Diabetes Flashcards
What are the risk factors for diabetes?
- Hypertension
- Impaired glucose tolerance
- Insulin resistance
- Metabolic syndrome
- Dyslipidemia
- Obesity
- Hypertension
- Smoking, alcoholism
- Genetic predisposition
- Environmental factors
Type 1 Diabetes Pathophysiology
- (Genetic Predisposition + Environmental Factors) -> influence formation of auto antigens on insulin-producing B cells & they circulate in the blood stream & lymphatics
- Processing and presentation of autoantigen by antigen presenting cells leads to activation of T helper 1 lymphocytes and/or T helper 2 lymphocytes
- T helper 1 lymphocytes:
o Activation of macrophages with release of IL-1 and TNF-alpha - resulting in destruction of B cells & decreased insulin secretion
o AND/OR activation of auto antigen-specific T cytotoxic (CD8) cells - resulting in destruction of B cells with decreased insulin secretion - T helper 2 lymphocytes:
o activation of B lymphocytes to produce islet cell autoantibodies and antiGAD antibodies - resulting in destruction of B cells with decreased insulin secretion
What are the steps in Insulin-dependant Carb Metabolism in a normal fed state?
- Consume carbs in meal
- Increase [Blood glucose (BG)] stims pancreases secrete insulin
- Insulin binds to receptors in adipose tissue & liver:
a. Stims translocation of GLUT-4 receptors to cell surfaces in muscles and adipose tissue
b. GLUT-4 then allows glucose into the cells out of blood
c. Inhibits hormone sensitive lipase in adipose - which decreases lipolysis -> TG not broken down -> No FFA & Glycerol formed - In muscles: Glucose can be used for energy (glycolysis) OR stored as glycogen for later
- In liver:
a. Takes up blood glucose & converts glucose to glycogen
b. Decreased glycogenolysis & gluconeogenesis -> decreased hepatic glucose production - This decreases [BG]
What are the major effects of insulin?
- Promotes anabolism [uptake, rebuilding & storage]
a. Increased Glucose uptake
b. Increased Glycolysis in all tissues
c. Increased Glycogen synthesis in liver & muscle
d. Increased Protein synthesis in muscle
e. Increased Uptake of ions - Inhibits catabolism [breakdown & release]
a. Decreased Gluconeogenesis in liver
i. Blood glucose (BG) can’t be increased by release of glucose from the liver
b. Decreased Glycogenolysis in muscle & liver
c. Decreased Lipolysis in adipose tissue
d. Decreased Ketogenesis in liver
e. Decreased Proteolysis in muscle - In the liver:
a. Increased FFA uptake
b. Increased De novo lipogenesis
What are the steps of insulin-dependant Carb metabolism in an insulin resistant state?
- Insulin doesn’t bind to receptors
- Decreased ability to inhibit lipolysis at adipose tissue -> FFA & glycerol form -> increased plasma FFA and glycerol
- Excess FFA in plasma -> decreased Insulin-inhibition of hepatic glucose output
- Increased Gluconeogenesis and glycogenolysis -> increased hepatic glucose output
- Reduced ability of insulin to stimulate glucose uptake (decreased insulin signaling of GLUT4 translocation)
- Results in hyperglycemia maintained -> compensation of even more insulin secretion -> hyper insulinemia
- Increased Plasma FFA -> hyperlipidemia: risk for ectopic [abnormal positioning] fat deposition
What are the negative effects of excess FFA?
- Excess FFA have a direct toxic effect on pancreatic β-cells
- Increased FFA cause:
o Formation of DAG (glycerol with 2 FA):
• DAG promotes muscle insulin resistance & impairs fat oxidation via negative feedback mechanism
o Excess ceramide & sphingolipid accumulation in skeletal muscle -> decreased insulin signaling -> insulin resistance
o Taken up by various tissues and esterified into triglycerides -> triglyceride accumulation in tissues is associated with tissue & systemic insulin resistance
o ER stress (endoplasmic reticulum)
o Inflammation, ROS Generation, Mitochondrial Dysfunction
o Increased TG in liver -> Increased VLDL -> Increased LDL -> Increased HL -> Decreased HDL
What is the relationship between Obesity, Insulin Resistance & Dyslipidemia?
Central obesity -> Inc. FFA ( Insulin Resistance) -> Inc. ApoB & Inc. Hepatic Lipase (HL) -> Inc. TG ;
Inc. Small, dense LDL -> Dec. HDL
What is the effect of FFA on B-cells of the pancreas?
- FFA is essential for glucose-mediated insulin secretion in pancreatic islet B-cells
- Persistent excess FFA augments glucose-mediated insulin secretion
- This plus hyperglycemia – B-cells want to secrete even more insulin
- Results in impairment of insulin synthesis and B-cell apoptosis
What is mitophagy?
Control process that removes damaged mitochondrion
What is the Mitochondrial Dysfunction association with Insulin Resistance?
