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
Hypoglycemia unawareness
Loss of adrenergic warning signs
Altered mental status with no warning
More common in patients who have frequent hypoglycemia:
- alterations in delivery of glucose to the brain
- Blunted counter-regulatory response
Treatment: avoidance of hypoglycemia for 3 or more weeks
fasting hypoglycemia
more significant than reactive (postprandial) hypoglycemia
Whipple’s triad:
- biochemical hypoglycemia
- with symptoms
- relieved by glucose
Hypoglycemia not due to diabetes
Insulinoma
Ethanol
Interferes with gluconeogenesis
Non-Beta-cell tumors
Large mesenchymal tumors, hepatoma, etc.
Production of IGF-I or IGF-II
Severe liver disease
Adrenal insufficiency
Renal failure (kidneys make up to 25% of glucose produced by the body)
drugs or factitious: insulin or oral antidiabetic agents
(high insulin), esp sulfonylureas (high insulin and C peptide)
Pancreatic beta cells can normally adapt to changes in insulin action
if there is a decrease in insulin action for any reason, beta-cells increase insulin secretion to maintain euglycemia. The converse also occurs.
Type 2 DM: both decreased beta-cell function and decreased insulin sensitivity (insulin resistance– can’t stimulate glucose uptake and can’t suppress endogenous glucose production by liver)
Which has a greater familial aggregation, type 1 or type 2 diabetes?
type 2, but exact mode of inheritance unknown (polygenic)
NO HLA associations in type 2.
Concordance rate for identical twins: 90-100% (as opposed to
environmental factors for T2D
-sedentary lifestyle and obesity
Defective insulin secretion (phases)
- abnormalities of insulin secretion in T2D
- acute (first phase) insulin release in response to IV glucose is lost T2D
- more prolonged (second phase) response is preserved or exaggerated.
After 10 years with T2DM
Insulin secretion is diminished in nearly all patients with type 2 DM for more than 10 years, making insulin necessary for optimal glycemic control.
glucose toxicity
prolonged hyperglycemia itself can produce a state where insulin secretory capacity is impaired.
When is aggressive control of diabetes most important?
early diabetes– long term effects on diabetes complications
insulin resistance: hepatic vs skeletal/adipose
Hepatic insulin resistance results in loss of insulin suppression of hepatic glucose output. Insulin resistance in the skeletal muscle and fat leads to defects in insulin-mediated storage of glucose and, fat and protein.
Insulin resistance in the liver leads to fasting hyperglycemia while resistance in peripheral tissues (muscle, adipose) leads to post prandial hyperglycemia
Metabolic syndrome: clinical manifestations
- clustering of comorbid conditions that contribute to an increased risk of macrovascular disease, the major cause of death in type 2 DM.
- Clinically: Central (abdominal) obesity, glucose intolerance, hypertension, atherosclerosis, polycystic ovary syndrome (PCOS)
Metabolic syndrome: biochemical manifestations
Altered carbohydrate metabolism: insulin resistance, hyperinsulinemia and carbohydrate intolerance
Dyslipidemia: high triglycerides, low HDL-cholesterol, small, dense LDL particles
Procoagulant state: impaired fibrinolysis, increased plasminogen activator inhibitor, type 1 (PAI-1)
definition of metabolic syndrome (if 3+ are present)
Waist circumference >40 inches in men and >35 inches in women
Triglycerides >150 mg/ld.
HDL-cholesterol 130/85 mm Hg
Fasting plasma glucose >100 mg/ld
Prevention of type 2 diabetes and metabolic syndrome
lifestyle modifications
Common cause of DKA
-INFECTION, often w/ omission of insulin.
Adrenergic sx of hypoglycemia
sweating tremor tachycardia anxiety hunber
Neuroglycopenic sx of hypoglycemia
dizziness headache decreased mental activity clouding of vision confusion convulsions loss of consciousness
Recovery from hypoglycemia
glucagon and epi
After a variable duration of diabetes, glucagon responsiveness to hypoglycemia is lost and epinephrine becomes the primary defense against hypoglycemia.
Epinephrine can be blunted in recurrent hypoglycemia. Cortisol and growth hormone also raise blood glucose, but do so much more slowly. They do little in the acute setting but will cause insulin resistance during recovery.
