PATHOPHYS 6.1 - Diabetes Mellitus
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116 terms
Terms | Definitions |
|---|---|
 What are incretins and when are they released? | GIP, GLP, ( amylin) Released with Oral Glc not IV Cause Insulin secretion via cAMP |
| How does Glc cause insulin secretion? | Glc - via Glucokinase - G6P and ATP - ATP closes ATP dep K ch - depol - open Vg-Ca channel - stimulate insulin release |
| Whats the rate lim step in insulin release? | Exocytosis |
| So, cAMP and Ca... | Increase insulin secretion |
| Why dont CCBs shut doen insulin secretion completely? | Glc also stimulates IP3 pathway. This stimulated Ca from SER. |
| Location: preproinsulin, proinsulin, insulin | Prepro --> pro: RER Pro --> insulin: Golgi, secretory granules |
| proinsulin-‐split products | Amylin, c-peptide |
| actions of pro-insulin split products | amylin is an incretin (insulin release via cAMP) C-Peptide: +NO synth, +Na/K ATPase activity, +neutrophilic factors, improve microvascular fxn, helps fix nerve structural abnormalities, DIAGNOSTIC tool *remember, INSULIN & C-PEPTIDE are released together |
| Hypoglycemia with HIGH C-Peptide | Insulinoma |
| Hypoglycemia with LOW C-Peptide | Injecting Insulin (exogenous) |
| What is MODY? | Maturity onset diabetes of Youth (Type II MODY) |
| MODY II MoA: | inherited B-cell dysfxn: DEC GLUCOKINASE activity. Can't phosphorylate Glc --> develop MILD NON-KETOTIC HYPERGLYCEMIA prior to age 25 years. (mild b/c ONLY GLC-STIM INSULIN SECRETION effected) |
| ROle of B2 receptors | +INsulin |
| ROle of a2 receptors | -Insulin (G protein, K ch, dec cAMP) |
| MODY pt on Beta Blocker | dec insulin BUT if pt takes insulin pt can become HYPOGLYCEMIC! (why? b/c bb dec gluconeogenesis in the liver!) |
| Phases of Glc-stimulated insulin secretion | Phase 1: preprackaged insulin released (5%) Phase 2: newly synthesized insul (15 mins) (95%) |
| Oral vs IV insulin. What phases occur? | IV has both phases. Oral has phase 2 (why? glc doesn't stim pancreas fast enough) |
| whats the first sign of an unhealthy beta cell? | No phase I with IV glc (Type II DM) |
| What is GLucotoxicity? | chronic hyperglycemia leading to DEC glc-stimulated insulin by 75% (other stimulators of insulin still work) |
| Glycotoxicity causes what cellularly? | 1. DEPLETED insulin stores (beta cell exhaustion) 2. DESENSITIZED ATP-sens K ch in Beta cells 3. MITOCHONDRIAL INJURY reduces ATP synthesis |
| what about too much FFA? | same as Glucotoxicity |
| Types of Diabetes Mellitus? | I beta cell destruction 2 insulin resistance, beta cell loss 3 MODY, 2º forms 4 gestational |
| Type I DM: Genetics | HLA-DR3, DR4 on ch 6 |
| Type I DM: Environmental triggers and MoA | infection (rubella), food allergy (milk) activate CD8+ T cells in pancreas via Cytokines (TNF-A, IL-1B) --> INSULITIS |
| Type I DM: Ab markers? | anti-INSULIN, anti-GAD 65 Ab just markers. does not mean they are damaging anything. |
| Type I DM: Pre-diabetes indicator; Diabetes indicator | Loss of FPIR (first phase insulin release-prepackaged insulin) Abnormal GTT (Glc tolerance test) -->no longer prediabetes with HYPERGLYCEMIA |
| Type I DM: Pathogenesis | 1 Destruction of Pancreatic B-cell 2 Normal insulin sensitivity (unless obese) 3 Elevated plasma glucagon (a-cells are okay) |
| Type II DM: Major risk factors | Abdominal Obesity & Positive Fm Hx (polygenic --ATP-SENSITIVE K CH GENE Kir6.2) |
| Type II DM: Pathogenesis: Initiating Event | Insulin Resistance (fat, sk m, liver) |
| Type II DM: What is Insulin Resistance Characterized by? | 1 Dec NUMBER of receptors in adipose tissue 2 Abnormal intracellular SIGNALING in adipose, sk m, liver *(-PI3K and +MAP-K signaling)* |
| Type II DM: What is PI3K signaling? | PI3K is phosphatidylinositol-3 kinase. Noramlly, it stores glc (-->glycogen/fat stores/protein) & inc glc receptors in cell membrane |
