Unit 2- Metabolic (Glucose and Fat) Flashcards

Question

insulin signaling pathways

Answer 1

2 special signaling molecs: IRS PI3K pathway - metabolic pathway, glucose uptake/disposal and vasodilation - decreasing hepatoglucose output - increasing insulin secretion - sensitive pathway- doesn't like sugar, cytokines, or insulin to be high - insulin resistance knocks this side out IRS MAPK pathway -cell growth, mitogenesis, vasoconstriction

Answer 2

reduce hepatic glucose output - reduce glycogenolysis - reduce gluconeogenesis inc peripheral glucose disposal - inc glucose uptake by muscle and fat - activate glycolysis, glycogen synthesis, and de novo lipogenesis inc fat uptake by adipose tissue reduce fat release from adipose tissue fed hormone insulin works against glucagon and EPI insulin resistance o Inc liver glucose production o Reduced peripheral glucose disposal o Inc fat release from adipose tissue o Most of the time insulin resistance lives downstream ♣ Nl Insulin signaling happens when IRS get phosphorylated (pY- tyrosine) ♣ Insulin resistance appears to be nl IRS phosphorylated on different AA substrates (serine/threonine)

Answer 3

o Low glucose- you have high glucagon and low insulin High sugars- you have low glucagon and high insulin, as long as cells/receptors are interpreting signals appropriately DM2 is marked by blunted insulin response and inadequate glucagon suppression after meals o Could be from glucose toxicity- when your blood sugar is really high it becomes somewhat toxic, but insulin deficiency is somewhat reversible

Answer 4

Give pt a glucose and measured plasma glucose over several hours either oral or IV infusion ♣ IV and oral glucose levels are the exact same ♣ It’s not same insulin though o If you give glucose by mouth, you get way more insulin than by IV ♣ The beta cell is responding to glucose and something else (In GI tract?) ♣ Glucagon-like peptide-1 GLP-1 • Product of proglucagon gene from intestinal L cells • Release is rapid in response to meals • Potent insulinotrophic hormone • Impaired glucose tolerance IGT and type 2 DM manifest w/ lower plasma GLP-1 compared to healthy controls • GLP-1 facilitates glucose-stimulated insulin release • Incretin, GLP-1 stimulates insulin release and inhibits glucagon release; both causing lowering of blood glucose • Actions of GLP-1 o Lowers appetite, lowers blood sugar and appetite

Answer 5

high blood glucose; enough to cause microvascular diseases blunted insulin response after eating kidneys- leak of protein into urine nerves- neuropathy eyes- retinopathy inc risk for microvascular disease, but we don't define diabetes this way ``` Dx criteria: fasting glucose OGTT HbA1c 2 times in absence of illness ``` Nl <100 <140 <5.7 Pre 100-125 140-199 5.7-6.4 ``` DM >126 >200 >6.5% random glucose >200 + typical symptoms ```

Answer 6

``` Type 1 10-20% low insulin white's nl weight autoimmune markers DKA can happen FHx is somewhat- 10-20% peak in childhood/adolescence ketosis common path: autoimmune assoc w/ autoimmune thyroid disease; Celiac; Addison's ``` ``` Type 2 80-90% IR + insulin deficiency AA, Native Americans, Hispanics, Pac islanders overweight/obese, weight loss No markers DKA not typical FHx: strongly genetic 80-90% age post-pubertal ketosis uncommon but possible path: insulin resistance assoc w/ obesity, lipid abnormalities, PCOS, NAFLD ```

Answer 7

gestational: high blood sugar during pregnancy o Occurs during pregnancy and goes away after; important to screen between 24 and 28 weeks pregnant o Pregnancy causes you to be very insulin resistant pancreatic: drink alcohol and get recurrent pancreatitis to kill off beta cells no glucagon low weight- exocrine insufficiency

Answer 8

immune mediated disease --> metabolic disease o Common and inc T cell mediated autoimmune disease ♣ Incidence is rising 3-5%/yr o Assoc w/ other autoimmune diseases o Now predictable in humans (islet autoantibodies and genes) o Environmental determinants unknown Large immune intervention trials are underway Prevalence of DM1 by 20yo o General pop 1:300 o First degree relatives 1:20 o High genetic risk general population 1:15 o High genetic risk FDR 1:4 to 1:2 (first degree relative) o Monozygotic twins 1:3 to 1:1 o Pediatrician w/ 2000 pts will have 3-6 in practice natural history: o Nl individual: beta cell mass is relatively high o Genetic predisposition: some sort of trigger (environmental?) causes you to lose beta cell mass and beta cell function o Insulitis (beta cell injury) in the autoimmunity part -T cell autoimmunity o Then autoantibodies kick in and you have pre-diabetes -humoral autoAb's (IAA, anti-GAD65, 1A-2Ab, ZnT8, etc) -loss of 1st phase insulin response (IVGTT) -glucose intolerance (OGTT) o Then clinical onset you have diabetes A1C >6.5% monitoring natural history: markers of immune sys response to the beta cell - autoAb's (islet cell autoAbs: insulin, IA-2, GAD65, ZnT8) - T cell response (active area of research) markers of metabolic changes IV glucose tolerance test OGTT mixed meal tolerance test MMTT

Answer 9

Autoimmune ♣ Thyroid autoimmunity 15-20%; TSH testing ♣ Celiac disease 5-10%; TTG autoAb’s ♣ Addison’s disease 1-1.5%; 21(OH) autoAb’s Complications ♣ Macrovascular (CVD, PVD) ♣ Microvascular (retinopathy, nephropathy, neuropathy) ♣ Psychosocial (depression, anxiety)

Answer 10

Genome-wide associations in T1D o Specific HLA genes (Immunity); many other immunity genes o INS (insulin production and metabolism) ``` Major histocompatibility complex o HLA genes are on Chr 6 o Encode class 1,2,3 molecs o Class 1 present peptides to CD8 cells o Class 2 present to CD4 cells o Most of risk is in DQ and DR ♣ Allele: 1 DQ/DR haplotype ``` T cell recognition of antigen on an APC -APc endocytosis antigen (insulin) and presents it to CD4+ T cell, which then targets beta cells ``` major islet auto antigens o mIAA (insulin autoantibodies) o GAA (GAD65) o IA-2 (ICA512BDC) o ZnT8 o Others ``` DAISY study diabetes autoimmunity study in the young diabetes onset: GAD and ICA512 become positive over 10 yrs, if you have 2 Ab's your risk is 70%; 3 Ab's risk is 90% --T1D is predictable!

Answer 11

patchy- not all-or-none destruction lobular beta cell destruction islets are still there but don't have beta cells

Answer 12

Infections ♣ Viruses, immunizations ♣ No assoc b/w immunizations and islet autoimmunity- no difference in %, age of vaccinated, or age of onset Diet ♣ Breast feeding/cow’s milk ♣ Timing of introduction of foods in infancy ♣ Omega-3 fatty acids/Vitamin D Weight Accelerator hypothesis o The inc in T1D incidence has occurred parallel to inc in obesity o Hyp: obesity causes beta cell stress and results in exposure of beta cell antigens to immune sys Hygiene hypothesis o We are too clean! o Hyp: lack of immune stimulation at young age suppresses natural immune sys development leading to more allergies and autoimmune disorders

Answer 13

latent autoimmune diabetes of adulthood ♣ 30-70 yo at dx ♣ >=6 mo of non-insulin requiring diabetes ♣ presence of diabetes associated autoAb’s ♣ it’s like type 1.5 Diabetes

Answer 14

