Pathophysi of Diabetes Flashcards
hockerman
criteria for diagnosis of diabetes (ADA)
A1C ≥ 6.5%
Fasting plasma glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L)
2 hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during OGTT (oral glucose tolerance test)
a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) with symptoms of diabetes
other names of T1DM
Insulin Dependent Diabetes Mellitus (IDDM)
Juvenile Onset Diabetes Mellitus (JODM)
prevalence of T1DM
10% of diabetic population
cause of T1DM
autoimmune response targeting pancreatic beta cells (may be triggered by viruses, chemicals, etc in genetically predisposed individuals)
typical treatment of T1DM
dependency on exogenous insulin
characterization of T1DM
no functional insulin-secretion
near complete loss of pancreatic beta cells
glucose interolance
common complication of T1DM
tendency towards ketoacidosis
mean age of onset T1DM
12
is family history often a factor in T1DM?
family history often negative
ICA
islet cell cytoplasmic antibodies
IAA
insulin autoantibodies
presence of ICA or IAA
means the immune system has initiated a response against the pancreatic beta cells
after initiation of autoimmune response, what happens to BCM?
gradual loss of BCM
what happens to FBG after initiation of autoimmune response?
FBG levels remain normal until about 70% of BCM is lost
C-peptide
a product of endogenous insulin that is a marker for insulin secretion in the presence of exogenous insulin
stage 1 of autoimmune response
normal glucose-stimulated insulin release
normal FBG
ICA-positive
IAA-positive
stage 2 of autoimmune response
progressive loss of glucose-stimulated insulin release
normal FBG
abnormal OGTT
stage 3 of autoimmune response
overt diabetes
high FBG
C-peptide present
autoantibodies associated with T1DM
islet antigen 2 (IA-2)
phogrin (IA-2B)
Zinc transporter (ZnT-8)
Glutamic acid decarboxylase (GAD65)
Voltage-gated Ca++ (Cav 1.3)
Vesicle-associated membrane protein-2 (VAMP-2)
antibodies against one or more B-cell proteins signals an increased risk for developing diabetes
IA-2 accuracy
57% sensitivity –> 57% of non-diabetics who have it will develop type 1 diabetes
99% selectivity –> 99% of type 1 diabetics have Abs
prevalence of non obese T2DM
10%
prevalence of T2DM
80%
age of onset of non-obese T2DM
often under 25
age of onset of obese T2DM
usually over 30
another name of T2DM
Non-insulin dependent diabetes mellitus (NIDDM)
Maturity onset diabetes of the young (MODY)
Adult onset DM
is family history often a factor in T2DM?
yes
insulin secretion in response to glucose challenge (non-obese)
low
insulin secretion in response to glucose challenge (obese)
low for body mass
cause of non-obese T2DM
mutations in specific proteins
cause of obese T2DM
insulin resistance
decreased BCM
consequence of lack of insulin
hyperglycemia
glucosuria
hyperlipidemia
uninhibited glucagon
source hyperglycemia due to lack of insulin
- decreased glucose uptake in cells where glucose uptake is insulin-dependent
- decreased glycogen synthesis (process in the liver where glucose is stored for later release into the blood stream)
- increased conversion of amino acids to glucose (in the absence of insulin there is nothing to inhibit gluconeogenesis)
source of glycosuria due to lack of insulin
high glucose concentration in renal filtrate, overwhelming of glucose transporters in the kidneys, glucose spills into the urine
source of hyperlipidemia due to lack of insulin
increased fatty acid mobilization from fat cells (lipids are broken down to fatty acids and distributed through the body to use for fuel instead of carbs)
increased fatty acid oxidation (ketoacidosis)
ketoacidosis
high rate of B-oxidation and accumulation of their byproduct, ketone bodies
leads to a large amount of acid in the body
source of uninhibited glucagon due to lack of insulin
increased glucagon levels in the presence of increased blood glucose levels, this process is usually inhibited by insulin
complications of hyperglycemia (CV)
micro and macro angiopathies
leads to compromised blood flow to parts of the body
complications of hyperglycemia (NS)
neuropathy
cause of neuropathy
high BG level
increase utilization of polyol pathway
water accumulation in neurons/reduced protection from oxidative damage
complications of hyperglycemia (eye)
cataracts
retinal micro aneurysms
hemorrhage
complications of hyperglycemia (infections)
increases susceptibility to infections
goal of insulin therapy historically
reduce acute symptoms (polyuria, dehydration, ketoacidosis)
current goals of insulin therapy
keep an average blood glucose level below 150 mg/dL
prevent/delay onset of complications
A1C ≤ 6 (ideal) or <7 (goal)
risk of insulin therapy with aggressive goals
increased risk of hypoglycemia
why is glucose so toxic?
oxidation products of glucose react irreversibly with proteins –> forms advanced glycation end products (AGEs) –> loss of normal protein function and acceleration of aging process
Theorized to account for many long-term complications of diabetes
RAGE
receptors for advanced glycation end products
when peptides containing CML (glyoxal) and CEL (methylglyoxal) bind, inflammation is promoted
polyol (aldose reductase) pathway
glucose –> sorbitol –> fructose
effect of increased glucose in polyol pathway
increased accumulation of sorbitol –> increases the osmolality of the cell –> swelling and damage
increased glucose in hexosamine pathway
increased formation of energized glucosamine-6-P (UDP-GIcNAc) which can diminish function of proteins/genes
increased glucose in protein kinase C pathway
leads to excess of various signaling