| Type II DM: What is MAP-K signaling? | mitogen activated protein kinase. Normally increases sm m prolif, inc cell adhesion molecule synth, elevates PAI-1 levels, dec NO (basically atherosclerosis!) |
| Type II DM: Visceral adiposity: Humoral Theory of IR | visceral adipose tissue alters release of bioactive substances, leading to development of Insulin resistance: Inc Resistin, TNF-a, IL-1B, IL-6, FFA Dec Adiponectin |
| Type II DM: What is Lipotoxicity? | FFAs... Dec Insulin signaling in M Inhib GLUT-4 insertion into sk m |
| Type II DM: Transcriptional Regulator Thoery? | ... |
| Type II DM: After the Initiating event, what happens? | after insulin resistance develops... -Hyperglycemia causes Increased Pancreatic Insulin Secretion -B-cell dysfxn develops (phase 1 lost, phase 2 maintained but not as high as it should be) -B-cell failure develops (of genetically at-risk B-cells) -B-cell numbers decrease (takes 5-10 years) |
| Type II DM: When does fasting hyperglycemia occur? | B-cells decrease by 70-80% |
| Type II DM: What is required for ketoacidosis? | NO insulin release (DM I) and Increased Glucagon secertion |
| Type II DM: Role of Liver and Pancreas in dev DM type II? | Glucotox and Lipotox... -cause HEPATOCYTES to become insulin resistant (+glycogenolysis, +gluconeogenesis) -cause pancreatic a-cell dysfxn (^glucagon!) |
| Secondary Forms of Diabetes: types | 1 From Decreased Insulin Secretion 2 Inherited defects of Insulin receptor or Insulin signaling pathways 3 Insulin Antagonism by excess counter-regulatory hormones |
| Diabetes From Decreased Insulin Secretion: types | Pancreatic destruction Pheochromocytoma Somatostatinoma |
| Diabetes From Inherited Defects of Insulin REceptor or signaling pathways: | Obese pt with Acanthosis Nigricans + Hirsutism + PCOS Leprechaunism |
| Diabetes From INsulin antagonism by excess counter-regulatory hormones: | Glucagonoma Glucocorticoids (Prednisone >30 mg/day) |
| Which Secondary forms of diabetes ahve ketoacidosis? | NONE! all have enough insulin to prevent this complication |
| Pt presents with Postprandial hyperglycemia, fasting hypoglycemia, Gall stones and Steatorrhea | Somatostatinoma causing diabetes Somatostatin blocks insulin or glucagon. 1 SST dec insulin --> POSTPRANDIAL HYPERGLYCEMIA 2 SST dec glucagon --> FASTING HYPOGLYCEMIA 3 SST dec CCK --> gall stones (x gallbladder contraction) pt also has STEATORRHEA |
| Pt presents with HTN + Mild HYPERGLYCEMIA | Pheochromocytoma causing Diabetes Cortisol xs Hyperaldo |
| MoA of Acanthosis nigricans in obese diabetics? | xs Insulin --> INCREASES FREE IGF-1 --> +IGF-R --> promotes Hyperkeratosis PCOS pts have dec # insulin receptors --> xs Insulin too |
| What clinical presentation do Obese diabetics present with? | Obesity + Acanthosis Nigricans + Hirsutism + PCOS |
| MoA of Leprechaunism, Characteristics | Total or sub-total absence of insulin receptors. Rare and Fatal Congenital dz. Characteristics: Dwarfism, dysmorphic facies, FTT, hirsutism, AN |
| Pt presents with Hyperglycemia and a red rash on their face and extensor surfaces | Glucagonoma causing Diabetes xs Glucagon --> inc Gluconeogenesis (hepatic) --> HYPERGLYCEMIA. Classic symptom: Necrolytic Migratory Erythema on FACE and EXTENSOR SURFACES |
| DM can lead to what acute complications? | Fluid and Electrolyte abnorms AB abnorms Diabetic emergencies (DKA, hyperosmolar coma) |
| How does Uncontrolled Hyperglycemia cause Fluid and Electrolyte abnormalities? | Cellular Dehydration --> Hypertonic Hyponatremia + Translocational Hyperkalemia Glucosuria, OSMOTIC DIURESIS, Polyuria --> Hypovolemic Hypernatremia --> Hypovolemic HypoKalemic HypoNatremia (BUT K looks normal, translocation) |
| What vision changes with uncontrolled hyperglycemia? why? | Myopia: aldose reductase in lenses --> glc to sorbitol --> lens thickens RVSBL |