``` tx of T1D- insulin deficiency o dec glucose transport into cells ♣ GLUT4 glucose channel o Inc glucose production ♣ Glycogen, gluconeogenesis o Inc activity of hormone sensitive lipase ♣ Mobilization of FFA ♣ Beta-hydroxybuterate and acetoacetate (ketones) ``` management o Wide fluctuations w/ long periods of hyperglycemia and freq hypoglycemia o Don’t have to be perfect, but try to minimalize the fluctuations o Intensive insulin therapy ♣ Continuous glucose monitors ♣ Continuous subcutaneous insulin infusion

Answer 15

Primary prevention ♣ Genetically at risk ♣ Goal is to stop progression to auto immunity ♣ Dietary intervention in infancy- study still going on, but unlikely helpful Secondary ♣ Pts are antibody positive, but don’t have clinical disease yet ♣ Parenteral insulin does not delay development of T1D ♣ Oral insulin study- projected 4.5-5 yr delay with IAA >80; IAA >300 delay 10 yrs? • Oral insulin doesn’t alter blood sugar, but insulin is taken up, chopped into protein, and protective cells of (cytokine) c-insulin and can inhibit beta cell autoantibodies and prevent/prolong diabetes Tertiary ♣ Early in clinical disease ♣ Preserve beta cells and STOP complications ♣ Anti-CD3 (CD8, CD4 T cell marker) provides C-peptide preservation • Unfortunately large phase 3 trial didn’t show benefit ♣ Abatacept (autoimmune tx) blocks costimulatory molec needed to activate T cells • Delay inability to make own insulin ~9.5 months Insulin is still mainstay tx; no immune therapies are robust enough

Answer 16

o 29.1 million or 9.3% of US have diabetes (422 worldwide- pandemic) ♣ many are undiagnosed, and many are underdiagnosed DM screening o We’re screening earlier and more often o Overweight and additional risk factors of being inactive, FHx, gestational diabetes, ethnicity/race, HTN, low LDL, PCOS, and everyone >45 yo should be screened Criteria for screening for T2DM in children and adolescents: ♣ Overweight plus any 2: • FHx of T2DM in 1st or 2nd degree relative • Race/ethnicity • Signs of insulin resistance or conditions assoc w/ insulin resistance • Maternal history of diabetes of GDM ♣ Age of initiation 10 yrs or at onset of puberty ♣ Freq: every 3 yrs ♣ Screen w/ A1C

Answer 17

glucose metabolism is tightly regulated o nl conc 5 g glucose in vascular system- 1g/L; diabetics have >7g in blood o brain and NS consumes 100-125 mg/day- it’s the main user o the cutoffs for dx are based off of evidence of microvascular injury

Answer 18

o Genes and environment (decreased exercise) contribute to insulin resistance o Which leads to dec insulin secretion Which gives you T2DM

Answer 19

Hyperglycemia tells you you have diabetes- nonspecific for which one Specifically type 2 diabetes: ♣ Liver is making glucose despite the fact the pt already has hyperglycemia ♣ Muscle has dec glucose uptake; muscle is resistant to action of insulin telling you to store it ♣ Pancreas cells aren’t making adequate insulin for the inc in glucose in the environment ♣ Hyperglycemia makes muscle more insulin resistant ♣ Impaired beta cell function even further causes beta cell dysfunc- overwhelming

Answer 20

Nl: insulin receptor signaling through IRS, and in fat cell it’s storing lipids Stress: insulin receptor is unable to signal through PI3K- you have cytokines and inflamm going on ♣ Sick, so fat cells are breaking down into FFAs, causing insulin receptors to not work well, and create a vicious cycle ♣ This can happen acutely in hospital ICU; but this can go away as soon as you have stress controlled • Body puts insulin regulation on back burner when it’s sick, which is beneficial when you’re sick but not when you’re obese and sedentary o You inherit insulin resistance, and then over time your beta cells fail- mainly due to genetics ♣ Blood glucose will only show insulin resistance once your beta cells stop working

Answer 21

Approximately 50% of beta cell function has already been lost at time of dx o That will deteriorate over time Hepatic insulin resistance: inc hepatic glucose output o Nl people will go up and down between meals, and liver will compensate when we need it o DM2’s livers will make a bunch of glucose because their liver hasn’t been shut down by insulin, even if their blood sugar level is super high Peripheral glucose uptake o Pts w/o diabetes had nice robust use of glucose o Pts w/ diabetes had much smaller clearance of glucose- less able to dispose of glucose even if you give them a lot of insulin

Answer 22

Insulin and glucagon in nl glucose tolerance o We now know that in fed state when glucose is inc, beta cells will secrete insulin o Low glucose situation- glucagon will be secreted and stim hepatic glucose output; which recently found that can be further manipulated by the gut o Fatty acids and AAs can also stimulate glucagon, which happens at night when you’re transitioning to a fasting state o C peptide represents insulin secretion ♣ Incretin effect- if you give oral glucose, plasma glucose and C-peptide (insulin) goes up together; but if you do IV glucose, the same plasma glucose gives a much lower C peptide level

Answer 23

maturity onset diabetes of young o Beta cell disorder o Either glucose can’t get metabolized (glucokinase defect) or a transcription factor defect o Hyperglycemia: chronic: readily releasable insulin pool in the granules gets depleted, so you lose 1st phase insulin secretion and later lose insulin production

Answer 24

Pathophysiology informs tx o Lifestyle prevents diabetes o Diet and exercise affect glycemic ♣ Dec carb or refined carb ingestion; gives liver less work to do ♣ Exercise: by using muscle, every contraction pulls glucose into muscle for storage; deplete glycogen storage so glucose can be utilized; muscle and fat will in general become more insulin sensitive- good thing o Brain, gut, kidney, liver all having their own demands/methods causing hyperglycemia

Answer 25

carbohydrate regulatory proteins ♣ insulin (only hormone that decreases glucose*- new research on FGFs though) • pancreatic beta cells • stimulates glycogen storage in the liver • decreases hepatic gluconeogenesis • stimulates glucose uptake and utilization in muscle and fat carbohydrate counter-regulatory proteins (inc glucose) ♣ glucagon: pancreatic alpha cells • stimulates glycogenolysis in the liver • hepatic release of glucose ♣ EPI • Stims glycogenolysis from liver • Inc peripheral insulin resistance • Primary defense against hypoglycemia in T1 diabetics ♣ Cortisol and growth hormone • Raise blood glucose much more slowly • May be helpful in recovery from prolonged hypoglycemia

