Trumbly - Metabolic Syndrome/Diabetes
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1.
Complications
from
hyperglycemia.
Which tissues are
affected? Which
organ functions
are impaired?
-tissue that doesn't require insulin for
glucose uptake is susceptible:
5.
Drug therapy for Type 2
diabetes
1. increase insulin secretion
-agents that stimulate secretion
are called secretatogues
-two examples are sulfylurea and
meglitnides
-work to close K+ leak channel
in B cells
lens epithelium, Schwann cells in
peripheral nerves, papillae in kidney,
islets of Langerhans
impaired Kidney function (nephropathy)
→ hypertension (retention of sodium and
thus water) and gout (retention of uric
acid)
2.
Describe process
of Obesityinduced
inflammation
starting with
nutrient excess
and ending with
atherosclerosis
Nutrient excess → expansion of fat mass
→ adipocyte production of cytokines and
chemokines → endothelial cell
expression of adhesion molecule
→monocyte recruitment and
differentiation → macrophage
infiltration and cytokine production →
obese
2. Increase insulin sensitivity of
target tissues
-biguanides (metformin)
-thiazolindinediones (TZDs)
6.
Hemoglobin A1C
Describe the
process of
developing IR
from excess
cellular fat and
describe role of
TZD drugs
amount of Hb A1C is
proportional to long-term
(several months) plasma glucose
levels
A1C > 6.5% (~140 mg/dL)
suggested as another criterion
for diagnosis of diabetes
DAG from excess cellular fat directly
inhibits insulin signaling
7.
in lipodystrophies (disorders where fat
cells cannot be formed) there is high IR
because there's no place to store fat
how do Biguanides
(Metformin) work?
Biguanides (Metformin):
-decreases hepatic
gluconeogenesis
-reduces cardiovascular
components (unique to this
drug)
-activates AMP-activated protein
kinase to upregulate insulin
targets
How do TZD drugs affect
hyperglycemia and the
liver and muscle?
They restore insulin sensitivity:
TZD drugs restore insulin sensitivity
partly by expanding fat stores
insulin sensitivity improves
cardiorespiratory fitness: increases
burning of fat by mitochondria
4.
Diagnostic
Criteria for
Diabetes
Fasting blood glucose
Normal: <99 mg/dL
Prediabetes: 100-125 mg/dL
Diabetes: >126 mg/dL
still under srcutinization:
AIC > 6.5% (~140 mg/dL) glycosylated
Hb
Glucose + proteins →
glycosylated proteins
glycated Hb = hemoglobin A1C
cytokines/chemokines, adhesion
molecules and macrophages infiltration
→ proinflammatory and proatherogenic
mediators → insulin resistance and
atherosclerosis
3.
2 approaches:
8.
↓ gluconeogenesis (in liver)
↑ glucose uptake (in muscle)
→ reduction of hyperglycemia
9.
How do TZD
drugs work?
TZD drugs:
bind to nuclear transcription factors PPAR
gamma which:
12.
- ↑ differentiation of fibroblasts to adipocytes
(more storage for fat means more insulin
receptors available)
→ insulin sensitivity increases
How does
insulin
resistance
result in
atherosclerosis?
What is the
atherogenic
triad?
- ↑ translation of adiponectin (a cytokine)→
upregulates AMP-kinases → inhibits lipolysis
(inhibits breakdown of lipids into FFA) →
increase muscle cell insulin sensitivity
- ↑ translation of leptin → insulin
sensitization (tells brain not hungry so eat
less → produce less glucose → produce less
insulin)
11.
How does
body fat
distribution
influence
morbidity
due to
obesity?
Android → high TG and low HDL cholesterol,
diabetes mellitus hypertension or CHD
How does
glucose
stimulates
insulin
release from
beta cells
insulin synthesized in pancreas and stored in
storage granules in pancreas
Gynoid (pear) → more common in women
when sufficient glucose in blood, it's taken up
into beta cells by GLUT2 transporter
(unregulated)
Glucose gets metabolized via glucokinase
(phosphorylates it) to glucose-6-P which goes
to glycolysis and respiration → ATP:ADP ratio
↑
ATP interacts with ATP-sensitive potassium
leak channel to close it → cuts off efflux of K+
→ buildup of K+ causes depolarization →
activates voltage gated calcium channel →
influx of Ca++ → stimulates insulin storage
granule release
more VLDL circulating due to IR → ↑
lipoprotein lipase activity (trying to bring
lipids into cells to get out of blood)
↑ VLDL synthesis + ↓ VLDL clearance →
accumulation of TG in plasma →
atherogenic triad
atherogenic triad = high TG, low HDL,
small LDL
13.
- inhibits resistin, another cytokine (therefore
opposes insulin resistance) → increases
insulin sensitivity
10.
insulin resistance (IR) means
upregulation of HPL activity because no
insulin to inhibit or regulate it. HPL thus
stimulates lipolysis in adipocytes → ↑
FFA in plasma → ↑ TG synthesis in liver
→ ↑ TG-rich VLDL production in liver
How does Type
II diabetes
contribute to
hyperglycemia?
eventually you get decreased insulin
secretion from the pancreas
↓ insulin → inappropriate ↑ hepatic
glucose synthesis → hyperglycemia
↓ insulin → impaired disposal of dietary
glucose in muscle → hyperglycemia
14.
