Block 3 - metabolic syndrome and glucose homeostasis (L1-2) Flashcards
What are the traditional risk factors for CVD?
dyslipidemia (high cholesterol)
obesity
hypertension (high BP)
smoking
diabetes
What are the other major clinical conditions which are risk factors for CVD?
insulin resistance and hyperinsulinemia
glucose intolerance
Most risk factors for CVD are also risk factors for…
Type 2 Diabetes
Do risk factors for T2D and CVD occur more often together or more often individually?
together
What are the major risk factors for both CVD and T2D?
high BP
dyslipidemia (high triglycerides and low HDL cholesterol)
raised fasting glucose
central obesity
What is the Metabolic Syndrome?
clustering of specific pathologies that represent and increased risk of CVD and therefore increased probability of heart attack or stroke
What are other names for the Metabolic Syndrome?
syndrome x
insulin resistance syndrome
cardio metabolic syndrome
What is the prevalence of metabolic syndrome?
40% of adults over 50 have it
What are the defining components of metabolic syndrome?
visceral (central) obesity
insulin resistance
hyperinsulinemia
glucose intolerance
dyslipidemia
essential hypertension
Besides the major components, what are other components of the metabolic syndrome?
adipocyte dysfunction
accelerated atherosclerosis
endothelial dysfunction
renal dysfunction
hepatic steatosis
inflammation
hypercoagulability
Describe visceral obesity as a core component of metabolic syndrome
increase in visceral (abdominal) adipose tissue
- closely associated with components of the metabolic syndrome, such as insulin resistance, due to adipose tissue-derived factors
assessment of overall overweight or obesity is done by BMI (kg/m^2), but this doesn’t reflect fat distribution
assessment of visceral obesity is done by waist circumference and MRI
The umbrella factor that all other components stem from is…
increase body size (BMI and central adiposity)
Describe the relationship between visceral fat and insulin sensitivity. What is the M value?
As adipose tissue volume increases, glucose disposal decreases
M value measures insulin sensitivity
Underweight individuals have a —– risk compared to normal weight individuals.
increased/higher
Describe insulin resistance as a core component of metabolic syndrome
the state in which normal or elevated circulating insulin does not elicit the expected response
What are the primary and other organs of insulin resistance?
primary - skeletal muscle
other - liver and adipose tissue
What qualifies someone as “pre-diabetic”? What effects does this have for them?
- insulin resistant but not showing signs of hyperglycemia due to compensatory hyperinsulinemia
- already at increased risk of heart attack and stroke
It often takes how long for diabetes to be diagnosed after the initial onset of visceral obesity? Why?
years to decades
It takes that long for insulin resistance to peak and then for fasting blood glucose levels to finally start rising and produce symptoms
Microvascular complications start to occur when…
fasting blood glucose begins to rise (diabetes), which is often years after glucose tolerance has been impaired
Describe hyperinsulinemia as a core component of metabolic syndrome
increase in insulin secretion compensates for the insulin resistance, keeping blood glucose as close to normal as possible
degree to achieve normal glucose regulation cannot be maintained over time, so a relative dysfunction in insulin secretion will allow hyperglycemia to develop (eventually insulin secretion wares out and also drops, so then blood sugar goes up)
Describe glucose intolerance as a core component of metabolic syndrome
abnormal response to an oral glucose tolerance test (OGTT, ingestion of 75g glucose and assessing the blood glucose over the next 2-3 hours)
with impaired glucose tolerance, glucose levels increase higher than normal and stay high for longer than normal
Describe dyslipidemia as a core component of metabolic syndrome
- excess plasma triglycerides and free fatty acids, both fasting and after eating
- decrease in HDL cholesterol and post-heparin lipolytic activity (PHLA, a decreased ability to catabolize lipids in response to the drug heparin)
- increased small dense LDL (very atherogenic)
overall exacerbates insulin resistance and increases risk of CV events
Describe essential hypertension as a core component of metabolic syndrome
elevation in systolic and diastolic BP
insulin resistance and compensatory hyperinsulinemia can cause:
- increased central sympathetic outflow
- peripheral vasoconstriction
- renal retention of sodium and water
- increase blood volume and total peripheral resistance, resulting in hypertension
How do hyperinsulinemia and hypertension link?
hyperinsulinemia increases SNS activity and increases salt and water retention at the kidney, which both cause hypertension
How does the timeline of hypertension and dynlipidemia compare to the timeline of insulin secretion, insulin sensitivity, and fasting blood glucose?