Answer 26

♣ 10-15 cases every 1000 pt-yrs ♣ most cases occur in pre-dx diabetes ♣ fatality rate of almost 10% • DKA unrecognized as the clinical presentation of T1DM in children • Precipitated by severe illness: sepsis or MI in adults ♣ ***Can't get DKA unless you have low insulin or high glucagon/ CR response*** ``` Pathogenesis of DKA (hormonal) o Absolute or relative lack of insulin o Inc counter-reg hormones ♣ insulin deficiency ♣ activated lipolysis (adipose tissue) ♣ inc plasma FFA ♣ inc liver fatty acids accelerated ketogenesis (occurs in the mitochondria DKA) ``` Ketone body production (biochemical) o Inc FFA flux from adipocytes o Intrahepatic glucagon/EPI induced inc carnitine acyltransferase and dec malonyl CoA activity permitting mitochondrial ketone body production (this needs to be reversed to clear DKA) Hyperosmolar hyperglycemia syndrome HHS o Osmotic diuresis o Dec free water

Answer 27

``` precipitating factors DKA: no insulin in pt w/ known T1DM (20%) or new-onset T1DM (25%) ♣ New dx ♣ Eating disorder ♣ Fear of weight gain ♣ Fear of hypoglycemia ♣ Rebellion ♣ Stress of chronic dz ♣ Insulin pump failure ``` HHS: ♣ New-onset DM in elderly ♣ unawareness of thirst ♣ restricted water intake ``` o Omission of insulin o Infection o New-onset o Unknown o MI, CVA, PE, mesenteric thrombosis o Acute pancreatitis o ARF/HD/uremia o Thyrotoxicosis, Cushing’s, acromegaly o Meds: glucocorticoids, thiazides, dobutamine, antipsychotics, cocaine o Burns ``` History Symptoms of hyperglycemia: polyuria, polydipsia, weight loss, weakness o DKA: ♣ Rapid-onset hours after precipitating event(s) ♣ Nausea and vomiting ♣ Abdominal pain which correlates with severity of acidosis ♣ 30% may present with hyperosmolarity o HHS ♣ Insidious onset - days or weeks ♣ Only 30% become comatose ♣ Altered MS usually not seen unless Sosm>320 ♣ Less frequent: focal neurologic deficit, seizure disorder ``` Exam o Signs of hypovolemia ♣ Poor skin turgor ♣ Tachycardia ♣ Hypotension, esp. orthostatic o Altered mental status o Absence of fever even with infection because of peripheral vasodilation o Hypothermia - poor prognostic sign o DKA ♣ Hematemesis from GI hemorrhage ♣ “Acetone” breath ♣ Kussmaul respirations with more severe acidosis o Functional ileus* o Coma (more in HHS) ```

Answer 28

``` Labs o Fingerstick glucose o Urine ketones (dipstick) o Initial ABG o Plasma glucose o Serum ketones o BUN, creatinine o Urinalysis o CBC with diff o EKG o Cultures – urine, blood, etc. o CXR o (HbA1c) o ELECTROLYTES*** ``` o Calculate AG o = Na+- Cl- - HCO3- o Correct Na+ for high glucose o Na+ + 1.6 x (Glu–100)/100 o Calculate effective serum osmolality o = 2(meas Na+) + Glu/18 Lab findings- not sure if she actually went over these things in lecture o inc WBC. If >25,000, more likely from infection o dec Na+ (hyperglycemia causing water shift from IC to EC space) o inc K+ (shift to ECF from insulin deficiency, hypertonicity, acidemia) ♣ Deficit as great as 500-700 mEq ♣ If not elevated, pt. has SEVERE total body K+ deficit. Needs close cardiac monitoring and aggressive K+ replacement since insulin will lower K+ further ♣ EKG can confirm that the intracellular K+ not elevated o inc lipase, amylase can occur from DKA per se ♣ ? non-pancreatic (e.g. parotid)

Answer 29

Goal: stop ketone body production IV fluids (rehydration will decrease counter -regulatory hormones) ♣ Glucagon blocks glycolysis by decreasing levels of fructose 2,6 biphosphate ♣ Glucagon inhibits Acetyl CoA carboxylase and decreases Malonyl CoA, this leaves CPT 1 active and FA enter the mitochondria for ketone body production. Insulin ♣ Lowers plasma glucagon levels ♣ Decreases FFA and AA flux from the periphery ♣ Enhances peripheral utilization of glucose

Answer 30

Normal fasting blood glucose is 70 to 115 mg/dl ``` Symptoms of hypoglycemia usually begin when the plasma blood glucose falls to 50 or 60 mg/dl ♣ vary from patient to patient ♣ may lessen with duration of diabetes ♣ Will be severely* blunted with frequent hypoglycemia o Adrenergic ♣ Sweating ♣ Tremor ♣ Tachycardia ♣ Anxiety ♣ Hunger o Neuroglycopenic ♣ Dizziness ♣ Headache ♣ Decreased mental activity ♣ Clouding of vision ♣ Confusion ♣ Convulsions ♣ Loss of consciousness- can crash your car ``` Type 1 diabetes >> type 2 diabetes o Hypoglycemia is about 2-3xmore common in patients trying to normalize blood glucose with intensive insulin regimens (DCCT) targeted to prevent diabetic complications o Insulin>>glyburide>other oral sulfonylureas >repaglinide>metformin, thiazolidinediones, alpha glucosidase inhibitor (Later agents rarely cause hypoglycemia if used alone)

Answer 31

It’s easy to get the insulin dose wrong and cause hypoglycemia Ideal Basal/Bolus Insulin Absorption Pattern o Ideally, what is needed is: o A short-acting insulin with immediate onset and a shorter duration of action; and o A long-acting insulin that provides consistent insulin availability—sufficient to prevent interruptions in basal insulin levels. Currently these two preparations are in development (short-acting insulin aspart and long-acting insulin glargine), and it is anticipated that they will be available in 2000.