- Direct consequence of oxidative stress & Inc. pro-inflammation cytokines
- Occurs late – i.e. not primary cause of IR in obese persons
- Promotes further ROS production
- Results in impaired mitochondrial FA oxidation
- Worsened by FA accumulation & lipotoxicity
- Impaired mitophagy
o Damaged mitochondria aren’t removed and replaced - All of these lead to accumulation of dysfunctional mitochondria
What are the symptoms of T1 DM?
3 P’s:
o Polydipsia: Excessive thirst
o Polyphagia: Excessive hunger/increased appetite
o Polyuria: Frequent urination
What are the symptoms of T2 DM?
- Any Type 1 symptom
- Frequent infections
- Blurred vision
- Cuts/bruises that are slow to heal
- Tingling/numbness in the hands/feet
- Recurring skin, gum, or bladder infections
What is FPG?
Fasting Plasma Glucose
What is IFG?
Impaired Fasting Glucose
What is IGT?
Impaired Glucose Tolerance
What is OGTT?
Oral glucose tolerance test
What is RPG?
Random plasma glucose
What is HbA1c?
Glycated hemoglobin
Is 1 single abnormal test enough to diagnose diabetes in an asymptomatic individual?
No.
1 single abnormal test must be repeated to confirm diagnosis of diabetes, IFG or IGT, using the same testing method
Is 1 single abnormal test enough to diagnose diabetes in non-pregnant individuals with classic symptoms?
Yes
What is the preferred test for diabetes in high-risk individuals and in those with inconclusive results from other tests?
OGTT
On which patients only must a RPG be performed?
Patients with classic symptoms or hyperglycaemic crises
What are the microvascular long-term complications of DM?
- Neuropathy o Problems with nervous system - Nephropathy o Problems with kidneys - Retinopathy o Problems with eyes
What are the macrovascular long-term complications of DM?
- CVD
o People with Diabetes have 2-5x increase in CVD risk & more CVD-related death - Hypertension
- Dyslipidemia
o Inc. cholesterol
o Inc. LDL oxidation
o Inc. LDL:HDL ratio - Can be controlled by glycemic control – blood glucose regulation
What Cardiovascular diseases are related to DM?
Peripheral vascular Disease
Coronary Artery Disease
Cerebrovascular Disease
What characterises Peripheral Vascular Disease?
An associated long-term complication of Diabetes
- Decreased blood flow in peripheral arteries (usually legs and arms)
- Caused by atherosclerosis
- Atherosclerosis caused by:
o Production of advanced glycation end products (AGE)
o Abnormal activation of signaling cascades
o Increased production of ROS
o Abnormal stim of hemodynamic regulation systems
What characterises Coronary Artery Disease?
Plaque build-up in heart vessels by atherosclerosis in the coronary arteries that supply blood to the heart
What characterises Cerebrovascular Disease?
Decreased blood flow to the brain also mainly due to atherosclerosis
What are the 2 types of Neuropathy?
Autonomic: Affects nerves that control various organs
Peripheral: Affects nerves that control sensation in hands & feet
What are the 5 types of Autonomic Neuropathy?
- Cardiovascular
- Genito-Urinary
- Sudomotor
- Autonomic
- Gastrointestinal
What are the symptoms of Cardiovascular neuropathy?
- Poor exercise tolerance
- Postural hypotension, dizziness
- Decreased responsiveness to cardiac nerve impulse
What are the symptoms of Genito-Urinary neuropathy?
- Erectile dysfunction
- Vaginal dryness
- Urinary frequency & urgency
- Nocturia
- Urinary retention (can’t empty bladder)
- Urinary incontinence
What are the symptoms of Sudomotor neuropathy?
- Anhidrosis/hyperhidrosis (sweat abnormalities)
- Heat intolerance (uncomfortable in hot)
- Dry skin
What are the symptoms of Gastrointestinal neuropathy?
- Esophagus: Nausea, Esophagitis
- Stomach: Gastroparesis
- Small bowel: Loss of nutrients
- Large bowel: Diarrhea/constipation
How do you treat gastroparesis?
- Dietary treatment:
o Blood glucose control
o Medical nutrition therapy (MNT) – minimize abdominal stress
o Small frequent meals
o Decreased fiber & fat
o If patient is on insulin:
• Adjust injection time to match delayed nutrient absorption
- Pharmacological treatment: o Prokinetic agents • Stims GIT contractions o Antiemetic agents • Relief nausea and vomiting
What are the symptoms of peripheral Neuropathy?
o Numbness o Sensory loss o Nighttime pain o Burning, pricking o Pins & needles
What are the 5 stages of Nephropathy?
- Present at time of diagnosis – Hyper-function & Hypertrophy
- First 5 yrs – silent stage (Thickened basement membrane)
- 6-15yrs – incipient stage (microalbuminuria)
- 15-25 yrs – over diabetic nephropathy (macroalbuminuria)
- 25-30 yrs – uremic
What percentage of diabetes mellitus patients develop nephropathy?