| MoA of Cataracts in diabetes | 1 Sorbitol accumulation 2 dec NADPH and glutathione (aldose reductase) --> OXIDATIVE DAMAGE 3 GLYCATION (NEG) of lens **only sorbitol accumulation is reversible |
| Whats the two diabetic emergencies? | Ketoacidosis and Nonketotic hyperosmolar coma |
| Who gets Ketoacidosis and their plasma glc? | Young Type 1 Plasma glc 300-800 mg/dL |
| Who gets Non-ketotic hyperosmolar coma? | Elderly Type II Plasma glc >1000 mg/dL |
| Alternate fuels sources after glc? | FFA (kidneys, liver, sk m , heart) Ketoacids (CNS) |
| Sources of fuel for Brain in fasting | Glc --> Glycogen --> Gluconeogenesis --> Ketoacidosis (never FFA) |
| Why does Ketoacidosis develop? | Insulin deficiency & XS CATs* --> stimulate FFA release. *Increased Carnitine Palmitoyltransferase (CPT) transports more FFA into mitochondria [normally: insulin --> +Malonyl-coA --> -CPT] FFA converted to KA in MITOCHONDRIA of hepatocytes |
| Rate-limiting step in KA production? | *FFA (substrate) availability* |
| FFA --> KA | FFA -> acetyl-CoA --> HMG-CoA --> KA HMG-CoA reductase is Rate-lim step |
| KA happens in Diabetes and fasting. Higher in which? Why? | Higher in Diabetes. Not from insulin (insulin is increased same in both) Hyperglycemia causes OSMOTIC DIURESIS --> decreases plasma volume --> Inc CATs !!! --> cranksup FFA and KA production |
| Why can't Hepatocytes use KA? | Lack mitochondrial enzyme that transfers CoA from succinyl CoA to acetoacetate: Succinyl-CoA:3-ketoacid-coenzyme A transferase * |
| Events that precipitate DKA | MI Infxn trauma pregnancy EtOH intoxication med non-compliance |
| Manifestations of DKA: pH, HCO3-, AG | pH < 7.3 HCO3- <18 AG > 20 (AG met acidosis) |
| Manifestations of DKA: clinical | anorexia, N/V, Tachy, Kussmaul respirations, Acetone halitosis (fruity breath), abdominal pain, Leukocytosis (not >25,000 x 10^6 then think infxn), Obtundation leading to Coma |
| Manifestations of Non-ketotic Hyperosmolar Coma: Plasma Glc, Serum osm, pH, HCO3-, AG | Plasma Glc >1000 Serum osm >350 pH > 7.3 HCO3- >20 AG < 16 |
| Manifestations of Non-ketotic Hyperosmolar Coma: Clinical | SLOW ONSET, CNS symptoms from cell shrinkage Lethargy, drowsiness, confusion, obtundation, coma |
| Mortality of Non-Ketotic Hyperosm Coma? | 50% die from DEHYDRATION leading to THROMBOTIC EVENTS: MI, Stroke, mesenteric thrombosis |
| Infectious complications. Why? | DM pts have increased rate of infections b/c... -Glycation of C3 --> defective opsonization -Hyperglycemia impairs Neutrophils -Hyperglycemia impairs B/T lymphocytes |
| Infectious complications. What organisms/lesions? | Soft tissue infxns (Candida, Staph au) Mucormycosis, Pseudomonas aeruginosa (malignant otitis externa) Polymicrobial foot ulcerations (--> osteomyelitis) |
| MCC of death in Type 2 DM? MCC of death in Type 1 DM? | 2: Macrovascular complications (MI > Stroke) 1: Diabetic Nephropathy |
| Macrovascular Complications. e.g.? | atherosclerosis: Coronary heart dz (MI, HF, Sudden death) Cerebrovascular dz (Thrombotic, embolic stroke) Peripheral arterial dz (aortic-iliac femoral atherosclerotic occlusion, lower extremity amputations) |
| Microvascular Complications: e.g.? | Kidney dz, Retinopathy, Neuropathy, Dermopathy, Osteoarthropathy |
| Macrovascular Complications: Ticking Clock hypothesis | Prior to onset of Hyperglycemia --Macrovascular At onset of Hyperglycemia --Microvascular (retinopathy, CKD, neuropathy) |
| Macrovascular Complications: What does the dyslipidemia look like in type 2 DM? | Increase in TG, VLDL, LDL; Decrease in HDL --> atherosclerosis Note: type 1 DM pts have normal lipid profiles |
| Macrovascular Complications: How does HTN, Inflammation, and Thrombosis develop? | Hyperglycemia, High FFA, Insulin resistance --> OXIDATIVE STRESS, PKC activation, RAGE activation --> 1. endothelial dysfxn, vasoC (ATNII), VSM growth 2. inc NF-kB --> chemokines, cytokines, CAMs 3. inc *PAI-1* --> inhibit tPA (can't activate plasminogen) --> hypercoagulation, platelet activation |