Answer 32

Hypoglycemic unawareness: hypoglycemia begets hypoglycemia o Loss of adrenergic warning signs o Altered mental status with no warning o More common in patients who have frequent hypoglycemia ♣ alterations in delivery of glucose to the brain ♣ Blunted counter-regulatory response o Treatment: avoidance of hypoglycemia for 3 or more weeks Hypoglycemia not due to diabetes o Fasting hypoglycemia is more sig than reactive (postprandial) hypoglycemia ♣ Whipple’s triad: not all low blood glucose is clinically relevant • biochemical hypoglycemia • with symptoms • relieved by glucose DDX of hypoglycemia in adults o Drugs or factitious ♣ Insulin: High insulin, low C-peptide ♣ Oral anti-diabetic agents (sulphonlyureas): o High insulin, high C-peptide ♣ C-peptide differentiates between endogenous or exogenous hyperinsulinemia because C-peptide is co-secreted in equimolar amounts with endogenous insulin ``` o Hypoglycemia not due to diabetes ♣ Insulinoma ♣ Ethanol • Interferes with gluconeogenesis ♣ Non--cell tumors • Large mesenchymal tumors, hepatoma, etc. • Production of IGF-I or IGF-II ♣ Severe liver disease ♣ Adrenal insufficiency ♣ Renal failure (kidneys make up to 25% of glucose produced by the body) ```

Answer 33

``` MEN I ♣ Pituitary adenoma • Prolactin, GH, ACTH ♣ Parathyroid (97%) ♣ Pancreas • Gastrin (40%0 • Insulin (10%) • Glucagon, VIP ``` ``` MEN II ♣ Parathyroid (hyperplasia) ♣ Thyroid (medullary Cancer) ♣ Adrenal (Pheo) • (MEN IIb: mucosal neuromas, marfanoid, low incidence of hyperparathyroid) ```

Answer 34

Cost- #2 in total costs to US healthcare system; $216 billion if you include pre-diabetics Morbidity- ♣ Diabetic cardiovascular disease • 2- to 4-fold higher risk of heart disease in diabetes ♣ Diabetic retinopathy • #1 cause of blindness in working-age adults ♣ Diabetic nephropathy • #1 cause of end-stage renal disease ♣ Diabetic amputations • #1 cause of nontraumatic lower-extremity amputations

Answer 35

``` microvascular disease metabolic syndrome lipid and lipoprotein abnormalities in diabetes cholesterol HTN diabetes related procoagulant state diabetes-induced activation of PKC retinopathy nephropathy diabetic neuropathy ```

Answer 36

♣ (AKA: MI, stroke, peripheral vascular dx) ♣ 16 million Americans have diabetes ♣ CVD is the leading cause of death in diabetes ♣ Most common reason for hospitalization ♣ 2-4 times more common than general population ♣ more common, more severe, more deadly ♣ Ischemic heart disease is main cause of death in people w/ diabetes by a big margin ♣ Survival post-MI is lower, esp in women

Answer 37

Factors accelerating atherosclerosis in diabetes ``` • Insulin resistance leads to: o Hyperinsulinemia o Glucose intolderance o Increased triglycerides--? Small, dense LDL o Dec HDL cholesterol o Inc PAI-1 o Inc BP ``` • And all of these cause macrovascular disease: eg, coronary heart disease

