Pathophysiology of Type 2 Diabetes (review with handout)

Question 1

Diabetes Mellitus diagnosis criteria

Answer 1

HgbA1c >6.5%
FPG >126 mg/dL
2h postload glucose >200
Sx of DM and random plasma glucose conc >200

Question 2

Normal labs w/o dm

Answer 2

HbA1c:

Question 3

Prediabetes Dx

Answer 3

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

Question 4

Carb tolerance

Answer 4

> 7g diabetes

Question 5

Type 1 vs Type 2

Answer 5

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

Question 6

Gestational Diabetes

Answer 6

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

Question 7

Metabolic defects in type 2 diabetes

Answer 7

• liver making glucose (increased hepatic glucose production)(even when you don’t need it)
• decreased glucose uptake in muscles
• decreased insulin secretion

Question 8

Insulin action

Answer 8

• 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

Question 9

RF for Type 2 diabetes

Answer 9

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)

Question 10

At dx, % of beta cell function lost

Answer 10

at least 50%

Question 11

eaten vs fasted state

Answer 11

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

Question 12

MODY

Answer 12

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

Question 13

Major diabetic emergencies

Answer 13

• DKA

- Hypo/hyperglycemia related death

Question 14

Insulin

Answer 14

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

Question 15

Glucagon

Answer 15

Pancreatic alpha cells
Stimulates glycogenolysis in the liver
Hepatic release of glucose

Question 16

Epinephrine

Answer 16

Stimulates glycogenolysis from the liver
Increases peripheral insulin resistance
Primary defense against hypoglycemia in T1 diabetes

Question 17

Cortisol and growth hormone

Answer 17

Raise blood glucose much more slowly

May be helpful in recovery from prolonged hypoglycemia

Question 18

DKA

Answer 18

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

Question 19

DKA tx

Answer 19

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

Question 20

Hypoglycemia

Answer 20

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)

Question 21

Hypoglycemia untreated

Answer 21

may lead to unconsciousness/seizure.

Question 22

Hypoglycemia tx

Answer 22

consuming a carbohydrate-rich food or an injection of glucagon if the person is unconscious or unable to swallow.

Question 23

Hypoglycemia T1D and T2D

Answer 23

type 1 diabetes&raquo_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)

Question 24

Sx of hypoglycemia

Answer 24

Adrenergic:	
Sweating	
Tremor	
Tachycardia	
Anxiety	
Hunger	

Neuroglycopenic:
Dizziness	
Headache	
Decreased mental activity	
Clouding of vision
Confusion	
Convulsions	
Loss of consciousness

Question 25

Hypoglycemia unawareness

Answer 25

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

Question 26

fasting hypoglycemia

Answer 26

more significant than reactive (postprandial) hypoglycemia

Whipple’s triad:

• biochemical hypoglycemia
• with symptoms
• relieved by glucose

Question 27

Hypoglycemia not due to diabetes

Answer 27

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)

Question 28

Pancreatic beta cells can normally adapt to changes in insulin action

Answer 28

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)

Question 29

Which has a greater familial aggregation, type 1 or type 2 diabetes?

Answer 29

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

Question 30

environmental factors for T2D

Answer 30

-sedentary lifestyle and obesity

Question 31

Defective insulin secretion (phases)

Answer 31

• 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.

Question 32

After 10 years with T2DM

Answer 32

Insulin secretion is diminished in nearly all patients with type 2 DM for more than 10 years, making insulin necessary for optimal glycemic control.

Question 33

glucose toxicity

Answer 33

prolonged hyperglycemia itself can produce a state where insulin secretory capacity is impaired.

Question 34

When is aggressive control of diabetes most important?

Answer 34

early diabetes– long term effects on diabetes complications

Question 35

insulin resistance: hepatic vs skeletal/adipose

Answer 35

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

Question 36

Metabolic syndrome: clinical manifestations

Answer 36

• 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)

Question 37

Metabolic syndrome: biochemical manifestations

Answer 37

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)

Question 38

definition of metabolic syndrome (if 3+ are present)

Answer 38

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

Question 39

Prevention of type 2 diabetes and metabolic syndrome

Answer 39

lifestyle modifications

Question 40

Common cause of DKA

Answer 40

-INFECTION, often w/ omission of insulin.

Question 41

Adrenergic sx of hypoglycemia

Answer 41

sweating
tremor
tachycardia
anxiety 
hunber

Question 42

Neuroglycopenic sx of hypoglycemia

Answer 42

dizziness
headache
decreased mental activity
clouding of vision
confusion
convulsions
loss of consciousness

Question 43

Recovery from hypoglycemia

Answer 43

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.