185/186. Diabetes I/II Flashcards
Dx Criteria for normal BG, impaired fasting glucose, impaired glu tolerance, diabetes
Why was the BG cutoff value picked for DM?
What is HbA1c and why is it used?
Quick definitions of:
Type 1 DM
T2 DM
Gestational DM
Normal: fasting BG <100mg/dL; 2-hr oral glu BG <140
Impaired glu tolerance: 2-hr oral glu BG: 140-200
Impaired fasting glu: FBG 100-125
DM: FBG > 126mg/dL OR 2hr glu tol >200
BG level picked due to hugely increasing risk of diabetic retinopathy after BG = 126mg/dL
HbA1c: glycation of glu to Hb (irreversible glycation lasting RBC lifespan 3-4mo) = average levels of BG over previous SEVERAL MONTHS; indicates DM CONTROL, does not correlate with random BG but does correlate with avg BG over time
T1DM: beta cell destruction, leading to absolute ins deficiency (immune-mediated or idiopathic)
T2DM: range from ins resistance w/ relative ins deficiency to secretory deficit with ins resistance
GDM: occurs for 1st time during pregnancy
T1 DM
- immunologic hx/course
- what does insulinopenic mean
- presentation: age, sex, sx
- genetics
- incidence
- enviro RF
Hx: 1. innate immune cells enter pancreatic islets (priming), 2. antigens trigger T cells (TTT) - T cells arrive from LNs = INSULITIS, 3. destructive insulitis, 4. remission if intervene, disease onset w/o intervention (destruction of beta cells)
Insulinopenic: dependent on exogenous ins for life, prone to ketosis under basal conditions
Presentation: from infancy to adulthood (peak 10-14 yo)
affects boys and girls equally
Sx: Polyuria (glu spillover), Weight LOSS (less ins effect), Fatigue
Genetics: 95% assoc with HLA DR3 or DR4 allele (protected by DR2, DR5, DQB1*0602)
variants in variety of other genes show small risk assoc - some genes assoc with other autoimmune conditions
key genes: HLA DR3, DR4, INS, PTPN22 (intracellular phosphatase), IL2RA (immune regulation)
Incidence: trends INCREASING OVER TIME
Enviro: Enteroviral infections, dietary factors (breast feeding protective, early introduction of cow’s milk or solid food bad?, toxic/chemical compounds), beta cell stress secondary to insulin demand
T1 DM
- islet cell antibodies
- specific types of auto-antibodies
- staging of disease
Frequently present at dx (marker of autoimmunity, NOT causative of disease -TTT cell mediated)
Used to predict and dx disease in non-classic presentations
Can present years-months before onset of clinical T1DM! (younger pts with more Ab’s more likely to get T1DM than older pts with less Abs)
Over disease course, auto-Ab’s diminish as Beta cells destroyed
Specific types: ICA - islet cell Ab GADA IA2A - insulinoma assoc 2 auto-ab IAA - insulin auto-ab ZnT8 auto antibodies (Zn transporter than loads Zn into ins granules)
Staging:
At risk - B cells 100% fx
Stage 1 - B cell autoimmunity develops [normoglycemic and pre-sx] - we have more b cells than we need
Stage 2 - B cell autoimmunity [dysglycemic and pre-sx] = losing more b cells
Stage 3 - dysglycemia and sx (sufficient b cell destruction, 10% fx’l)
Pre-sx T1DM is Stage 1 + 2; Sx T1DM is Stage 3
Is there a medicine that can prevent onset of T1DM?
what are the acute effects of lack of insulin on the liver, in blood and in periphery?
Teplizumab: inhibits effector T-cell activity, delayed onset of T1DM by 2 years!, boosts C-peptide secretions, possible tx of pre-sx T1DM (secondary prevention)
NO INSULIN
Liver: increase glycogenolysis, FA oxidation, gluconeogenesis (from AA, glycerol)
Blood: hyperglycemia (cannot be utilized), increased FFA and ketone body levels from FA oxidation = low pH (DKA)
Periphery: increased glycosuria, proteolysis, lipolysis (cannot sense glu)
Diabetic Ketoacidosis (DKA)
- what is it
- pathophysiology
- what is immediate tx of DKA
Insufficient ins action = hyperlipolysis (increased ketoacids) and hyperglycemia (glycosuria = polyuria)
Pphys: polyuria = hypovolemia = renal hypofx = more ketoacidosis = more polyuria (positive feedback)
Tx:
1. Insulin: move pt from catabolic to anabolic state
2. Fluids: replace loses
a. replete volume loss with isotonic fluid
b. replete with hypotonic fluid to restore OsM
c. correct acidosis with NaHCO3 if necessary
d. add glu to fluids as levels fall (help move from fasting to fed state)
e. ADD POTASSIUM - avoid the hypokalemia from transcellular shift during H/K exchange of ketoacidosis
T2 DM
- differences from T1 DM
- genetics
- cause of hyperglycemia
- prevalence
Not absolutely dependent on exogenous ins, not prone to DKA, often obese, may be relatively free of classical sx
Genetics: complex polygenic disorder, no major gene locus, just many genes slightly increasing risk; T2DM pts carry slightly more risk alleles but other RFs involved (more gene variants = higher prevalence of T2DM)
Causes of hyperglycemia: ins resistance in periphery creates increased ins demand + impaired ins secretion (supply cannot keep up with demand, causes increased glu production in liver due to not enough insulin)
T2 DM: Insulin Resistance
- definition
- why do T2DM pts have higher fasting BG than healthy pts?