Answer 38

``` ♣ Hypertriglyceridemia (VLDL, IDL, remnants) ♣ dec HDL cholesterol ♣ Lipoprotein composition • inc TG • inc cholesterol/lecithin ♣ Glycation/oxidation ♣ Small dense LDL ♣ inc Lp(a) (renal disease) ``` cholesterol lowering in diabetes: pts w/ diabetes should be tx as though they have CVD ♣ Decreases plaque progression by 50% ♣ Decreases nonfatal CV events by 40% ♣ Decreases mortality by approximately 30% ♣ By the new cholesterol management guidelines all people with diabetes between that ages of 40-75 should be on a statin • This lecturer says EVERYONE should be on a statin

Answer 39

♣ Definition: SBP>140 and/or DBP>90 ♣ Quoted target (JNC VIII): 140/90* ♣ Quoted target (ADA): 140/80 (90)* ♣ DOD 140/90 (has best evidence) ♣ This is a moving target ♣ *130/80 w/ proteinuria ♣ HTN contributes to all complications of diabetes HOT (hypertension optimal tx) ♣ 67% risk reduction in diabetic pts for CV mortality (events per 1000 pt-yrs) if diastolic P <80 mmHg

Answer 40

♣ cytokines, insulin, high glucose, modified LDL, modified VLDL can lead to ultimately inc activated plts, plasminogen, tPA, and inc fibrin deposits

Answer 41

Treat cholesterol, HTN, and glucose levels**

Answer 42

♣ Retinopathy ♣ Neuropathy ♣ Nephropathy ♣ *primarily caused by elevated blood glucose ♣ if you control someone’s blood sugars, their risk reduction goes down for any diabetes-related endpoint ♣ polyol pathway- inc glucose leads you to inc sorbitol then inc fructose • inc therapeutic target? ♣ Advanced glycation end-products • Interfere with basement membrane function • Squelch nitric oxide and impair vasodilation • Bind to AGE cellular receptors o Production of matrix proteins such as type IV collagen by renal mesangial cells o Expression of adhesion molecules on endothelial cells o Production of growth factors such as VEGF • Intracellular AGEs can crosslink and disrupt DNA function and repair.

Answer 43

Hyperglycemia leads to: • Oxidative stress • Advanced glycosylation end products • Diacyglycerol generation ♣ these lead to PKC activation ♣ PKC activation leads to retina, vasculature, kidney, and heart

Answer 44

Diabetes is the leading cause of blindness in the U.S.. By ten years duration of diabetes, approximately 90% of individuals with diabetes will have some degree of retinopathy. Pathogenesis • Pericyte drop-out • Loss of autoregulation of blood flow to the retinal capillary bed. • Capillary drop-out • Basement membrane thickening • Leakage of intravascular fluids leading to soft and hard exudates • Hypoxic stress and local production of cytokines and growth factors (vascular endothelial growth factor-VEGF) • Neovascularization and proliferative retinopathy. ``` Stages of diabetic retinopathy • 1. Early preproliferative • 2. Mild preproliferative • 3. Severe preproliferative ** (time for intervention) • 3. Early proliferative • 4. Neovascularization disc/elsewhere • 5. Macular edema ``` retinopathy is preventable • Annual ophthalmologic examinations permit identification of individuals with progressive retinopathy. Two large multi-center studies have proven that early intervention at this stage with panretinal photocoagulation can prevent or decrease visual loss. • The Diabetes Control and Complications Trial and the UKPDS have established that tight glycemic control can prevent or delay retinopathy • Early intensive control gives you legacy effect- both micro and macrovascular perspectives Additional ocular complications of diabetes • Macular edema * o most common complication of the eye in type 2 diabetes o Photocoagulation, steroids, and VEGF inhibitors all effective • Corneal ulceration • Glaucoma • Cataracts

Answer 45

♣ Diabetes was listed as the primary cause of kidney failure in 44% of all new cases in 2011. ♣ 35% of diabetic pts will dev diabetic neophropathy ♣ often a long preclinical phase w/ nl or supranormal GFR ♣ proteinuria is critical marker of impending seirous renal disease ♣ without tx decline in GFR is rapid ♣ 5-10% of pts w/ diabetes req dialysis ♣ once started on dialysis only 20% of diabetic pts will be alive in 5 yrs pathogenesis • Hyperfiltration (secondary to the increased osmotic load of hyperglycemia) • Intrarenal and peripheral hypertension • Basement membrane thickening • Mesangial proliferation • Glomerular obliteration ♣ You can slow progression via ACE inhbitiors, ARBs, protein restriction, and tight glucose control

Answer 46

Mononeuritis multiplex Can present w/ ptosis or something that looks bad, but not as bad as you think- good news bad news Distal symmetric polyneuropathy • Most common, but the others can look like storke or something very bad, so you want to recognize that DM can be the contributer • More in pts who are taller- longer the nerve is the more possible it is to be bathed in high glucose and injury • May first present in tingling, numbness, hyperalgesia, but then when pain goes away (good news) but then you can’t feel feet (bad) or lose feeling in your hands- very disabling Autonomic neuropathy Diabetic amyotrophy Diabetic foot disease • Diabetes is associated with impaired blood flow and sensation to the extremities. This leads to a high incidence of mechanical trauma and infectious complications leading to amputation and hospitalization. This complication is largely preventable by appropriate footwear, examination and education. • Amputations o About 60% of non-traumatic lower-limb amputations among pts >20 yo have been dx w/ diabetes o Contractures- hammer toe- improper weight bearing- ulcer- infection – osteomyelitis- amputation CNS problems- men can lose erections

Answer 47

o Diabetes is common and the complications are devastating AND preventable o Diabetic cardiovascular disease ♣ 3 to 5-fold higher risk of heart disease in diabetes o Diabetic retinopathy ♣ #1 cause of blindness in working-age adults o Diabetic nephropathy ♣ #1 cause of end-stage renal disease o Diabetic amputations ♣ #1 cause of non-traumatic lower-extremity amputations

Answer 48

ALL pts w/ T1D | many (advanced) pts w/ T2D

Answer 49

most available as U100 (100 units/mL) in 10mL vials 0.3, 0.5, and 1.0 mL syringes High conc’s (lower vol’s) are absorbed better, so more effective insulin pens Rapid acting insulin analogs are made by modifying human insulin ♣ Human insulin w/ A chain and B chain ♣ Lispro- proline and lysine were reversed • Forms monomers more quickly than human insulin ♣ Aspart ♣ Glulisine • AA substitutions in both/all of these

Answer 50

lispro (Humalog) Aspart (Novolog) Glulisine (Apidra) "no LAG" ``` o Onset of action 5-15 min o Peak 1-1.5 hr o SQ injection or insulin pump o Given just prior to a meal o Dissociates rapidly into monomers after injection ```

Answer 51

Afrezza ``` o Onset of action: 5 min o Peak 1 hr o Duration 2 hrs o Set-dose cartridges for inhalation device o Administered just prior to a meal o ``` Can dec pulm func, can’t used w/ asthma or COPD

Answer 52

"Regular" Humulin R; Novocain R ``` o Onset of action: 30-60 min o Peak 2 hr o Duration 6-8 hrs o SQ injection, IV infusion o Inject 30 min before eating o Difficult to time correctly, and lasts too long ```

Answer 53

NPH ``` o Onset of action 1-3 hr o Peak 6-8 hr* difficult o Duration 12-16 hr o SQ injection only ♣ >=2x/d for basal coverage ♣ cloudy soln – the only one that’s supposed to be cloudy ```

Answer 54

• glargine (Lantus), Detemir (Levemir), Degludec (Tresiba) o onset of action: 1-1.5 hr o no pronounced peak o duration 24 hr (glargine); 12-20 hr (detemir), 42 hr (degludec) o SQ injection only o Cannot be mixed in the same syringe w/ any other insulins

Answer 55

Mixture of intermediate- and short- or rapid-acting insulins- basal AND meal insulin needs Used 2x/day just before AM and PM meals o SQ injection only Insulin analog premixes: inject 15 min QAC ♣ Intermediate plus homolog: 75/25, 50/50 ♣ Intermediate plus novolog: 70/30 NPH + regular: inject 30 min QAC: 70/30, 50/50

Answer 56

the actual pharmacokinetics of injected insulin may vary o Volume o Conc o Body site (thigh vs abdomen vs upper arm) o Presence of lipodystrophy o Intradermal vs subcutaneous (ideal- abdominal fat)* vs intramuscular ♣ Esp if site is warm, rubbed or exercised We try to mimic the same normal profile of inc in insulin w/ inc in glucose (delta 30-50mg/dL) o MDI- multiple day injection therapy o Basal bolus o Intensive insulin therapy o Basal insulin ♣ Insulin taken to suppress hepatic glucose production and to maintain normal fasting blood glucose levels o Bolus/prandial insulin ♣ Insulin taken to cover rise in glucose from a meal: fixed dose OR according to carb content of meal ♣ Lispro OR aspart OR glulisine OR inhaled insulin before each meal o Correction dose insulin ♣ Insulin taken to correct pre-meal hyperglycemia • Using rapid-acting insulin • Often added to meal/prandial dose • Can be taken alone (in between meals) • Caution: do no “stack” corrections

Answer 57

Use long acting insulin (glargine) 1x/day and 3 short-term per day Detemir 2x/day and same 3 injections of rapid acting insulins CSII continuous subcutaneous insulin infusion therapy (insulin pump) ♣ Dosage instructions are entered into the pump’s small computer and the appropriate amount of insulin is then injected into the body in a calculated, controlled manner Advantages • Eliminates multiple daily injections • Different basal rates (“dawn phenomenon” or “workweek/weekend”) • Small increment boluses are possible • Different bolus types (Square vs dual wave) ``` Caveats • Upfront cost • Significant training • Motivation • Ability to troubleshoot • Interruption of infusion or “bad site” can lead to major problems (DKA) within hours ``` ``` Artificial pancreas ♣ “closed loop system” ♣ “bionic” pancreas ♣ FDA- approved in sep 2016 ♣ Continuous glucose monitoring combined w/ insulin pump that maintains nl glucose w/o much intervention by the pt ```

Answer 58

``` When ♣ If lifestyle modifications and non-insulin combinations don’t achieve target A1C ♣ Or if contraindications to other meds • Renal or heaptic dysfunc • CHF ``` ``` ALWAYS if: Signs of insulin deficiency on presenation o Weight loss o Fasting blood glucose >250 o Random blood glucose >300 o A1C >10% ``` Hospital admission for diabetic emergency o Hyperglycemic hyperosmolar state o Diabetic ketoacidosis

Answer 59

Pt ♣ Fear of intections, hypoglycemia, gaining weight ♣ Believe that insulin means serious DM ♣ Belief that insulin causes blindness, etc ♣ Inconvenience, stigma Physician ♣ Uncertainty about whether insulin is really necessary ♣ Difficulty initiating and adjusting therapy • Time, experience, staffing ♣ Fear of hypoglycemia, or inducing weight gain

