Endocrine 11: Metabolic Homeostasis Flashcards
What are the physiological effects of starvation?
- proinflammatory cytokines
- constant activation of HPA (catecholamines)
- dysregulation of GH and IGF1 (no IGF1 b/c no insulin)
- catabolic state (fat, protein, glycogen)
- ketogenesis
What are the major physiological conditions associated with Syndrome X/Metabolic Syndrome
- visceral obesity (waist circumference >40in. (M), >35in. (F))
- insulin resistance (FG > 100 mg/dL)
- dyslipidemia (TG > 150 mg/dL; HDL 135/80)
Define obesity.
- BMI over 30
- waist-hip ratio greater than 0.95 (M) or 0.85 (F)
Define adipocyte.
triglyceride storage cell
List the endocrine secretions of adipocytes.
- main hormone = leptin
- SREBP-1C (Sterol Regulatory Binding Protein) TF
- PPARg
Define SREBP-1C.
Sterol Regulatory Binding Protein (transcription factor)
- stimulates TG synthesis
- activated by lipids and insulin (anabolism)
- increases glucokinase activity (traps glucose inside cell to be used for storage)
Define PPARg.
- transcription factor
- steroid nuclear hormone receptor
- binds to lipids
- regulates TG storage and adipocyte differentiation
Define TZDs.
Thiazolidinediones
- PPARg agonists
- promotes differentiation of fat cells => more insulin receptors => increases insulin sensitivity
- problem = increase fat mass
- used as Tx for T2DM (called Avandia)
What are the effects of leptin?
- production correlates with amount of fat cells (more fat = more leptin)
- inhibits appetite by inhibited neuropeptide Y and agouti-related peptide (ARP) in the hypothalamus (these are appetite stimulators)
- stimulates appetite inhibitors by stimulating aMSH (from POMC) and CART (cocaine-amphetamine related factor)
Describe leptin levels in obese individuals.
lots of fat mass = lots of leptin
=> leptin resistance
=> don’t respond to more leptin
Define insulin resistance.
- reversible stage
- insulin cannot efficiently transport glucose into cells
- high BG => saturation of insulin independent receptors
- initially, hyperinsulinemia => downregulation of insulin receptors => resistance
- over time, beta cell death => T2DM => T1DM
Describe insulin levels in obese individuals.
For the same plasma glucose levels, obese individuals produce MUCH more insulin.
What are the diagnostic parameters for T2DM?
- HbA1C > 6.5%
- fasting glucose > 126 mg/dL
- oral glucose tolerance test > 200 mg/dL
What are the diagnostic parameters for prediabetes?
- fasting glucose > 100 mg/dL
- oral glucose tolerance test > 150 mg/dL
Describe the symptoms of T2DM.
- polyphagia = ineffective glucose uptake into cells makes body think it is starving
- polyuria = saturation of glucose reabsorption transporters in kidney => osmotic diuresis of water and electrolytes
- polydipsia = dehydration from polyuria leads to increased thirst
- impaired beta cell function and insulin resistance
List treatment options for T2DM.
- sulfonylureas (glyburide, glipizide) - block ATP-sensitive K channel (keep it closed) => easier to depolarize => pushes out as much insulin as possible from cell (assists in first response)
- biguanides (metformin) - blocks hepatic gluconeogenesis and increases peripheral insulin sensitivity, increased glucose uptake
- alpha-glucosidase inhibitors (precose, glyset) - slows gastric emptying to allow beta cells to catch up and have proper first response
List proposed mechanisms of beta cell dysfunction.
- amyloid plaques
- stress
- lipotoxicity
- glucose toxicity
- reduced beta cell differentiation in childhood
- incretin hormone dysregulation
- islet inflammation
Characterize T1DM.
- juvenile onset
- constant state of catabolism
- ketogenic
- tx = lifelong insulin, tight glycemic control
- destruction of beta cells (autoimmune)
Define DKA.
Diabetic Ketoacidosis
- low insulin, high counterregulatory hormones (glucagon, catecholamines)
- FFA release leads to ketone formation (b/c no glucose uptake)
- causes acidosis
- dehydration b/c ketones cause diuresis of cells => neurons shrink =====> coma, death
- usually, this is how T1DM is treated
Describe the physiological state during starvation.
- no glucose = no insulin
- catecholamines => excess glucagon (no negative feedback b/c no glucose)
- proteolysis => GH
- no IGF (no insulin)
- cortisol => lipolysis, glycogenolysis
Describe the physiological state during T1DM.
same as starvation except you have high glucose and ketones
Describe the physiological state during T2DM.
same as T1DM
- some insulin (also balances glucagon)
- no ketones
What are some genetic risk factors for T2DM?
- most genes affect beta cell differentiation
- some linked to insulin, obesity, and glucose transport
- TCF72 is the most common polymorphism (associated with incretin production)
What are important genes/factors in beta cell development?
- PDX1 is needed for islet neogenesis and beta cell proliferation (if defective = no islet cells)
- TCF72 is a TF that regulates beta cell differentiation
- neurogenin 3 is also required for endocrine cell development
List some environmental risk factors for T2DM.
- malnutrition or maternal factors during pregnancy can lead to impaired beta cell development in childhood
- high calorie diet and lack of physical inactivity can predispose you to insulin resistance
- acquired organ dysfunction characterized by impaired insulin biphasic response (reversible)
Define exenatide.
- GLP1 mimetic
- improves insulin biphasic response in T2DM
- warning = pancreas toxicity
