Diabetes Pathophysiology Flashcards
Glucose metabolism is important because ____ and ____ are pivotal branch points in carbohydrate metabolism
Glucose metabolism is important because pyruvate and Acetyl-CoA are pivotal branch points in carbohydrate metabolism
Glucose metabolism is important for the production of ________ used for DNA and RNA synthesis
Glucose metabolism is important for the production of nucleic acid intermediates used for DNA and RNA synthesis
Glucose metabolism is important for the production of ________ for protein metabolism
Glucose metabolism is important for the production of amino acid intermediates/metabolism for protein metabolism
Glucose metabolism is important in ________ by providing important intermediates such as Acetyl-CoA and glycerol-3-phosphate
Glucose metabolism is important in fat synthesis and metabolism by providing important intermediates such as Acetyl-CoA and glycerol-3-phosphate
Endocrine glands secrete ____ into the ____
Endocrine glands secrete hormones into the blood
Exocrine glands secrete their products through ____
Exocrine glands secrete their products through ducts
The pancreatic ________ are the regions of the pancreas that contain its endocrine (hormone-producing) cells
The pancreatic islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells
What are the 4 cell types of the Islet of Langehans and what do they produce?
- Alpha (a) cells –> Glucagon
- Beta (B) cells –> Insulin
- Delta cells –> Somatostatin
- PP cells –> Pancreatic Polypeptide
The Islet of Langerhans also has ____ input (adrenergic and cholinergic)
The Islet of Langerhans also has neural input (adrenergic and cholinergic)
The liver assists with glucose regulation through (3 examples)
The liver assists with glucose regulation through:
- Glycogen Storage
- Glycogenolysis
- Gluconeogenesis
Fat tissues plays a role in glucose regulation through ________
Fat tissues plays a role in glucose regulation through TAG synthesis, storage, and release
Skeletal muscle plays a role in glucose regulation through ____ storage.
Skeletal muscle disposes of __% of a glucose load.
Skeletal muscle plays a role in glucose regulation through glycogen storage.
Skeletal muscle disposes of 80% of a glucose load.
The three main forms of glucose control are:
- Regulatory ____
- ________ utilization
- ____ glucose output
The three main forms of glucose control are:
- Regulatory hormones
- Peripheral tissue utilization
- Hepatic glucose output
GLUT __ is the only insulin-dependent transporter and is found on ________ and ________
GLUT4 is the only insulin-dependent transporter and is found on adipose tissue and skeletal muscle
GLUT__ is bidirectional and found on the ____, ____, ____,and ____
GLUT2 is bidirectional and found on the B islet cells, liver, kidney,and GI tract
How do B cells recognize glucose and trigger insulin release?
- Glucose uptake via GLUT2
- Glucokinase cell sensor
- ATP production
- ATP sensitive K+ channel closes –> depolarization
- Ca2+ to cytoplasm via ER voltage gated Ca2+ channels
- Ca2+ induces insulint vesicle fusion and insulin release
____ are hormones from the GI tract produced after a meal, and they facilitate ____ secretion
____ are metabolized by ________; an important one is ____
____ inhibitors are clinically available and prolong incretin biological effects
Incretins are hormones from the GI tract produced after a meal, and they facilitate insulin secretion
Incretins are metabolized by dipeptidyl dipeptidases (DPPs); an important one is DPP-4
DPP-4 inhibitors are clinically available and prolong incretin biological effects
Glucocorticoids are released from the ________ and have the following effects:
- Enhance ____ catabolism to glucose intermediates
- Increases ____
- Are ____ (favor diabetes development)
Glucocorticoids are released from the adrenal gland and have the following effects:
- Enhance protein catabolism to glucose intermediates
- Increases gluconeogenesis
- Are diabetogenic (favor diabetes development)
Note: virtually all cells have glucocorticoid receptors, and the receptors of glucocorticoids act as a transcription factor
