Exam 3: Diabetes Flashcards
What is insulin resistance?
- Insulin does not ……
- Plasma glucose levels are ____ - saturating
- Insulin levels are _____ (what does that do to insulin receptors?)
- ________ process
- Over time pancreas reduces insulin output leading to diabetes mellitus
- What causes the convertion from type 2 to type 1 diabetes?
Insulin Resistance:
- Insulin does not effeciently transport glucose into cells
- Insulin levels are high - hyperinsulinemia downregulates insulin receptors
- Gradual process - can take decades to develope into diabetes
- Over time pancreas reduces insulin output leading to diabetes mellitus
- Beta cell depletion or exhaustion will cause conversion from T2DM to T1DM
Insulin response is ____ in obese individuals to same plasma glucose levels (this eventually causes beta cell dysfunction)
Insulin response is MUCH GREATER in obese individuals to same plasma glucose levels (this eventually causes beta cell dysfunction)
Obesity is number one risk factor for T2DM
T2DM:
Characterized by _______ and ________
Symptoms:
1
2.
3.
T2DM:
Characterized by impaired beta cell function and insulin resistance
Symptoms:
- Polyphagia - excessive hunger due to inability to utilize glucose “cellular starvation”
- Polyuria: excess glucose in blood leads to increased plasma osmolality, excessive water and sodium loss
- Polydipsia - excessive third due to severe dehydration
Diabetes Mellitus Type 2:
Diagnosis is Elevated HbA1C (_______ mMol/L) which is what percent?
Measures average blood glucose concentration over long period of time
Average RBC lifespan is 120 days, glucose increases the number of glycosylated RBCs
What is a normal fasting blood glucose level? Prediabetes? T2DM?
Oral glucose tolerance test: 8 hour fast, glycose measured before and 2h post consumption of 75g glucose. What is prediabetes and T2DM levels?
Diabetes Mellitus Type 2:
Diagnosis is Elevated HbA1c (> 48mMol/L or 6.5%)
HbA1c measures average blood glucose concentration over a long period of time (3 months specifically)
Normal fasting blood glucose level is 100 or less, prediabetes is 100-125, and diabetes is over 125 mg/dL
Oral Glucose Test: Normal is less than 140, prediabetes is 140-199, T2DM is greater than 200
Explain levels indicating normal, prediabetes and T2DM for the following:
HbA1c
Fasting Blood Glucose
Oral Glucose Test
HbA1c: prediabetes is 5.7-6.5%, diabetes is greater than 6.5%
Fasting Blood Glucose: prediabetes is 100-125 mg/dL, diabetes is 126+
Oral Glucose Test: prediabetes is 140-199, and 200+ is T2DM
T1DM:
Characterized by development of _____ in the absence of insulin therapy
_____ onset
Destruction of _______
Treatment?
T1DM:
Characterized by development of ketoacidosis in the absence of insulin therapy
Juvenile onset - approx 2-5% of diabetes cases
Destruction of pancreatic beta cells - insulin dependent
Treatment: insulin injections, close monitoring of blood glucose levels, diet
T1DM: Dominant catabolic state
Ketones are produced due to lack of insluin and increased substrates (explain how this happens)
Brain still receives high amounts of glucose
- GLUT 4 is insulin dependent, therefore without insulin (T1DM), glucose cannot get into skeletal muscle or adipose tissue
- Glycogen starts to get broken down in skeletal muscle creating lactate
- Protein starts getting broken down as well, producing AA
- TGs broken down in adipose tissue to make glycerol
lactate, glycerol, and AA are turned into ketones
Both ketone bodies and glucose are all being supplied to the brain
Explain what happens with hormone levels during the normal fed state
With a mixed meal and a protein only meal
Normal Fed State
Mixed meal:
- carbs : insulin
- fat: insulin
- protein: glucagon mostly
Protein only: glucagon only, barely any insulin
When insulin is present: AA from proteins stimulate GH which stimulates IGF-1
IGF-1 stimulates glucose uptake into muscle, proliferation of visceral organ tissues; inhibits proteolysis
GH opposes insulin lipogenesis
Explain what happens with hormones during Starvation:
Insulin?