| Macrovascular Complications: What is RAGE? | Receptor for advanced glycation end-products Activation leads to inc MAP-K, PI3-K, NK-kB mediated inflammation |
| Macrovascular Complications: How does Insulin resistance and PAI-1 cause Thrombosis? | Insulin --> PAI-1 gene transcription --> inhibit tPA (no more plasminogen) Hyperglycemia --> inc aldose reductase activity (accum sorbitol) --> depleted NADPH --> decreased NO synthesis --> platelet adhesion, vasoC, leukocyte adhesion |
| Microvascular Complications: Stages of Kidney dz that may develop? | PreDiabetic Nephropathy Diabetic Nephropathy |
| Large kidneys with INC GFR MICROalbuminuria (level?) | Microvascular Complications: Prediabetic nephropathy (30-299 mg/d) |
| Small Kindeys in DEC GFR MACROalbuminuria (level?) | Microvascular Complications: Diabetic Nephropathy (>299 mg/d) with glomerulosclerosis and HTN |
| Microvascular Complications: MCC of ESRD? | Diabetes (50%) > HTN |
| What complication does not depend on how long you've had diabetes? peak incidence? | Diabetic Nephropathy of Type 1 diabetics (leading cause of death) Peak incidence is 15-17 years |
| Microvascular Complications: Prediabetic nephropathy, what's the 1st Morphological change? | Renal hypertrophy (Both glomeruli and tubules) |
| Microvascular Complications: Prediabetic nephropathy, what's the 1st Fxnl change? MoA? | Increased GFR (25-40% higher than normal) [seen at time of diagnosis of type 1, in type 2 they prolly have RAS so won't see] MoA: Dilation of Afferent arterioles |
| Microvascular Complications: Prediabetic nephropathy, role of ATN II and AGE formation. | Stimulated by hyperglycemia. Alters chemical composititon of GBM --> dec neg-charged sialic acid and heparan sulfate --> hyperfiltration of albumin Stimulates mesangium --> secrete GF --> Type IV collagen, laminin, fibronectin --> *mesagnial expansion, nodular glomerulosclerosis (Kimmelstein-Wilson Dz) |
| Microvascular Complications: what does having glomerulosclerosis indiciate? | decrease in GFR occurs --> renal failure 10-15 years |
| Microvascular Complications: Diabetic nephropathy, role of ATN II and AGE | cause *Tubulo-interstitial fibrosis --> GFR decreases 10 ml/year --> dialysis/transplant |
| Microvascular Complications: Fxnl Pre-diabetic nephropathy changes | Afferent arteriole dilation Inc GFR Glomerular HTN Urine albumin <299 mg/d (microalbuminuria) |
| Microvascular Complications: Morphologic Pre-diabetic nephropathy changes | Large kidneys (Glomerular and Tubular hypertrophy) GBM alteration Mesangial proliferation |
| Microvascular Complications: Functional Diabetic nephropathy changes | Dec GFR Urine albumin >300 mg/d (macroalbuminuria) HTN, Edema Renal failure |
| Microvascular Complications: Morphologic Diabetic nephropathy changes | Glomerular sclerosis Interstitual fibrosis Small kidneys |
| Microvascular Complications: When do patients become aware of their nephropahty? | when GFR drops below 30 ml/min (norm is 100) --presents with dependent edema, HTN, Fatigue (from chronic anemia! stage 3 ckd in diabetics) |
| Can Progression to ESRD be stopped? | No. but it can be slowed. 1. BP control <125/75 *** 2. ACE I, ARBs (DOC, dilate efferent arterioles) 3. LDL cholestrol <90 mg/dl 4. Tight glc control (type I) 5. Dietary protein <0.8 mg/Kg/day (type I) |
| Diabetic Retinopathy: Non-proliferative stage, main MoA? | aldose reducatse --> sorbitol accumulation in capillary pericytes --> osmotic lysis --> MICROANEURYSMS --> leak --> HEMORRHAGES and HARD EXUDATES (serum) --> ischemia and hydropic swelling of retinal ganglion fibers --> COTTON WOOL SPOTS (edema) Cotton wool spots in macula is only time you get vision loss in NPDR |
| Diabetic Retinopathy: Proliferative stage, defining feature | Neovascularization |