20-40%
What percentage of diabetes mellitus patients develop retinopathy?
15-35%
How can you treat/monitor long term complications of diabetes?
- Optimal glucose control o Achieve BG and HbA1c targets - Consider bariatric surgery if BMI >35 & co-morbidities - Physical activity and dietary guidelines - Supervision during intercurrent illness - Effective management of hypoglycaemia - Reduce CVD risk: manage BP & dyslipidemia - Screen for, monitor and manage early: o Nephropathy o Retinopathy o Neuropathy - Monitoring of blood glucose: o Continuous glucose monitoring (CGM): • Sensor inserted underneath skin • Reads Glucose every 5mins • Displayed on monitor • Alerts highs, lows, rise/drops in BG o HbA1C: • 2x annualy o Self-monitoring of BG: • Insulin pump before each meal 7 snack
Endothelial dysfunction in diabetes
- Decreased Release of and responsiveness to NO
o -> Impaired endothelial function & reactivity - Increased Expression, synthesis and plasma levels of endothelin 1
o -> Vasoconstriction & hypertension - Increased Adhesion-molecule expression
o -> Inc. monocyte adhesion to vessel wall - Increased Adhesion of platelets and monocytes
o -> Foam cell formation, thrombosis, inflammation - Increased Procoagulant activity
o -> Inc. Thrombosis - Increased Advanced glycosylated end products
o -> Inc. Stiffness of arterial wall - Impaired fibrinolytic activity
o -> Decreased clot breakdown
What are advanced glycation end products, and what effect do they have?
- AGEs are Proteins or lipids that become glycated after exposure to sugars
- AGEs affect extracellular and intracellular structure and function
- AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE)
- AGEs contribute to the development of atherosclerosis:
o Soluble AGEs activate monocytes
o AGE-bound RAGE increases endothelial permeability to macromolecules
o AGEs block NO activity in the endothelium and cause the production of ROS
What are 8 benefits of exercise?
- Weight loss & Incr. muscle strength
- Incr. Glucose control
- Incr. Insulin sensitivity
- Incr. Cardiovascular fitness
- Incr. Blood flow and blood pressure
- Incr. Cholesterol levels
- Incr. Increases feeling of well being
- Mental health benefits:
a. Boosting happy chemicals (endorphins)
b. Reduces stress
c. self-confidence
d. Helps with anxiety
e. Better sleep
f. Improves work flow
What is the effect of diabetes on exercise?
- DM results in exercise impariement because:
o Decr. cardiorespiratory fitness and exercise tolerance
o Accentuates blood pressure response to exercise
o Reduces Oxygen uptake by up to 15%
- Reasons for these losses:
o Decr. HR variability
o Left ventricular diastolic dysfunction (LVDD)
o Decr. lung capacity - Diabetes exaggerates exercise effort
o Exercise feels more difficult to sedentary people with type 2 DM than their similarly obese & sedentary counterpats without DM
Why does exercise decrease the risk of DM?
- Weight loss (must be associated with healthy nutrition program) -> Decr. inflammation & oxidative stress
- Incr. Insulin Sensitivity
- Incr. Endothelial Function
- Incr. Autonomic Nervous System Function
What are the affects of Circadian misalignment?
- Incr. both diastolic & systolic bp
- Incr. CVD risk factors
- Decr, epinephrine excretion & markers of parasympathetic tone which may explain increase in BP
- Incr. inflammatory markers
- Has an influence on atherosclerosis (C rhythms influence supply of leukocytes & lipids in circulation & behavior of endothelial cells)
What is the effect of Exercise on Insulin Sensitivity and Resistance?
- Decr. Oxidative stress
o 10 weeks of aerobic training reduces ROS production - Decr. Glycated hemoglobin
- Incr. GLUT4 translocation
o Key for letting glucose out of blood into the cells
o Exercise-induced Incr. in GLUT4 contributes to Increased glucose uptake & glycemic regulation – EVEN in insulin resistance
o Exercise can bypass insulin signaling by activating an alternative signaling path (IP3-kinase) - Decr. Inflammation
- Incr. Insulin Sensitivity
- Moderate physical activity-> Incr. NO & ROS and Decr. oxidative stress
Why does exercise lead to an increase in insulin sensitivity?
- Overloaded FFA & Hyperglycemia -> Incr. ROS -> mutations etc. -> mitochondrial dysfunction -> insulin resistance
- PGC1-A decreased in diabetics -> decreased mitochondrial biogenesis
- Exercise -> increased PGC-1A -> Incr. quality & quantity of Mitochondrion -> increased insulin sensitivity
- AMPK (AMP Kinase):
o Intermediate in high-intensity training - forms PGC-1A
o AMPK activity in women
o Obese T2DM patients might need to exercise at higher intensity to increase AMPK activity - PGC-1A:
o Chronic & single bouts of exercise can increase PGC-1A in healthy & T2D patients