Glucose?
What stimulates glucagon?
GH? IGF-1? Cortisol?
Starvation:
Negligible insulin
Low glucose
Catecholaimes and low glucose stimulate glucagon
GH increases due to increased AA (proteolysis)
No-GF-1, no negative feedback on GH
Cortisol - stress
Permissive effects on lipolysis, glycogenolysis
Type 1 DM:
Explain what happens to the following hormone levels
Insulin, glucose levels, catecholamines, GH, IGF-1, cortisol
T1DM
No insulin, high glucose
Catecholamines stimulate glucagon
GH increases due to increased AA
No IGF-1, no negative feedback on GH
Cortisol- stress, permissive effects on lipolysis, glycogenolysis
Type 2 DM:
Insulin levels, glucose leves, what happens with catecholamines, etc
Type 2DM:
Relative insulin deficiency, some insulin maybe not effective
HIGH glucose
Catecholamines stimulate glucagon, insulin inhibits
Cortisol - stress
Insulin inhibits ketogenesis
Explain what happens in the following:
T1DM: in the absence of insulin therapy, T1DM patients get _____lipidemia, _____acidosis, ___glycemia, T1DM mobilize their energy stores by increasing _____ to liver to turn into ketones
T2DM: _____ inhibits the ketogenesis pathway, still get ___glycemia
Both types of diabetes result in ____osmolarity, causing what?
T1DM: in the absence of insulin therapy, T1DM patients get hyperlipidemia, ketoacidosis, hyperglycemia. T1DM mobilize energy stores by increasing FFA to liver to turn into ketones. Increasing ketacidosis.
Hyperlipidemia is only really found in T1DM patients
T2DM: insulin inhibits the ketogenesis pathway, still get hyperglycemia
In both types of diabetes, result in hyperosmolarity, causing impaired renal function, excess thirst, and excess urine output
Diabetic Ketoacidosis:
Acute pathological condition – usually occurs in ___
Explain the progression
Step 1 —-> step 2 —-> step 3—-> step 4
Diabetic Ketoacidosis:
Acute pathological condition — usually occurs in T1DM patients
Decreased insulin and increased counter regulatory hormones ——->
FFA release (hepatic precursor for ketone acids)—->
Metabolism of ketone bodies for energy results in increased blood acidity (H+) ——->
Diabetic coma: severe dehydration and acidosis
Mental Acuity as a Function of Osmolality:
When plasma osmolaltiy is greater than _____ we get lower and lower brain function
When plasma osmolality > 330 mOsm/kg we get lesser and lesser brain function
This is because fluid will leave the neurons to combat high osmolality and thus shrinking the neurons
Explain the differences in T1DM and T2DM in the following categories:
onset
risk factor
beta cells
insulin levels
glucose intolerance
insulin dependent and insulin resistance
T1DM: juvenile onset, autoimmune risk factor, destroyed beta cells, none inulin levels, severe glucose intolerance, yes to insulin dependency, no to insulin resistance
T2DM: mostly adult onset, obesity and other risk factors, partially functioning beta cells, variable insulin levels, variable glucose intolerance, variable insulin dependency, yes to insulin resistance
What is the insulin resistancy for T1DM vs T2DM patients?
T1DM: are NOT insulin resistant
T2DM: are insulin resistant
T2DM WHat is the first phase of the disease progression?
