2/20: Insulin and Glucagon Flashcards
What kind of cells does the pancreas contain?
Islet of langerhans
What do alpha cells secrete?
Glucagon
What do beta cells secrete?
Insulin
What do delta cells secrete?
Somatostatin
What is somatostatin?
Inhibits glucagon and insulin
What constitutes a majority of the cells in the islets?
Alpha and beta cells
What majority of the pancreas is composed of acinar cells which produce _____________
Digestive enzymes (exocrine portion)
What is insulin secretion associated with?
Energy abundance
What is insulin composed of?
Two amino acid chains, conected by disulfide linkages
What happens when A and B chains split?
Functional activity of insulin molecule is lost
What kind of activity do proinsulin and C peptide have?
Virtually no activity
How does insulin circulate?
Entirely unbound (doesn’t need to bind to function)
What is insulin first made as?
Proinsulin
What is proinsulin cleaved into in the golgi?
Cleaved to form C peptide and insulin
What are incretins?
Hormones produced by the digestive system that work to stimulate insulin secretion BEFORE plasma glucose is elevated
What are examples of incretins?
Glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)
What is the sulfonyluera receptor?
The closing of this channel causes insulin release
What is the key regulator of insulin secretion?
Glucose
- Amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion
What are the mechanisms of insulin secretion?
- Glucose enters beta cell via GLUT transporter down it’s concentration gradient (high-> low)
- Inside the beta cell, glucose is metabolized and ATP is produced
- ATP sensitive K+ channel is stimulated; SUR channel closes when ATP levels are elevated
- Closing of the SUR channel causes depol. moving away from K equilibrium; opening Ca2+ channels
- Ca2+ channel opening causes exocytosis
What does an increase in blood glucose cause?
An increase in insulin release
What is an antagonist of insulin?
Glucagon
- glucagon levels decrease as blood glucose levels increase
What kind of receptor is the insulin receptor?
Tyrosine kinase linked receptor
How do target cells respond quickly (seconds)?
Increased glucose uptake, especially by muscle cells and adipocytes due to translocation of vesicles containing GLUT-4 to the membrane
How do target cells respond slower (10-15min)?
Change in enzyme activity leading to changes in metabolism
How do target cells respond slowest (hours-days?
Changes in gene expression and growth
What are the effects of insulin on muscle?
Promote muscle glucose uptake and metabolism-anabolic effect via GLUT4
What is the resting muscle membrane permeable to?
Slightly to glucose
What does insulin stimulation increase?
Glucose transport
What are anabolic effects of insulin on muscle?
- increases glycogen storage in skeletal muscle
- increases protein synthesis and inhibits protein degradation
What are effects of insulin on protein metabolism and growth?
- promtoes protein synthesis and storage
- inhibits protein degradation
What does insulin interact synergistically with?
Growth hormone to promote growth
What does a lack of insulin cause?
Protein depletion and increased plasma amino acids
What are the effects of insulin on the liver?
Promotes the uptake and storage of glucose (as glycogen) by the liver
What are the mechanisms for the effects insulin has on the liver?
- increases glucose uptake (glucokinase)
- increase glycogen synthase -> increase glycogen synthesis
- decrease breakdown of glycogen by inhibiting liver phosphorylase
What does insulin promote the conversion of in the liver?
Conversion of excess glucose into fatty acids
What does insulin inhibit in the liver?
Gluconeogenesis
What are the effects of insulin on fat metabolism?
Promotes fat synthesis and storage
What does insulin enhance in fat metabolism?
glucose transport into adipocytes
What does insulin inhibit in fat metabolism?
hormone-sensitive lipase (how fatty acids are released into blood)
What does insulin activate in fat metabolism?
lipoprotein lipase to help fatty acids enter the adipose cell (absorption of fat into fat cells)
What does lack of insulin in fat metabolism cause?
causes lipolysis and release of FFA (diabetic ketoacidosis) and inc plasma cholesterol and phospholipids
What are the target tissues of insulin?
Muscle, liver, and adipose
How does glucose enter adipose and muscle cells?
Via increased GLUT4 receptors
What are the net effects of insulin in plasma levels?
Decrease glucose
Decrease free fatty acids
Decrease ketoacids
Decrease amino acids
What are things that increase insulin secretion?
- Increased blood glucose, increased blood free fatty acids, increased blood amino acids
- Incretins, activate beta cell to secrete insulin (gastrointestinal hormones like GIP and GLP)
- Glucagon, growth hormone, cortisol (cause inc in blood glucose -> insulin secretion)
- Parasympathetic stimulation via acetylcholine
- Sulfonylurea drugs (close K/ATP channel in beta cell)
- Insulin resistance (if target cells are resistant to glucose, then more insulin would have to be produced to lower blood glucose)
What are things that decrease insulin secretion?
- Decreased blood glucose, fasting
- Somatostatin/GHIH
- a-Adrenergic activity Leptin
What is the hormone of starvation?
Glucagon
What is glucagon secretion stimulated by?
Hypoglycemia, epinephrine (B2) and the vagus nerve
What is the primary target of glucagon?
Liver, to increase blood glucose
How does glucagon increase blood glucagon?
