Liver/Fat/Muscle, taken up by Brain
Insulin circulating to Liver/Fat/Muscle
Insulin and Glucagon levels during Exercise:
↑Glucagon → ↑hepatic glucose production → ↑muscle glucose uptake through contraction, Brain takes what it needs
↓Insulin circulating to muscle
↑Glucagon, ↓Insulin
Glucagon and Insulin levels during carbohydrate meal:
↓Glucagon → ↓hepatic glucose production
obtain glucose from meal → ↑glucose uptake for storage in liver, muscle, fat
↑Insulin circulating to liver, muscle, fat
↓Glucagon, ↑glucose uptake, ↑Insulin
Overall Stimulatory actions of Insulin
Glucose uptake in muscle and adipose tissue
Glycolysis
Glycogen Synthesis
Protein Synthesis
Uptake of ions (especially K+ and PO4-3)
Overall Inhibitory effects of Insulin:
Gluconeogenesis
Glucogenolysis
Lipolysis
Ketogeneis
Proteolysis