it increases gradually over time
What are some of the brain consequences of metabolic syndrome?
cerebrovascular disease (transient ischemic attack, cerebrovascular accident, cognitive impairment)
What are some of the heart consequences of metabolic syndrome?
coronary artery disease (coronary syndrome, myocardial infarction, congestive heart failure)
What are some of the extremities consequences of metabolic syndrome?
peripheral vascular disease (ulceration, gangrene, amputation)
What are some of the eye consequences of metabolic syndrome?
retinopathy
cataracts
glaucoma
What are some of the kidney consequences of metabolic syndrome?
nephropathy (microalbuminuria, gross albuminuria, kidney failure)
What are some of the nerve consequences of metabolic syndrome?
peripheral and autonomic neuropathy
What is the ADA criteria for impaired glucose tolerance? For Type 2 Diabetes?
impaired glucose tolerance: blood glucose concentration from 140-200 mg/dL 2 hours out from an oral glucose tolerance test
T2D: above 200 mg/dL at 2 hour mark
What is the normal set point for blood glucose?
90 mg/dL
What are the 3 classic diagnostic indicators of Type 2 Diabetes?
- polyphagia
- polyurea
- polydipsia
What are the primary organ systems involved in glucoregulation, and what are their general roles?
hypothalamus - nutrient sensing and neural output (ANS sympathetic and parasympathetic to organs)
adipose tissue - glucose storage and adipokine secretion
liver - glucose storage and production
pancreas - insulin and glucagon secretion
muscle - glucose storage and utilization
Muscle is the major tissue responsible for…
disposal of glucose in response to an oral glucose load or during a bout of endurance exercise
Glucose transport into muscle cells is stimulated by either….
hormonal factors (insulin) or contractions
Glucose can be either….or….depending on….
stored as glycogen or oxidized to produce ATP (depending on the hormonal state and energetic needs of the cell)
The liver is an important site for…
glucose disposal from the hepatic portal circulation/general circulation
glucose production (hepatic glucose production)
Hepatic glucose production is mediated by…
breakdown of glycogen stores (glycogenolysis) and synthesis of new glucose molecules (gluconeogenesis) from a variety of precursor molecules
HGP (and glycogenolysis and gluconeogenesis) are under control of…
hormonal factors like glucagon and insulin in accordance with blood glucose levels
The endocrine pancreas has what kinds of cells and what do they do?
B cells: synthesize and secrete insulin (affect glucose transport and storage)
a cells: synthesize and secrete glucagon (affect HGP)
The role of adipocytes in glucoregulation is…
act as a site of insulin-stimulated glucose transport, with glucose carbons being stored as glycogen or triglycerides
critical site of synthesis and secretion of key regulatory factors called adipokines (adipocytokines)
What are adipokines?
secreted in the circulation, act in negative and positive ways on target cells including those in the CNS, skeletal muscle, and liver
very important roles in modulating insulin sensitivity and impacting whole-body glucoregulation
What are some the adipokines that elicit positive reponses?
adiponectin
leptin
What are some of the adipokines that elicit negative responses?
TNF-a
resistin
interleukin-6
plasminogen activator inhibitor
angiotensinogen
Neurons in the hypothalamus can be sensitive to —- and —— such as…..
nutrients or hormones such as glucose, FFAs, insulin, or adipokines
The hypothalamus plays a role in the central assessment of…
whole body energy balance and glucoregulation
The hypothalamus initiates appropriate neural signaling from the —- to the —– via….
CNA to peripheral organs via sympathetic and parasympathetic branches of the ANS
Long term hyperglycemia can have negative effects becauseof the increase in…
oxidative stress (excessive formation of reactive oxygen species, ROS, or advanced glycation end products, AGEs)
Where are reactive oxygen species formed?
mitochondria and cytoplasm
Can ROS be too low? What happens if they are too low or high? How are ROS levels maintained?
yes - too low or too high can impair physiologic function
too high - cell damage and impaired signaling pathways causing aging/disease
too low - decreased proliferation and defective host defenses
ROS levels are maintained by antioxidant defenses
AGEs are formed by….
non-enzymatic modification of proteins, lipids, and nucleic acids, by glucose
Regarding oxidative stress and AGE, what is the difference between metabolic syndrome+IGT and metabolic syndrome+diabetes?
metabolic syndrome+diabetes has a major role of oxidative stress and AGE while metabolic syndrome+IGT is only a limited role