15.
How to genetics,
aging and
decreased
exercise lead to
inhibited
insulin
signaling?
genetics, aging and ↓ exercise → reduced
mitochondrial activity (FA oxidation)
Insulin pathway
on target cell
insulin binds to insulin receptor (tyrosine
kinase receptor) which
autophosphorylates and activates 2
pathways:
↓ FA oxidation → ↑ DAG + Acetyl-CoA →
inhibits insulin signaling
MAP K signaling pathway & IP3 K
signaling pathway
MAP K → cell growth, proliferation and
gene expression
IP3K → synthesis of lipids, proteins and
glycogens
IP3K → cell survival and proliferation
IP3K → GLUT4 vesicle → increase glucose
uptake
16.
Metabolic actions of insulin
insulin effects
18.
Nutrition therapy for
diabetes
in WAT:
glucose uptake ↑
lipogenesis ↑
lipolysis ↓
BLOOD LIPID LEVELS
-maintain optimal levels of
LDL cholesterol (<100)
in skeletal muscle:
glucose uptake ↑
glycogen synthesis ↑
protein synthesis ↑
if elevated serum TG persists:
-increase fat intake
(monounsaturated)
-decrease carb (especially
sugar) and alcohol
in liver:
gluconeogenesis ↓
glycogen synthesis ↑
lipogenesis ↑
17.
NCEP: Clinical Management
of Metabolic Syndrome →
how does it work?
if low HDL-C persists:
-increase fat intake
(monounsaturated)
Management of underlying
causes: obesity and lack of
physical activity
19.
Weight control → lowers
LDL-C and reduces risk
factors
Physical activity → reduces
VLDL and LDL-C,
increases HDL-C
Treatment of lipid and
nonlipid risk factors:
-hypertension
-elevated TG
-low HDL-C
Use aspirin in CHD
patients and Statins to
reduce LDL-C
DIET
-appropriate caloric intake
-distribution of calories (50%
carb, 30% fat, 20% prot)
-Sat fat <7% of calories
Prevalence of
Atherosclerosis and CHD
in Diabetic patients
80% of diabetic mortalities
caused by atherosclerosis
>50% of patients with newly
diagnosed Type II diabetes
have CHD
20.
Symptoms and signs of
diabetes
HYPERGLYCEMIA:
-polyuria (peeing often)
-thirst
-protein glycation (Hb A1C)
-glycosuria (BG > 180
mg/dL) glucose in the urine
21.
What are the differences
between PPAR alpha and
gamma with respect to
tissues effected, drugs used
and effect?
PPAR alpha:
25.
tissue: liver & muscle
role: lipid oxidation
drug: fibrates
effect: ↓ TG, ↑ HDL-C
What is
metabolic
syndrome?
22.
What are the differences in
effects (comorbidity) and
complications of
hyperglycemia and insulin
resistance?
Hyperglycemia (impaired
capillary circulation) leads
to microvascular
complications:
→ retinopathy
→ nephropathy
→ neuropathy
Insulin resistance
(dyslipidemia,
hypertension) leads to
macrovascular
complications:
-CHD
-Stroke
-Peripheral vascular
disease
23.
What are the risk factors for
metabolic syndrome?
Blood pressure > 130/ >85
Fasting glucose > 110
Met Syndrome diagnose: 3
or more factors true
What causes insulin
resistance? (2 theories)
26.
1. inflammatory cytokines
from adipocytes and
macrophages in visceral
adipose stores inhibit
insulin signaling
2. excess intracellular fat in
muscle and liver inhibits
insulin signaling
(lipotoxicity)
What is Type I
Diabetes
aka juvenile diabetes, insulin-dependent
diabetes mellitus
Destruction of beta cells in the pancreas by
autoimmune reaction of unknown cause:
cannot make insulin!
treat with injections of insulin
only 5-10% of diabetes are Type I
27.
What is Type
II Diabetes
decreased response to insulin in peripheral
tissues (insulin resistance)
initial hyperinsuinemia (too much insulin)
→ Beta cell dysfunction (beta cells think
there is enough insulin and they don't need
to produce more) → deficiency in insulin
28.
29.
HDL cholesterol <40 in
men, <50 in women
24.
more mortality from diabetes due to CVD
(must treat dyslipidemia to prevent)
Abdominal obesity
Triglycerides > 150
cluster of metabolic disturbances due to
inuslin resistance
often leads to type II diabetes
PPAR gamma:
tissue: adipose
role: lipid storage
drug: TZDs
effect: ↓ hyperglycemia
initially called Syndrome X
which agents
increase
insulin
sensitivity?
TZD drugs and biguanides (Metformin)
Which agents
increase
inuslin
secretion?
how do they
work?
sulfonylurea agents like Glyburide→ bind to
sulfonylurea receptor on the ATP-sensitive
K+ channel, inhibiting it
meglitinides → bind to and inhibit ATPsensitive potassium channel, inhibiting it
What are the effects of closing the K
channel?
→ inhibits escape of K+ ions → slight
depolarization (+) of membrane → opens
Ca+ channels → further depolarization and
Ca+ binds to insulin storage granules →
release of pre insulin