| Diabetic Retinopathy: Proliferative stage, initiating event | altered pericytes and bm --> inc PAI-1 (type 2) and leakiness (type 1 & 2) --> micro-occlusions and hemorrhages --> RETINAL ISCHEMIA |
| Diabetic Retinopathy: Proliferative stage, important players | Ischemia upregulates angiogenic factors: VEGF, erythropoietin, bradykinin, BMP, TGF-b. PEDF downreg (an anti-angiogenic factor) *new vessels are unstable and prone to bleeding, scarring, etc. |
| Diabetic Retinopathy: Drug to prevent progression from non-prolif to prolif stage? | ACE I's |
| Diabetic Retinopathy: How is vision in non-prolif adn prolif?: | Non-prolif: Vision is normal unless macula is affected Prolif: irreversible vision loss can occur with retinal detachment |
| Pt presents with Foot/Wrist drop, mild sensory loss. Pt presents with ptosis with pupillary sparing | Diabetic Neuropathy: Acute Mononeuropathy Effects: Large peripheral nerves --ulnar, median, peroneal n's --Motor deficits (foot/wrist drop) with minor sensory loss CNs --3, 4, 6 --Noncomitant strabismus (intensity changes with directions) --Diplopia --Ptosis with pupillary sparing (CN3) |
| Pt presents complaining of painful hand and foot bones bilaterally that wakes them up at night. PE finds loss of V/P in hands and feet, muscle wasting, and decreased Achilles reflex. | Diabetic Neuropathy: Chronic sensory polyneuropathy: Large A fiber polyneuropathy |
| Pt presents complaining of a severe burning sensation of their hands and feet, requesting amputation. PE reveals loss of Temperature and light touch in hands/feet bilaterally, strength and DTRs are normal. | Diabetic Neuropathy: Chronic sensory polyneuropathy: Small C fiber polyneuropathy |
| Pt presents complaining of indigestion, recent episodes of falling down, and leaky bladder. Has also noted stool changes and sexual dysfxn. | Diabetic Neuropathy: Autonomic neuropathy Gastroparesis, Orthostatic hypotension w/o tachycardia, Overflow urinary incontinence (pts can't tell when bladder is full), diarrhea or constipation, erectile dysfxn |
| Elderly male pt with type 2 diabetes presents with severe pain in thighs, hips, or buttocks not associated with exercise. PE finds that the proximal muscles are weak from atrophy. | Diabetic Neuropathy: Proximal motor neuropathy |
| Diabetic Neuropathy: MoA of Acute mononeuropahty | Ischemia (--> PAI-1 --> hypercoag --> thrombi --> occlusion) |
| Diabetic Neuropathy: MoA of Chronic Sensory polyneuropathy and Autonomic neuropathy | GLYCATION of neuronal membrane Decreased nerve GF Dec myoinositiol transpot --> dec Ca in nerves Inc sorbitol, DAG, PKC, C-peptide activity --> screws up N/K ATPase Microthrombi C-peptide def (type I) |
| Diabetic Neuropathy: Tx chronic sensory polyneuropathy | Gabapentin Carbemazapine |
| *Diabetic Dermopathy: e.g.?* | Microvascular occlusions --> 2-10mm brown atrophic skin spots Necrobiosis lipoidica diabeticorum --> 2-3 cm red brown waxy plaques of unknown cause |
| Foot ulcers: risk factors? | 15% of diabetics get these. NEUROPATHY, smoking, peripheral artery dz, foot deformity, poor glycemic control |
| Foot ulcers: can lead to? | skin/soft tissue infections, OSTEOMYELITIS, amputations |
| Osteoarthropathy: (Charcot joint) what is it? | midfoot/ankle joint destruction in Type 1 and 2 after 15 years Begins as painless unilateral swelling following a minor trauma *sensory neuropathy is a necessary prerequisite. |
| Requirements of Normal Penile Erection | 1. Testosterone 2. arterial blood flow 3. NANC neurologic fxn (non-adrenergic, non-cholinergic) |
| MoA of Erectile Dysfxn | Autonomic neuropathy --> injures NANC neurons traveling with sacral parasympathetics --> impairs NO release --> prevent cGMP relaxation of cavernous sinusoids Hyperinsulinemia decreases SHBG and total Te (type 2) |
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