Epinephrine effects glucose by:
- Decreasing ____ in the liver
- Increasing ____ in fat
- Essentially blocking residual ____ effect
Epinephrine increases the availability of fatty acids which can be converted into ketones. Thus epinephrine can play a role in ____
Epinephrine effects glucose by:
- Decreasing fatty acid synthesis in the liver
- Increasing lipolysis in fat
- Essentially blocking residual insulin effect
Epinephrine increases the availability of fatty acids which can be converted into ketones. Thus epinephrine can play a role in ketoacidosis
Insulin receptor pathway in muscle and fat
Insulin receptor pathway in muscle and fat
- Insulint binds receptor
- Receptor is a tyrosine-kinase type receptor –> phosphorylates tyrosine residues
- Receptor phosphorylates IRS (insulin response substrate) –> GLUT4 moves to cell surface
- Also activates MAP kinase pathway which favors cell growth and gene expression
Insulin promotes (5 examples)
Insulin inhibits (4 examples)
Insulin promotes:
- Glycolysis –> Glycerol-3-phosphate –> lipogenesis
- Glycolysis –> metabolic intermediates
- Glycogenesis
- Protein synthesis
- Active glucose uptake (muscle and fat)
Insulin inhibits:
- Lipolysis
- Gluconeogenesis
- Glycogenolysis
- Protein catabolism
Glucagon promotes (4 examples)
Glucagon inhibits (3 examples)
Glucagon promotes:
- Gluconeogenesis
- Glycogenolysis
- Fatty acid oxidation
Glucagon inhibits:
- Glycolysis
- Glycogen synthesis
- Fatty acid synthesis
____ diverts intermediates away from ketogenesis by:
- Decreasing ________ activity –> decreasing available fatty acids for FA oxidation to make Acetyl-CoA
- Decreasing ________ activity –> inhibiting the ketogenic pathway
- Favoring ____ production which inhibits the CPT1 of the ____ shuttle
Insulin diverts intermediates away from ketogenesis by:
- Decreasing hormone sensitive lipase activity –> decreasing available fatty acids for FA oxidation to make Acetyl-CoA
- Decreasing mitochondrial HMG-CoA synthase activity –> inhibiting the ketogenic pathway
- Favoring malonyl-CoA production which inhibits the CPT1 of the carnitine shuttle
Insulin favors ____ production which inhibits CPT 1 in the ____ shuttle. Long chain fatty acids require this shuttle to get into the mitochondria to be used for ketone production, thus insulin plays a role in preventing ____.
Insulin favors malonyl-CoA production which inhibits CPT 1 in the carnitine shuttle. Long chain fatty acids require this shuttle to get into the mitochondria to be used for ketone production, thus insulin plays a role in preventing ketoacidosis.
If complete insulin deficiency:
- No ____ to regulate the carnitine shuttle –> free access of LCFAs to ketogenic machinery
- Unregulated HSL –> increased ____ availability
- Unregulated mitochondrial HMG-CoA synthase –> increased ____
All of this leads to ____
If complete insulin deficiency:
- No Malonyl-CoA to regulate the carnitine shuttle –> free access of LCFAs to ketogenic machinery
- Unregulated HSL –> increased fatty acid availability
- Unregulated mitochondrial HMG-CoA synthase –> increased ketogenesis
All of this leads to ketoacidosis
Diabetes is the leading cause of:
- ________ disease
- Adult onset ____
- ________ amputations
Diabetes is the leading cause of:
- End stage renal disease
- Adult onset blindness
- Lower extremity amputations
Diabetic classical triad of symptoms include:
Diabetic classical triad of symptoms include:
- Polyuria
- Polydipsia
- Polyphagia
Combination of polyphagia (increased hunger) and weight loss suggest ____
Combination of polyphagia (increased hunger) and weight loss suggest type 1 diabetes
What causes polyuria and polydipsia in diabetics?
Glucose is an osmolite (water follows it), thus increased blood glucose levels lead to increased fluid in blood which then gets excreted as urine
What explains polyphagia (increased hunger) and weight loss in diabetics?
Diabetes causes protein catabolism which causes a negative energy balance (weight loss and polyphagia). Unintended weight loss combined with polyphagia is most often seen in type 1 diabetes.