T2DM first phase of disease:
impaired insulin release
instead of nice biphasic release, their insulin release is a lot weaker
If these patients are given GLP-1 agonists/incretin mimetics their biphasic insulin release improves
Explain the normal way insulin is released from beta cells, then explain how GLP-1 analogs can assist the process
Insulin Release: Glucose in blood activates GLUT 2 to transport glucose into beta cell, glucose gets phosphorylated by Glucokinase (trapping it into the cell), then Glucose-6-P metabolism produces ATP then then closes the K channel. Closure of the K channel causes depolarization, Ca2+ rushes in the cell, allowing for the release of vesicles containing insulin and C peptide (and amylin)
GLP-1 analogs, or incretins boost intracellular calcium to increase even more to get more insulin vesicles to be released
Explain the disease progression of T2DM
Early vs late stages in regards to insulin secretion adn Beta cell mass
Early stage T2DM: massive increase in insulin secretion and Beta cell mass during the early stages of T2DM
Mid to late stage T2DM: decrease in insulin secretion and beta cell mass
Proposed Mechanisms of Beta Cell Dysfunction:
-Islet amyloid buildup
(leading to ______ stress)
Lipotoxicity
Oxidative stress
Glucose toxicity
Beta cell differentiation - reduced expression of beta cell genes
Incretin hormone dysregulation
Islet inflammation
Proposed Mechanism of Beta Cell Dysfunction:
Islet amyloid buildup
leading to endoplasmic reticulum stress
Lipotoxicity
Oxidative stress
Glucose toxitiy
Beta cell differentiation
Incretin hormone dysfunction
Islet inflammation
T2DM Risk Factors:
Explain Enviornmental Risk Factors
Also explain “acquired organ dysfunction for glucose homeostasis”
T2DM Risk Factors;
Enviornmental
- impaired beta cell proliferation during childhood
- malnutrition
- maternal factors during pregnancy
- increased propensity for insulin resistance
- high caloric diet
- lack of physical activity
Acquired organ dysfunction for glucose homeostasis
- reversible
- first phase insulin secretion impaired - key early characteristic of disease
- hyperglycemic conditions result in organ dysfunction (liver, adipose, pancreas)
T2DM Risk Factors:
Genetic:
Most genes identified affect beta cells
Most highly associated genetic polymorphism is ____
T2DM Risk Factors: Genetic
Most genes identified affect beta cells
Some are linked to insulin signaling, glucose transport, or obesity
Most highly associted gene is TCF72
T2DM Chronic Pathologies
-Microvascular Disease: specific to _____
- retinopathy
- nephropathy
- neuropathy
Macrovascular Disease: major cause of death in ____
- coronary artery disease
- peripheral vascular disease
T2DM Chronic Pathologies:
Microvascular Disease: specific to diabetes (both type 1 and 2, don’t really see these in patients that don’t have diabetes)
- retinopathy - leading cause of new blindness
- nephropathy - kidney failure
- neuropathy
Macrovascular Disease: associated with diabetes; major cause of death in T2Dm
- coronary artery disease
- peripheral vascular disease
****** know this chart
Explain the chart of microvascular disease
Excess glucose entering the TCA cycle causes increased ROS
Which causes four things: (list them)
T2DM: Chronic Pathologies:
Retinopathy: 20% have this at time of diagnosis
- nonproliferative
- proliferative
explain the difference
Explain the leading cause of blindness in T2DM vs T1DM
Retinopathy: 20% have this at time of diagnosis
Nonproliferative:
- microaneurysns in retinal capillaries
- vascular permeability leads to macular edema - leading cause of blindless in T2DM
- capillary occlusion leads to ischemia
Proliferative:
- compensatory new vascular growth (leading casue of blindness in T1DM)
- abnormal networks result in retinal detachment
T2DM Chronic Pathologies:
Nephropathy - 50% of end stage renal disease patients are due to diabetes
- clinically defined as ______ mg urinary protein/day
- thickening and hardening of ____
- reduced ______
- development of glomerular lesions
_____ worsens with decreased renal function
_______ usually proceeds nephropathy
T2DM Chronic Pathologies:
Nephropathy: 50% of end stage renal disease patients are due to diabetes
- clinically definied as > 300 mg urinary protein/day
- thickening and hardening glomerular capillaries
- reduced filtration capacity
- development of glomerular lesions
Hypertensions worsens with decreased renal function
Retinopathy usually procedes nephropathy (later stage diabetes)
Neuropathy:
- Distal polyneuropathy
- ___ common
- resuts from demyelination of ____
- sensory loss in lower extremities, diabetic foot ulcers
- nerve damage due to increased activation of polyol pathway - increased ____
Mononeuropathy:
- acute painful motor loss
- involves cranial and peripheral nerves
- direct result of microvascular dysfunction - ischemia
Automatic (usually in ____)
- not as common
- usually involves GI and repro (erectile dysfunction)
- pathogenesis unclear
Neuropathy:
- Distal polyneuropathy
- most common
- results from demyelination of peripheral nerves
- sensory loss in lower extremities, diabetic foot ulcers
- nerve damage due to increased activation of polyol pathway - increased ROS
Mononeuropathy:
- acute painful motor loss
- involves cranial and peripheral nerves
- direct result of microvascular dysfunction - ischemia
Autonomic (mostly in T1DM)
- not as common
- usually involves GI and genitourinary system (erectile dysfunction)
- pathogenesis unclear
T2DM- Chronic Pathologies
Macrovascular Disease - 75% of diabetes related deaths are due to macrovascular disease
Atherosclerosis:
- increased _______
- increased ______ - in T1DM due to renal defeciency
- leads to MI, stroke, gangrene in lower extremities
Chronic Pathologies
Macrovascular Disease - 75% of diabetes related deaths are due to macrovascular disease
Atherosclerosis:
- increased hyperlipidemia
- increased HTN - in T1DM due to renal defeciency
- leads to MI, stroke, gangrene in lower extremities
T2DM:
treament goal is?