Answer 60

o Fasting BG 70-130 o 2 hr post-meal BG <180 o A1C <7%; <7.5% in childhood/adolescents, <8% in severe hypoglycemia, severe comorbidities or complications, limited life expectancy, <6.5% in pt w/o significant comorbidities

Answer 61

o Risks potentially assoc w/ hypoglycemia and other ADRs o Disease duration, life expectancy, important comorbidities o Estimate vascular complications o Potentially modifiable: pt attitude and expected tx efforts; resources and support sys

Answer 62

Starting: o Low complexity would be 1 injection/day, but less flexible o High complexity: multiple (3) injections/day, but more flexible o Typically start w/ single basal injection per day along w/ non-insulin agents adjusting: NPH QHS or glargine/detemir QD: 10 units or 0.1-0.2u/kg ♣ Check fasting BG every morning (QAM) ♣ Inc dose by 2 units q3 days unitl <130 mg/dL • If fasting BG >180, inc by 4 units q3 days check HbA1C q3 months if HbA1C is <7% after 3 months, continue same regimen if not (but fasting BGs are at goal), check BG pre-lunch, pre-dinner, and HS ♣ add a 2nd injection of rapid-acting insulin at the appropriate time, 4 u to start, and inc by 2 u q3 days until BG <130 mg/dL if hypoglycemia occurs or fasting glucose <70 mg/dL, reduce bedtime insulin dose by at least 10% ``` paradigm eliminate the lows first ♣ when is it happening/why ♣ ROS and BG records ♣ Reduce total daily dose of insulin by at least 10-20% in a targeted way ``` Eliminate the highs ♣ When and why ♣ ROS and BG records ♣ Inc total daily dose of insulin by 10-20% in a targeted way

Answer 63

``` Glucometers ♣ Quick results (seconds) ♣ Fasting, pre-lunch, pre-dinner, bedtime • At leas 2x/day • Optimally 4x/day • Some pts check 7-10x/day ♣ Some can help calculate doses ``` Continuous glucose monitors ♣ Very useful in pts w/ frequent hypoglycemia

Answer 64

causes: Pre-existing diabetes, DKA, HHS, gestational diabetes Stress hyperglycemia ♣ Medical illness, trauma, burns, surgery Medications: glucocorticoids ♣ Solid organ transplant, pulm/neurosurgery pts, chemo, bone marrow tx Enteral, parenteral nutritional therapy Renal disease, esp on dialysis Cystic fibrosis-related diabetes Managed w/ insulin therapy ♣ Stop non-insulin glucose-lowering agents in almost all pts being admitted hospital ♣Critically ill • If insulin is needed, use IV • Close glucose monitoring, hypoglycemia protocol ♣Non-critically ill • If insulin is needed, use scheduled insulin doses • Glucose monitoring 4x/day, hypoglycemia protocol ♣Re-evaluate insulin regimen daily

Answer 65

All pts w/ T1DM need it ♣ Intensive insulin therapy is standard of care*** ♣ Insulin analogs work better and provide flexibility- meals, activity Many pts w/ T2DM also need it ♣ Hospitalization for severe hyperglycemia ♣ Signs/symptoms of insulin deficiency ♣ Inadequate control on or contraindication to other agents Can be combined w/ noninsulin therapies Knowing the insulin lets you choose the right ones in regimens that make sense for your pt

Answer 66

Lifestyle changes- FIRST reinforcement/edu/goal-setting at every visit! ♣ Less calorie-dense foods ♣ More complete carbohydrates ♣ Higher fiber, lean proteins, smaller portions ♣ Inc physical activity ♣ Weight loss if overweight ``` Medications • Glucose-lowering medications- therapy classes o Sulfonylureas o Recombinant human insulin o Metformin o Acarbose o Insulin analog (Humalog) o T2D o Repaglinidine o Exenatide o Pramlintide o Sitagliptin o Canagliflozin ```

Answer 67

Biguanide Potentiates the suppressive effect of insulin on hepatic glucose production • Suppresses hepatic glucose output Does NOT stimulate insulin secretion OR inc circulating insulin levels Risk of lactic acidosis lower than a different drug in this class- pulled off US market for fatal cases of lactic acidosis Recent update: use eGFR to guide use Pros • MOA- not increasing insulin production (suppressing glucose output- attacking a root cause) • No hypoglycemia • Inexpensive ($4) • No weight gain • Combination pill with: o Fulfonylureas, thiazolidineodiones, DPP-4 inhibitor, SGLT-2 inhibitor Cons • Side effects: GI (nausea, bloating, diarrhea) • Risk of lactic acidosis with: Contrast media, CHF, renal insufficiency, liver disease

Answer 68

♣ What is the pt’s A1C?- insulin if high ♣ Is weight an issue? Is the pt willing to do injections? If yes to both, GLP-1RA ♣ If not willing to do injections, SGLT2-i ♣ CV comorbidities? SGLT2-I or GLP-1RA (some preliminary support for CV benefit) ♣ If insurance requires/restrictive formulary, sulfonylurea ($4) Eligible for any co-pay cards/discount programs? ♣ Metformin ($4) ♣ Sulfonylureas ($4) ♣ Insulin (NPH, regular) Compromised renal func or hepatic disease? ♣ Insulin- basal initially, possibly also bolus ``` Mainly a problem of insulin production? ♣ GLP-1RA ♣ Insulin ♣ Sulfonylurea ♣ (DPP-4i) ``` ``` mainly a problem of insulin resistance? ♣ Metformin ♣ GLP-1RA ♣ DPP-4i ♣ TZD ♣ Insulin ``` Either or both ♣ SGLT-2i

Answer 69

monitoring glycemic control o Glycosylated hemoglobin “A1c” o Measure of avg blood glucose over the period of 2-3 months Standard of care to: ♣ Measure this periodically (2-4x/yr) in ALL pts w/ diabetes ♣ Target certain levels to reduce risk and delay progression of complications o Metformin can lower A1C 1-2% o Insulin can lower 1.5-3.5 or more o Sulfonylureas 1-2 o All others are as little as half a percent

Answer 70

GLP-1 (glucagon-like peptide 1) ♣ Very effective for lowering glucose in diabetes GIP (gastric inhibitory peptide) DPP-4 inhibitors Secreted by L and K cells in GI tract to response to food intake Augments insulin secretion only if blood glucose is elevated Incretin effect is reduced in T2D o If you infuse glucose IV vs via mouth, you get different effects o If you have same blood sugar (glucose levels), but very different insulin concentrations ♣ Food by mouth- 2-3 fold higher insulin conc’s ♣ Food by IV is much lower o Incretins potentiate insulin production in response to oral food consumption o Insufficient insulin secretion and glucagon suppression in response to a meal in T2D ♣ Glucagon is a counterreg hormone for insulin, so it makes sense • Glucagon either stays the same or goes up, but is not suppressed appropriately incretin acting meds also act on brain and GI in glucose homeostasis never give the 2 incretin enhancers together at the same time- inc risk of side effects

Answer 71

lowers glucose via several mech's Food intake stimulates GLP-1 secretion by L cells of ileum • Stimulates glucose-dependent insulin secretion by pancreas • Also suppresses postprandial glucagon secretion by alpha cells in pancrease • Both of these decrease hepatic glucose output GLP-1 also slows gastric emptying and increases satiety (inhibits food intake) • Both of these also help normalize blood glucose GLP-1 alone is not a useful med • Native GLP-1 peptide is rapidly cleave and inactivated by DPP-4 within minutes of appearing in circ GLP-1 agonists: o exenatide, liraglutide, exenatide Qwk, albiglutide, dulaglutide ``` Pros • Multiple MOA to lower postprandial glucose • Effects are glucose-dependent • Weight loss • Recent trial suggesting CV benefit ``` Cons • SC injections • Side effects • Expensive

Answer 72

DPP-4 inhibition inc T1/2 of endogenous GLP-1 and GIP DPP-4 inhibitors: o Sitagliptin, saxagliptin, linagliptin, alogliptin ``` Pros ♣ Multiple MOAs to lower postprandial glucose ♣ Oral ♣ 1x/day ♣ weight neutral ♣ combination pill w/ metformin ``` cons ♣ less potent of glucose-lowering effect ♣ expensive ♣ side effects

Answer 73

Canagliflozin, dapaglifloxin, empagliflozin Nl individuals: ♣ Filtered glucose load: approx. 180 g/day ♣ Urinary glucose: <0.5 g/day ♣ Glucose reab occurs in proximal tubule through the action of SGLT1 and SGLT2 SGLT-2 inhibitors block glucose reuptake in the kidney ♣ You start to waste glucose in urine ♣ In pts at a blood sugar of 180-200 mg/dL, they’re at capacity, kidneys can’t reab glucose after that ♣ These inhbitors lower the threshold to about 100, so you reduce glucose reab even more and excrete via urine ♣ Causes you to lose ~100 g (400 cal) of glucose ``` Pros • Novel mech for controlling glucose • Weight loss • Pill • At least 1 available as combo pill w/ metformin • Recent trial suggesting CV benefit ``` ``` Cons • Inc risk for urinary tract and GU infections • Inc risk for hypokalemia • Expensive • ?? long term safety ```

Answer 74

glyburide, glipizide, glimepride once you remove pancreas it doesn’t work o these meds close ATP-sensitive K channels in beta cells ♣ when you have glucose that gets taken up by beta GLUT2 transporter, inc ATP/ADP ratio and closing K channel, but sulfonylureas bind directly to K channel, which depo’s membrane, causes Ca to flow in, and insulin secreted out of cell; doesn’t care what glucose level is*** ♣ act on beta cells to inc insulin secretion pros ♣ inexpensive ♣ combination pills available w/ metformin, thiazolidinediones cons ♣ weight gain ♣ hypoglycemia ♣ loses effectiveness with longer duration of diabetes

Answer 75