Insulin deficiency can also cause decreased ________ which leads to hyperlipidemia
Insulin deficiency can also cause decreased lipoprotein lipase which leads to hyperlipidemia
Screening for diabetes:
- Adults __-__ years of age should be screened for impaired gluocse (grade B evidence)
- Especially patients with a BMI > __ plus 1 additional risk factor
- Patients with 2 or more risk factors should be screened
Screening for diabetes:
- Adults 40-70 years of age should be screened for impaired gluocse (grade B evidence)
- Especially patients with a BMI > 25 plus 1 additional risk factor
- Patients with 2 or more risk factors should be screened
Diagnostic criteria for diabetes:
- Random glucose: ____ is diabetes
- 2 hour glucose tolerance: ____ is pre-diabetes and ____ is diabetes
- Fasting blood glucose: ____ is pre-diabetes and ____ is diabetes
- Hgb A1c: ____ is pre-diabetes and ____ is diabetes
Diagnostic criteria for diabetes:
- Random glucose: >200 is diabetes
- 2 hour glucose tolerance: 140-199 is pre-diabetes and >200 is diabetes
- Fasting blood glucose: 100-125 is pre-diabetes and >126 is diabetes
- Hgb A1c: 5.7-6.4% is pre-diabetes and >6.5% is diabetes
Type 1 Diabetes
- __% of diabetes cases; often present clinically or as ____
- Autoimmune destruction of ________
- Often ____ age group
- Possible ____ trigger
- Symptoms start at 70-90% loss of functional islet mass
- Ultimate absolute ____ deficiency - important in ____
Type 1 Diabetes
- 10% of diabetes cases; often present clinically or as ketoacidosis
- Autoimmune destruction of pancreatic islets
- Often younger age group
- Possible infection trigger
- Symptoms start at 70-90% loss of functional islet mass
- Ultimate absolute insulin deficiency - important in ketoacidosis
Type 2 diabetes
- __% of diabetes cases; often detected in routine screening
- A syndrome of ________ (relative ____ deficiency)
- Strong ____ component
- Associated with obesity, visceral fat accumulation, metabolic syndrome, and sedentary lifestyle
- ____ production capcity remains (usually) to prevent ketoacidosis
Type 2 diabetes
- 90% of diabetes cases; often detected in routine screening
- A syndrome of insulin resistance (relative insulin deficiency); lower insulin affinity
- Strong genetic component; first degree 5-10 fold risk
- Associated with obesity, visceral fat accumulation, metabolic syndrome, and sedentary lifestyle
- Insulin production capcity remains (usually) to prevent ketoacidosis
What does MODY stand for and what is it?
Maturity Onset Diabetes of the Young
Defects in glucose metabolism
Note: just be aware of this for now, will go into more detail in future blocks
Diabetes type 2
- Decreased ____ (hormone stimulates FA oxidation)
- Decreased ____ (hormone adequacy of fat stores)
- Pro-inflammatory via ____ and _____
- Insulin resistance through:
- Failed ____
- Failed expression of ____
Diabetes type 2
- Decreased adiponectin (hormone stimulates FA oxidation)
- Decreased leptin (hormone adequacy of fat stores)
- Pro-inflammatory via inflammasome and IL-1
- Insulin resistance through:
- Failed signaling
- Failed expression of GLUT4
In type 1 diabetes there is no insulin which causes an increase in certain hormones and catecholamines such as ____ and ____ which increases ____ availability that can feed into ____
In type 1 diabetes there is no insulin which causes an increase in certain hormones and catecholamines such as glucagon and epinephrine which increases fatty acid availability that can feed into ketogenesis
The lack of insulin in type 1 diabetes also blocks ____ synthesis, resulting in no ____ available to inhibit CPT1 which results in ____ going into the mitochondria via the carnitine shuttle to then be used for ____
The lack of insulin in type 1 diabetes also blocks FA synthesis, resulting in no Malonyl-CoA available to inhibit CPT1 which results in LCFAs going into the mitochondria via the carnitine shuttle to then be used for ketogenesis
Clinical/lab signs of diabetic ketoacidosis (common in type 1 diabtes)
Clinical and lab signs of diabetic ketoacidosis:
- Altered mental status/drowsy/coma
- Increased anion gap
- Arterial pH < 7.25
- Plasma glucose > 250 mg/dL
- Decreased serum bicarbonate
- Positive urine or serum ketones
- Positive urine glucose
Note: just have a general idea of the above
Long term hyerglycemia leads to 4 main consequences:
Long term hyerglycemia leads to 4 main consequences:
- AGE-RAGE binding
- Protein kinase C
- Polyols-oxidative stress
- Hexosamine pathway
Clinical/lab signs of hyperosmolar coma (common in type 2 diabetes)
Clinical/lab signs of hyperosmolar coma (common in type 2 diabetes):
- Stupor/coma
- Arterial pH > 7.3
- Effect serum Osm > 320
- Plasma glucose > 600
- Bicarbonate > 15
- Positive urine glucose
