Pathophysiology of Type 2 Diabetes (review with handout) Flashcards
Diabetes Mellitus diagnosis criteria
HgbA1c >6.5%
FPG >126 mg/dL
2h postload glucose >200
Sx of DM and random plasma glucose conc >200
Normal labs w/o dm
HbA1c:
Prediabetes Dx
HgbA1c 5.7-6.4%
FPG 100-126
2hPG: 140-199
Higher risk for developing diabetes and increased CVD risk.
- IFG/IGT are assoc w/ metabolic syndrome (can include obesity– esp abdominal; dyslipidemia– high triglycerides or low HDL; htn)
- yearly screening, weight loss, exercise and metformin help prevent/delay devel of DM
Carb tolerance
> 7g diabetes
Type 1 vs Type 2
Type 1 Usually younger Usually normal weight or thin at dx Usually no family hx Insulin sensitive Normal lipid profiles Requires insulin for treatment
Type 2 Usually > 40 yrs 90% obese Positive family hx Insulin resistant Dyslipidemia Often requires insulin for treatment after 10 years
Gestational Diabetes
Fasting ≥95 mg/dL 1 hr ≥180 mg/dL 2 hr ≥155 mg/dLhr 3 hr ≥140 mg/dL -Dx with 2 plasma glucose values equal or exceeding values above (don't memorize them)
- eval b/t 24-28 weeks if nml risk
- aggressive in diagnosis
10-30% greater risk of getting type 2 diabetes if had gestational diabetes
Metabolic defects in type 2 diabetes
- liver making glucose (increased hepatic glucose production)(even when you don’t need it)
- decreased glucose uptake in muscles
- decreased insulin secretion
Insulin action
- 2 alpha and 2 beta subunits on receptor
- phosphorylates self
- signaling thru insulin response substrates–>Akt/PKB: glycogen synthesis, glucose uptake, antilipolysis, protein synthesis, antiapoptosis, eNOS, inhib of PEPCK and IGFBP-1
messed up by inflammation and high glucose
IRS part of pathway gets blocked, and metabolic events downstream can’t happen–> insulin resistance in cells and in liver and muscle
RF for Type 2 diabetes
Family history of diabetes Hypertension and/or dyslipidemia Central obesity Gestational diabetes Birthweight more than 9 lbs. or SGA* Ethnicity (African-American, Hispanic, Native American, Pacific Islander)
At dx, % of beta cell function lost
at least 50%
eaten vs fasted state
Just eaten: insulin secretion in alpha cells, stimulate glucose uptake
Fasted state: insulin lvls down, fat and muscles begin to break down
- low insulin level secreted by Beta cells
- alpha cells make glucagon to stimulate hepatic glucose output
Type 2:
fewer Beta cells
increased alpha cells or at least producing more glucagon
MODY
maturity onset diabetes of young
-autosomal dominant
-impaired insulin secretion, but fine insulin action
-thin persons, insulin secretion first phase
then second phase
In MODY glucokinase defect (MODY 2). Glucose doesn’t get metabolized and beta cell doesn’t know it is high glucose state.
Can be treated with sulfonylureas.
-other defects: insulin transcription or ion channels
Major diabetic emergencies
- DKA
- Hypo/hyperglycemia related death
Insulin
Insulin (only hormone that decreases glucose):
Pancreatic beta cells
Stimulates glycogen storage in the liver
Decreases hepatic gluconeogenisis
Stimulates glucose uptake and utilization in muscle and fat
Glucagon
Pancreatic alpha cells
Stimulates glycogenolysis in the liver
Hepatic release of glucose
Epinephrine
Stimulates glycogenolysis from the liver
Increases peripheral insulin resistance
Primary defense against hypoglycemia in T1 diabetes
Cortisol and growth hormone
Raise blood glucose much more slowly
May be helpful in recovery from prolonged hypoglycemia
DKA
Usually extreme hyperglycemia (>300); increased anion gap metabolic acidosis (pH5mM)
Pathogenesis of DKA:
Absolute or relative lack of insulin and increased counter-regulatory hormones (glucagon, catecholamines, cortisol, growth hormone). Results in increased delivery of aa (gluconeogenesis) and FA (ketone production) to the liver. Low insulin/glucagon ratio promotes ketogenesis too.
Ketone body production (biochemical)
Increased FFA flux from adipocytes
Intrahepatic glucagon/epi induced increased carnitine acyltransferase and decreased malonyl CoA activity permitting mitochondrial ketone body production (* this needs to be reversed to clear DKA)
Hyperosmolar Hyperglycemia Syndrome (HHS)
Osmotic diuresis
Decreased free water
–>dehydration
Signs/sx: altered mental status, dehydration– skin turgor, hypotension, weakness, postural hypotension and tachycardia likely present
DKA tx
IV fluids (rehydration will decrease counter -regulatory hormones)
Glucagon blocks glycolysis by decreasing levels of fructose 2,6 biphosphate
Glucagon inhibits Acetyl CoA carboxylase and decreases Malonyl CoA, this leaves CPT 1 active and FA enter the mitochondria for ketone body production.
Insulin
Lowers plasma glucagon levels
Decreases FFA and AA flux from the periphery
Enhances peripheral utilization of glucose
Hypoglycemia
most common acute cause of diabetes
Normal fasting blood glucose is 70 to 115 mg/dl
Symptoms of hypoglycemia usually begin when the plasma blood glucose falls to 50 or 60 mg/dl
vary from patient to patient
may lessen with duration of diabetes
Will be severely blunted with frequent hypoglycemia
sx: adrenergic (excess epi) and neuroglycopenic (due to CNS dysfunction)
Hypoglycemia untreated
may lead to unconsciousness/seizure.
Hypoglycemia tx
consuming a carbohydrate-rich food or an injection of glucagon if the person is unconscious or unable to swallow.
Hypoglycemia T1D and T2D
type 1 diabetes»_space; type 2
Hypoglycemia is 2-3 time more common in patients trying to normalize blood glucose with intensive insulin regimens (DCCT) targeted to prevent diabetic complications
Insulin»glyburide>other oral sulfonylureas >repaglinide>metformin, thiazolidinediones, alpha glucosidase inhibitor (Later agents rarely cause hypoglycemia if used alone)
Sx of hypoglycemia
Adrenergic: Sweating Tremor Tachycardia Anxiety Hunger
Neuroglycopenic: Dizziness Headache Decreased mental activity Clouding of vision Confusion Convulsions Loss of consciousness