``` clinic visit- diabetes care o HbA1c monitoring o Review of home blood glucoses o Education- hypoglycemia, hyperglycemia, glucose-lowering meds o Screen for complications ``` using noninsulin therapies to lower glucose therapies to lower glucose in diabetes o good glycemic control reduces complications o many diff meds are available to control glucose o understanding mech’s, knowing the available therapies and their pros/cons allows you to recommend and combine the right ones for your pt o individualizing the A1c goal is important o edu and self-monitoring improve glucose control o appropriate preventative care lowers the risk for complications in your future pts

Answer 76

Structures o Glucose- terminal COH o Fructose- ketone on 2nd carbon o Galactose- diff C stereochemistry w/ glucose Sugar alcohols o Show up as carbohydrates; all alcohols; body doesn’t absorb (sorbitol) Classes of carbohydrates Monosaccharides (glucose, galactose, fructose)- 6 C Disaccharides (sucrose, lactose) Polyols (sugar alochols- sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates) Oligosaccharides (3-9 molecs) ♣ Malto-oligosaccharides (maltodextrins) ♣ Other oligosaccharides (raffinose, stachyose) Polysaccharides (9 molecs) ♣ Starch (amylose, amylopectin) ♣ Fiber (cellulose, hemicellulose, pectins) • Starch vs cellulose- different only in stereochemistry

Answer 77

o Outer coating to prevent drying out (cellulose) o Digestable/absorbable starch in the middle o Whole grains- have mix of both

Answer 78

Eating cellulose doesn’t have high glycemic index- not absorbable Refined carbohydrates- increase blood sugar; high glycemic index Glycemic load- a way to measure quality of starch in diet ``` Low GI (below 55) ♣ Sourdough break, apple juice, pumpernickel, oatmeal, pasta, indian basmati rice ``` ``` Intermediate GI (56 to 69) ♣ Croissant, coca-cola, raisin bran, wholemeal bread ``` ``` High GI (above 70) ♣ White bread, corn flakes, doughnut, white rice ``` Glucose measure does not measure fructose, only glucose Glycemic responses vary a lot by person to person; can’t predict; interpersonal variability but not intrapersonal

Answer 79

Relative amounts of fat or carbohydrate ``` Type of carbohydrate ♣ Sucrose, fructose ♣ Glycemic index and glycemic load ♣ Amylose, resistant starch, and fiber ♣ Whole rains, vegetables, legumes ``` Total calories, positive energy balance

Answer 80

Animal or in vitro studies ♣ Can provide the most detailed mechanistic information Epidemiological studies ♣ Population based intake data ♣ Nurses health study and health professionals follow up study, iowa women’s health study ♣ Issues: validity of intake data, reliability of IR dx, interraltionship of factors Short term intervention studies ♣ More definitive than epidemiological studies ♣ Problems with power, diet control, and endpoint Long term intervention studies ♣ Most definitive type of study ♣ Da Quing, Finnish Diabetes Prevention, DPP ♣ Once done will likely not be repeated with different dietary intervention ♣ Multiple interventions Data on food intake patterns: ♣ High carb diets cause diabetes • Increased intake of total carbs • Inc intake of refined carbs, esp high fructose corn syrup • Reduced intake of whole grain products • Temporally correlated w/ inc prevalence of obesity and diabetes ♣ High fructose corn syrup is going up, and so is diabetes prevalence ♣ But so is prevalence of smokers, age of having kids, room temps, time spent awake, etc. ``` ♣ Worrisome • Correlates doesn’t necessarily mean cause • Inc total E intake, reduced EE • Why are people eating this way? o Food industry/government is making them do it o They’re just dumb o Palatability is the priority • How are we going to impact this? ```