Explain what the following drugs do
- Sufonyleureas (close ATP dependent K channels causing…..)
- Metformin
- Alpha-glucosidase inhibitors
- SGLT2 inhibitors
T2DM :
Treatment goal is tight glycemic control
- Sulfonylureas: close ATP dependent K channels in beta cells causing insulin release
- Biguanides - Metformin:
- inhibits hepatic gluconeogenesis
- increases insulin receptor activity making cells more sensitive to insulin, increased glucose uptake
-
Alpha-glucosidase inhibitors:
* delays intenstinal absorption of carbs - SGLT2 inhibitors:
- inhibits glucos uptake in proximal convoluted tubule of nephron
- results in increased glucose clearance through urinary excretion
- SIDE EFFECT: Getinourinary infections (ew)
Islet Transplant:
-Reserved for cases of severe glycemic variability, life-threatening hypoglycemia, progressive complications (T1DM)
Limitations:
- lack of viable ____
- Immune ____ by host
- Beta cell survival not good
- Long term: many patients require insulin ____ post treatment
Islet Transplant:
-Reserved for cases of severe glycemic variability, life-threatining hypoglycemia, progressive complications (T1DM)
Limitations:
- Lack of viable donor material - porcine is good alternative
- Immune rejection by host
- Beta cell survival - isolation techniques not optimal; host microenviornment
- Long-term: many patients require insulin 5 years post transplant
Stem Cell Therapy:
Explain the following:
Mesenchymal Stem Cells:
- ubiquitous throughout body, easily obtained
- ______ derived
- have been shown to help with survival of ____
-
Hematopoetic Stem Cells:
- _____ derived
- stimulates vascular _____
- used locally to treat ischemia
- early studies show promise
Stem Cell Therapy:
Mesenchymal Stem Cells:
- ubiquitous throughout body, easily obtained
- umbilical cord blood-derived
- have been shown to help with survival of islet transplants
Hematopoetic Stem Cells:
- bone marrow derived
- stimulates vascular regeneration
- used locally to treat limb ischemia
- early studies show promise - inject into pancreas of T2DM
Stem Cell Therapy:
Human Embryonic Stem Cells:
- hES beta cell progenitors transplanted into mice results in _____
- pre-clinical tials ongoing
- risk of ____
- Ethical issues
Induced Pluripotent Stem Cells:
- preliminary proof of concept
- potential for oncogenesis
- no ethical issues
- good option for _____ due to autoimmune dysfunction
Stem Cell Therapy:
Human Embryonic Stem Cells (hES):
- hES beta cell progenitors transplanted into mice results in normoglycemia
- pre-clinical trials ongoing
- risk of tumorigenesis (tumors)
- ethical issues
Induced Pluripotent Stem Cells:
- preliminary proof of concept
- potential for oncogenesis
- no ethical issues
- good option for T1DM due to autoimmune dysfunction