Usually occurs i the elderly with comorbid conditions; dehydration often involved
Note: just have a general idea of the above
AGE-RAGE Binding is caused by long term ____ and leads to 2 main consequences:
AGE-RAGE Binding is caused by long term hyperglycemia and leads to 2 main consequences:
- Cross linking of extracellular matrix –> amplifies vascular damage
- Binding of RAGE receptors on T-cells/macrophages causing:
- Cytokine release (inflammation)
- ROS formation (tissue damage)
Long term ____ leads to activation of ____ which leads to cytokine exretion and gene expression which leads to renal, retinal, neuronal, and vascular implications
Long term hyperglycemia leads to activation of protein kinase C which leads to cytokine exretion and gene expression which leads to renal, retinal, neuronal, and vascular implications
Long term ____ leads to ________ which depletes NADPH in the aldose reductase reaction. NADPH not avaiable for reduction of oxidized glutathione –> deficient GSH –> oxidant stress, nerve damage, and peripheral neuropathy
Long term hyperglycemia leads to polyols and oxidatie stress which depletes NADPH in the aldose reductase reaction. NADPH not avaiable for reduction of oxidized glutathione –> deficient GSH –> oxidant stress, nerve damage, and peripheral neuropathy
Long term ____ leads to activation of the ____ pathway which leads to elevated plasminogen activator which increases risk of CVD
Long term hyperglycemia leads to activation of the hexosamine pathway which leads to elevated plasminogen activator which increases risk of CVD
Macrovascular pathology is essentially ____
This is much worse in diabetics and can lead to (3 examples)
Macrovascular pathology is essentially atherosclerosis
This is much worse in diabetics and can lead to:
- Coronary artery disease –> which can lead to heart attack
- Cerebral artery disease –> which can lead to stroke
- Peripheral vascular disease –> which can lead to limb pain and gangrene
Diabetics may experience microvascular pathology with hyaline arterosclerosis which inolves (3 examples)
This underlies the conditions (3 examples)
Diabetics may experience microvascular pathology with hyaline arterosclerosis which inolves:
- AGE mediated crosslinking of matrix
- Inductio of growth factors by signaling pathways
- Leakage of plasma proteins into vascular wall
This underlies the conditions:
- Nephropathy
- Retinopathy
- Some forms of neuropathy
Renal disease is diabetics is caused by ____ hyaline arteriolosclerosis.
May also include nodular glomerulosclerosis (kimmeistiel-wilson disease)
Diabetes is a major cause of ESRD
Progression from microalbuminuria to ____ nephrotic syndrome
Renal disease is diabetics is caused by efferent hyaline arteriolosclerosis.
May also include nodular glomerulosclerosis (kimmeistiel-wilson disease)
Diabetes is a major cause of ESRD
Progression from microalbuminuria to nephrotic nephrotic syndrome
Retinopathy in diabetics:
Non-proliferative retinopathy - early stage
- ____ due to loss of pericytes
- Increased vascular permeability
Proliferative retinopathy - late stage
- Secondary to ____ and ____
- Neovascularization under drive of ____
- Late retinal hemorrhage
- Can lead to vitreous ____ and retinal detachment
Retinopathy in diabetics:
Non-proliferative retinopathy - early stage
- Microaneurysms due to loss of pericytes
- Increased vascular permeability
Proliferative retinopathy - late stage
- Secondary to ischemia and infarcts
- Neovascularization under drive of VEGF
- Late retinal hemorrhage
- Can lead to vitreous hemorrhage and retinal detachment
Peripheral neuropathy in diabetics:
- Usually distal ____ neuropathy
- Involves sensory function
- ____ neuropathy is another variation which can include:
- Fixed tachycardia
- Orthostatic hypotension
- Erectile dysfunction
- Delayed bladder emptying
Peripheral neuropathy in diabetics:
- Usually distal symmetric neuropathy
- Involves sensory function
-
Autonomic neuropathy is another variation which can include:
- Fixed tachycardia
- Orthostatic hypotension
- Erectile dysfunction
- Delayed bladder emptying
Insulin therapies can come in regular, ____ acting, and ____ acting forms
Some examples include:
____ which decreases insulin resistance
____ inhibitors which prolong incretin effects
GLP-1 analog and GLP receptor agonists
Insulin therapies can come in regular, short acting, and long acting forms
Some examples include:
Metformin which decreases insulin resistance
DDP-4 inhibitors which prolong incretin effects
GLP-1 analog and GLP receptor agonists
Insulin therapy overdose can cause ____ for which the symptoms include (5 examples)
Insulin therapy overdose can cause hypoglycemia for which the symptoms include:
- Palpitations
- Diaphoresis
- Light headedness
- Anxiety/jitters
- Syncope