- Genetic and Enviro Factors causing ins resistance?
- how does obesity induce insulin resistance (3 ways)?
Decreased ability of ins to lower circulating glu levels, leading to impaired glu utilization by muscle and fat, and impaired suppression of glu production by liver
T2DM pts have higher hepatic glu output than healthy pt (less ins = less hepatic glu output suppression = higher fasting BG)
Genes: rare mutations in ins receptor, glu transporter, signaling proteins; most common are several genes with small effects
Enviro: inactivity, overeating, aging, meds, hyperglycemia, elevated FFA, OBESITY
Each unit BMI increases T2DM risk by 12.1% - more important than genetics!
High fat = decreased lipid storage capacity = excess FFA
1. Fat accumulates in liver = lipotoxicity = increased gluconeogenesis; (lipid stim DAG = active PKC = more ins resistance by modifying receptor = increased hepatic glu produciton)
2. fat accumulates in muscle = lipotoxicity = decreased fat oxidation, ins action, and glu uptake
3. adipose tissue inflammation = macrophage infiltration = FFA release (binds TLR4 on lymphocytes) = cytokine release = high TNFalpha, high IL6 = ins resistance (via IRS inactivation and decreasing downstream signaling paths)
T2 DM: Beta Cell Response to Insulin Resistance
- what is it
- normal ins release vs. T2 DM release
- causes of B cell failure
Abnormal B cells cannot keep up with hyperinsulinemia to maintain BG with ins resistance = relative ins deficiency
B cell fx increases as ins sensitivity decreases until b cell fx fails
Ins Release:
Normal - first phase (huge spike release of preformed ins), second phase (slow and large growing release of newly formed insulin)
T2 DM - lose first phase (contributes to hypoglycemia), second phase is slower and lower :(
Cause of B cell failure: GLUCOTOXICITY (high glu levels will exacerbate T2DM), lipotoxicity, ER stress, mito dysfx, ox stress, islet inflammation
What is the tx for T1 DM?
What are the regimens and routes of dosing?
INSULIN PREPARATIONS
Rapid Acting (3hrs): Lispro, Aspart, Glulisine
Regular (5-8hr): Insulin
Intermediate Acting (14-18hr): NPH
Long Acting (16-24hr): Glargine, Detemir (peakless)
Regimens:
Split-Mixed: short acting lispro 2x/day before big meals (handles food), intermediate acting NPH 2x/day before big meals (handles baseline)
Glargine-Lispro: short acting lispro at each meal, long-acting glargine 1x/day handle basal level
Routes: Syringe, pump, pen
What are non-pharm approaches to T2DM tx?
Nutrition: low fat/total calories, low sat fat, low Na if HTN, healthy diet, weight reduction in obese pts
Exercise: increase EE with moderate intensity exercise (increase calorie burn and non-ins mediated glu uptake)
Lifestyle changes to reduce CVD RFs (smoking cessation)
Training in self-mgmt and self-monitoring BGs
Describe the mechanisms and key side effects of the following DM meds:
- Sulfonylureas
- Meglitinides
- GLP-1 Agonists
- DPP4 inhibitors
- Metformin
- Thiazolidinediones
- alpha-glucosidase inhibitors
- SGLT2 inhibitors
What is the approach to mgmt of T2 DM pt?
SUs: stim ins secretion thru B cell SU receptor
Meglitinides: same as SU
GLP-1 agonists: enhance GLP-1 (enhance glu-mediated ins secretion)
DPP4 inhibitors: enhance GLP-1
Metformin: decrease hepatic glu output (activates AMPK)
TZDs: activate nuclear receptor to enhance ins sensitivity (gene activation)
a-Glucosidase-i: inhibit glu absorption (block disaccharide breakdown, SE: bloating/flatulence)
SGLT2-i: prevent 90% glu reabsorption, cause glycosuria, lower HbA1c, weight loss, no hypoglycemia, increase urine volume, DECREASE CVD RISK
1st line: metformin
Add additional agents as needed to control BG
each agent should have different mechanism to lower BG (synergy)
What are the 3 main complications of uncontrolled DM?
What are the pros and cons of intensive DM control?
What is the mechanism of these microcellular complications (4)
Diabetic retinopathy (proliferative), nephropathy, neuropathy (many types sensory and motor)
Intensive: decreases risk of microvascular complications, increases risk of hypoglycemic event
EARLY INTENSIVE TX and control is KEY to preventing long term complications in T1 and T2 DM
Endothelial cell: GLUT1 (no ins needed)
DM = endothelial hyperglycemia = ox stress = DNA strand breaks = activation of PARP
PARP activation = BLOCKS GAPDH in glycolysis, causing:
1. more flux thru polyol pathway (glucose to sorbitol) = consusmes NADPH = less capacity for oxidation
2. more AGE formation (advanced glycated end product) = more ROS and altered matrix/integrin interaction
3. Activation of PKC = blood flow abnormalities, angiogenesis, capillary/vascular occlusion
4. more flux thru hexosamine pathway = glycolysates transcription factors = endothelial dysfx
What is the most frequent cause of death in DM pts?
What is the effect of intensive DM control on mortality?
What are the effects of weight loss?
Most frequent cause of death: ISCHEMIC HEART DISEASE
Intensive control: reduces CV events, but unclear if truly reduces all cause mortality
Weight loss
Reduces: HbA1c, BP, TGs
raises: HDL
No change to LDL or risk of CV events!! :(((((
