diabetes flashcards
what are the cardinal signs or “polys” for diabetes? specifically type 1
polydipsia (excessive thirst)
polyuria (excessive urination)
polyphagia (constant hunger/big appeptite)
what are the diagnostic criteria for diabetes? A1C, FBG, OGTT, random plasma glucose
A1C >6.5
Fasting blood glucose > 126 mg/dL
2hr OGGT >200 mg/dL
random glucose >200 mg/L
What are characteristics of type I diabetes mellitus?
complete glucose intolerance
no functioning insulin-secreting pancreatic beta cells
dependent on exogenous insulin; tendency toward ketoacidosis
early age of onset (autoimmune)
family history often negative
What are common autoantibodies found in type I diabetics?
ICA- islet cell cytoplasmic autoantibodies
IAA- insulin autoantibodies
What does presence of c-peptide indicate in a diabetic?
Indicates that some beta cell mass is left; beta cells are still secreting insulin
At what point does a type I diabetic begin to have abnormal FBG?
When >70% of beta cell mass is lost
What autoantigens are most associated with type I diabetes?
Islet antigen 2 (IA-2), phogrin (IA-2B), zinc transporter, glutamic acid decarboxylase, voltage gated Ca2+, vesicle-associated membrane protein2 (VAMP- 2)
What are characteristics of non-obese diabetes mellitus?
very small percent (10%)
onset around 25; maturity onset diabetes of the young
yes family history
low insulin secretion (insufficient for glycemic control)
includes mutations in specific proteins
What are characteristics of obese diabetes mellitus?
largest % of population (80%)
onset usually over 35yo
yes family history
insulin secretion low for body mass
insulin resistance in tissues + decreased BCM
What are consequences of lack of insulin?
hyperglycemia (decreased glucose uptake in cells, decreased glycogen synthesis, increased conversion of amino acids to glucose–ketoacidosis)
glucosuria (glucose in the urine)
hyperlipidemia (fatty acid mobilization from fat cells; ketoacidosis)
uninhibited glucagon (increased glucagon levels even with increased blood glucose levels)
What are complications of diabetes?
cardiovascular micro and macro angiopathies
Neuropathy
cataracts
nephropathy
susceptibility to infections
Goals of insulin therapy
reduce symptoms of diabetes
keep average blood glucose levels below 150mg/dL
prevent/delay onset of complications
What causes diabetic ketoacidosis?
uncontrolled oxidation of fatty acids (accumulation of ketone bodies) (byproduct organic acid)
What functional group in glucose makes it reactive?
aldehyde
What products can glucose be oxidized into?
reactive dicarbonyls
- glyoxal
- methylglyoxal
What is AGE/RAGE
AGE – advanced glycation end products
formed by oxidation products of glucose and proteins that bind irreversibly
results in loss of protein function
RAGE – receptor for advanced glycation end products
Where is RAGE located?
leukocytes and endothelial cells
cell surface proteins
peptides containing CML and CEL (lysine + glucose products) bind to RAGE and promote inflammation
what happens when rage is bound?
inflammation
what is aldose reductase pathway (poly pathway)? where is it located?
occurs in nerves; consumes large amounts of NADPH and causes oxidative damage of neurons
what pathway is aldose reductase in?
polyol pathway
what is the result of polyol pathway?
neuropathy
what/where is hexosamine pathway?
F6P accumulates; causes changes in protein function
What is rate-limiting step of glucose utilization?
fructose-6-phosphate –-> G3P
What happens in the protein kinase C pathway?
Buildup of G3P activates protein kinase C inappropriately
protein modification
What is the AGE pathway?
buildup of G3P (due to oxidative stress)
oxidized glucose (methylglyoxal) reacts with proteins to form AGE
causes loss in protein function and chronic inflammation
What is the effect of methylglyoxal on cardiovascular tone?
ACh and Nitric Oxide unable to relax smooth muscle
local control of cardiovascular tone lost
What kind of receptor is the insulin receptor?
receptor tyrosine kinase
What is the role of a-subunits in the insulin receptor?
represses the catalytic activity of the beta subunit
How does insulin binding activate the insulin receptor?
relieves the repression of beta subunit catalytic activity by binding
What is the role of beta subunits in the insulin receptor?
contain tyrosine kinase catalytic domains
autophosphorylate
Phosphorylation of what causes a rise in lipogenesis when insulin binds to the insulin receptor?
MAPK
What causes an increase in glycolysis when insulin binds to the insulin receptor?
PI3K
What is the effect of insulin binding ?
increased lipogenesis
increased glycolysis
increased glycogen synthesis
increased gluconeogenesis
What is the impact of insulin on the liver?
inhibits glycogenolysis
inhibits ketogenesis
inhibits gluconeogenesis
stimulates glycogen synthesis
stimulates triglyceride synthesis
What is the impact of insulin on the skeletal muscle?
stimulates glucose transport and amino acid transport
What is the impact of insulin on the adipose tissue?
stimulates triglyceride storage
stimulates glucose transport
Where does glucose get disposed/ used in the fasting state?
75% non-insulin dependent: Liver, GI, Brain
25% insulin dependent: skeletal muscle
glucagon is secreted
Where does glucose get disposed/used in the fed state?
80-85% is insulin depended in skeletal muscle (glut-4 transporters)
4-5% is insulin dependent in adipose tissue
glucagon secretion is inhibited
insulin inhibits release of FFA from adipose tissue
How do serum FFA levels impact insulin action/sensitivity?
decreased serum FFA enhances insulin action and reduces hepatic glucose production
increased FFA levels may decrease insulin sensitivity
Which glucose transporter stimulates secretion of insulin?
GLUT2 (located in beta cells; tells beta cells when to secrete insulin)
gets last dibs per km
What does glut3 do?
located in nervous system; transports glucose to neurons
gets first dibs per km
Which glucose transporter is insulin induced?
GLUT4!
located on skeletal muscle and adipocytes
What do pancreatic alpha cells produce?
glucagon
What do pancreatic beta cells produce?
insulin, amylin
what do pancreatic delta cells produce?
somatostatin
Effect of glucagon?
stimulates glycogen breakdown; increases blood glucose
Effect of somatostatin?
General inhibitor of insulin/glucagon secretion
Effect of insulin?
Stimulates uptake and utilization of glucose
effect of amylin?
co-secreted with insulin to slow gastric emptying, decrease food intake, and inhibit glucagon secretion; also reduced blood glucose
How is insulin processed?
Cleaved to A&B chains and c-peptide by proconvertases; causes oxidative stress if too much insulin is produced; b-cell death
What Regular human insulins are available?
humulin
novolin
What are the ultra rapid-onset, very short acting insulins?
Lispro (Humalog)
Aspart (Novolog)
Glulisine (Apidra)
What are the rapid onset/ medium- to short acting insulins?
Regular (R) human insulin
- Humulin, Novolin
What are the intermediate acting insulins?
NPH (N)
What are the slow-onset, long acting insulins?
glargine (Lantus)
detemir (Levemir)
degludec (Tresiba)