- Stimulated glycogenolysis and inhibiting glycogen synthesis
- Increasing gluconeogenesis
- Increases blood fatty acid and ketoacid levels to provide more substrates for gluconeogenesis
What are ketoacids?
(acetone, acetoacetate, beta-hydroxybutyrate) short chain fats that are substrates to make glucose and are energy substrates
What is diabetes mellitus?
metabolic disorder characterized by hyperglycemia due to insufficient insulin or cellular resistance to insulin
What are the two types of diabetes mellitus?
Type I: hypoinsulinemia (10%) – not making enough
Type II: hyperinsulinemia (90%) – resistance to insulin
What are symptoms of diabetes mellitus?
Urinating often (Polyuria)
Feeling thirsty (Polydipsia)
Feeling hungry (Polyphagia)
3 P’s
What are the diagnosis types for diabetes mellitus?
o Normal levels:
FFG (fasting plasma glucose, 8-hour fast): <100 mg/dL
2-h-PG: 2 hours post prandial glucose
A1C (hemoglobin, long term measurement): <5.6%
o Prediabetic levels: elevated from normal levels
o Diabetic levels: elevated (FPG >126 and A1C of >6.5%)
What is the pathophysiology of diebetes mellitus type 1?
o Accounts for 5-10% of diabetes cases
o Formerly called juvenile onset diabetes or insulin dependent diabetes (IDDM)
o Approximately 25% present in diabetic ketoacidosis (hyperglycemia >250 mg/dl)
What are risk factors for diabetes melltius type 1?
o Genetic predisposition - increased susceptibility
o Environmental triggers stimulate autoimmune response
- Viral infections (mumps, rubella)
- Chemical toxins
o Usually develops < age 40, non-obese younger patients
What are manifestations of DM type I?
o Beta cell destruction occurs slowly
o Hyperglycemia occurs when 80 – 90% of beta cells destroyed
o Often triggered by stressor or illness
What does hyperglycemia from DM type 1 lead to?
- Polyuria (hyperglycemia acts as osmotic diuretic)
- Polydipsia (thirst from dehydration from polyuria)
- Polyphagia (hunger and eats more since cell cannot utilize glucose)
- Glycosuria (presence of glucose in urine, renal threshold for glucose exceeded)
- Weight loss (body breaking down fat and protein to restore energy source
- Malaise and fatigue (due to muscle & electrolyte loss)
- Hyperkalemia (due to lack of insulin, normally activates Na/K pump)
- Insulin enhances action of Na/K, without insulin there is less activity so more K remains inside the cell (can cause changes in nerve excitability)
What is diabetic ketoacidosis due to?
Increased lypolysis of fatty acids to produce ketoacids
What is diabetic ketoacidosis?
response to cellular starvation brought on by relative insulin deficiency and counterregulatory or catabolic hormone excess (glucagon, catecholamines, cortisone and growth hormone) to increase blood glucose
What is the pathophysiologyo of diabetic ketoacidosis?
smotic diuresis and dehydration (hyperglycemia), metabolic acidosis (accumulation of ketones), fluid and electrolyte imbalances
What are signs and symptoms of diabetic ketoacidosis?
- Fruity breath (due to acetone)
- Nausea/abdominal pain
- Dehydration
- Tachycardia
- Lethargy, Coma (because acidosis depresses neuronal function since it blocks inward current of Na and Ca)
- Polydipsia, Polyuria, Polyphagia
- Kussmaul respirations (deep, labored breathing)
What are causes of diabetic ketoacidosis?
anything that increases stress causes increase of cortisol (antagonist to insulin)
I.e. surgery, trauma, infection, decrease or omission of insulin injection
What is diabetes mellitus type II?
Insulin resistance
* Fasting hyperglycemia despite availability of insulin
* Was called non-insulin dependent diabetes or adult-onset diabetes. Both misnomers, type II DM may require insulin and can occur in children
* Can be genetic
What is the pathophysiology of diabetes mellitus type II?
hyperinsulinemia due to insulin resistance (target cells)
Due to downregulation of insulin receptors in target tissue and insulin resistance
Early: target cells don’t respond to insulin like they should, so it doesn’t lower blood glucose. In response, beta cell produces more insulin
Late: can lead to beta cell dysfunctio
DM Type II is part of this cascade of disorders that lead to Metabolic syndrome. What disorders?
Obesity, insulin resistance, fasting hyperglycemia, lipid abnormalities (high TG and low HDL), hypertension
What are chronic complications of DM I and II?
- Retinopathy: leading cause of blindness in the United States
- Nephropathy: progressive renal dysfunction that can lead to end-stage renal disease
- Neuropathy: peripheral loss of sensation and dysesthesias
- Vascular disease: accelerated atherosclerotic cerebrovascular and peripheral vascular diseases, may occur due to abnormal lipid metabolism
- Myopathies: progressive weakness and diminished exercise tolerance
What are oral manifestations of DM?
o Periodontal Disease
o Salivary and taste dysfunction
o Oral bacterial and fungal infections (ex. candidiasis)
o Diminished salivary flow and burning mouth syndrome
o Delayed mucosal wound healing
o Xerostomia
How are diabetes linked to periodontal disease?
o Periodontal disease exacerbates diabetic complications
- Poor glycemic control
- Cardiovascular complications (stroke, ischemia, infarction)
o Control of periodontal infection may improve glycemic control