Answer 81

mixed data ♣ Fructose is not glucose and so doesn’t raise glucose levels ♣ However, has unique metabolic effects on liver ♣ Clearly causes hepatic insulin resistance in rodents independent of weight gain ♣ Growing evidence of adverse effects in humans ♣ Fructose metabolism is diff than glucose in that it bypasses PFK and as a result is rapidly driven down glycolysis in a manner that is less regulated than glucose ♣ Effects of fructose on body fat in humans trial: • Fructose has a much higher total body fat, and more visceral abdominal fat, than glucose • Plasma triglyceride levels were higher on fructose too • Insulin sensitivity changes on high fructose diet

Answer 82

o Inc fiber intake assoc w/ lower insulin levels and less diabetes o Glycemic load: GI times carbohydrate load ♣ Lower glycemic load is better for you o Glycemic index down and fiber up seems to be god for you Issues o High fat/sucrose/fructose foods have a low GI o GI information not on labels, fiber is o Complexity with sugar alcohols, amylose and resistant starch o GI altered by method of preparation and time of day

Answer 83

o High carb low calorie diets prevent diabetes o Gold standard o Used a range of interventions incl reduced total fat, reduced calories, reduced sat fat, inc fiber, inc physical activity o Goal standard study of Diabetes Prevention Program: ♣ Best prevention is low fat, calorie restricted diet w/ physical activity

Answer 84

NADH and FADH2

Answer 85

o Phsophenolpyruvate carboxykinase PEPCK activity inc in liver

Answer 86

GLP-1 agonist

Answer 87

o White bread (vs karo syrup, pure sucrose, snickers bar, oatmeal)

Answer 88

o Altered mental status, 20 glucose, inc insulin level and low C-peptide level o Admin of exogenous insulin

Answer 89

o Lactate levels would rise | o E is till trapped in NADH, pyruvate backs up, everything backs up

Answer 90

o de-branching enzyme deficiency

Answer 91

o is inhibited by the accumulation of ATP

Answer 92

PI3 Kinase

Answer 93

o PFK1 activity inc because F 2,6 bisphosphate inc because PFK2 activity inc

Answer 94

o Enhances glucose-stimulated insulin release

Answer 95

o inc lactate production

Answer 96

o Inc PEPCK activity

Answer 97

o ribose sugars

Answer 98

o doubly labeled water

Answer 99

o 187 g o wants us to remember calories/kg- 30 cal/kg o how many cal/g of food: 9 cal/g for fat, 4 cal/g for protein and carb

Answer 100

o dev of insulin resistance

Answer 101

o Activation of glycogen phosphorylase kinase by phosphorylation

Answer 102

o Glargine once a day and lispro before meals

Answer 103

o Their Vmax and Km

Answer 104

o higher risk than general pop and risk can be assessed by measuring islet cell autoantibodies in child

Answer 105

o insulin stim’s Glut4 insertion in muscle cells

Answer 106

bypasses PFK

Answer 107

• fat does not dissolve in water- water insoluble, nonpolar; separates the lipids from glucose • most of fat in diet is triglyceride o body breaks these down into free fatty acids and free cholesterol o interconversion between cholesterol and cholesterol ester o pancreas is secreting lipases to break down triglycerides into 2 FFAs and a monoacylglycerol to absorb fat acetyl CoA carboxylase

Answer 108

Fatty acids ♣ Acid COOH, with a C chain (18) saturated fat (no double bonds, all have 2 H’s); nonpolar; doesn’t dissolve in water • “A little polar” • If you put saturated fats together- they’re going to crystallize and be solid at room temp • Discouraged from eating too much saturated fat ♣ Omega-3 fatty acid- double bond 3 back from the end; double bonds give you cis configuration and make it kinked • Unsaturated fat- liquid at room temp; fats that have double bonds and are kinky ♣ Fatty acids can’t turn into glucose, but glycerol can ``` Triglycerides ♣ Fatty acid esterified to glycerol • The hydroxyl group goes away • Very nonpolar ♣ 3 fatty acids can be unsaturated, polyunsaturated, etc ``` cholesterol ♣ flat, planar structure w/ cyclics ♣ precursor for other molecs • cortisol, testosterone, estrogen, vit d ♣ also present in membranes, causes heart disease, etc ♣ a little polar from the OH group at the end cholesterol ester ♣ has an esterified fatty acid to cholesterol molec ♣ no charge from the original OH ♣ super non-polar phospholipids ♣ components of membranes; layers lipids and water • amphiphathic- polar and nonpolar segments ♣ polar head groups facing out and nonpolar tail facing in ♣ glycerophospholipid: glycerol backbone • esterify fatty acid on x2- nonpolar tail • PO4 is the polar head group on the 3rd part of the glycerol o might have something hooked onto it ♣ most polar (of the ones we’ve talked about)

Answer 109

o free fatty acids (circulates free), phospholipids (circulates in monolayers of bilayers), free cholesterol, cholesterol ester, triglyceride

Answer 110

de novo lipogenesis fatty acid oxidation ketone synthesis cholesterol synthesis

Answer 111

♣ make fat- fat synthesis; some ways analogous to glycogen synthesis ♣ when you’re overfed, you’ll store the extra when you have enough ATP from the cycle and TCA cycle gets backed up- make fatty acids ♣ take citrate out of TCA- convert it back to acetyl CoA, then make it into malonyl CoA to get to fatty acids ♣ acetyl coA to malonyl via Acetyl CoA carboxylase is the key step in this process* ♣ want to make fat when we’re fed; regulated by insulin (make it happen) and CRR (inhibit it) ♣ maolnyl coa to fatty acids via Fatty acid synthase ♣ if we have glycerol somewhere, we can combine glycerol w/ fatty acids to make triglycerides • now if you have liver cell, taking glucose from diet and turning it into fat and ship out to adipose tissue by turning it into triglyceride and secreting it as a lipoprotein (VLDL very low density lipoprotein) • lipoprotein lipase takes triglyceride and puts it into the adipose tissue; stored as triglyceride acetyl CoA--> malonyl CoA--> FAs --> phospholipids, triglycerides, or acyl carnitine

Answer 112

adipose tissue w/ triglyceride o heading for liver/muscle o using fat as a fuel (alternative fuel to glucose) o release triglyceride as a fatty acid when you exercise or fast and try to liberate fat ♣ it’s the first regulated step ♣ hormone sensitive lipase breaks TG into FAs ♣ insulin makes this go down, catecholemines makes it go up o fatty acid then comes into liver/muscle cell ♣ turn it into fatty acyl CoA to activate it and get it into mito ♣ trying to get E out of the fat; burn it and put it in TCA cycle to get E out of it ♣ fatty acyl CoA goes into mito via carnitine palmitoyl transferase** key regulated step to get it into mito • this is inhibited by malonyl CoA • malonyl CoA inhibits CPT1 he said? ♣ Now takes the fatty acid and takes off C’s 2 at a time and make acetyl CoA go to right into the TCA cycle • This is called beta oxidation- taking 2 C’s at a time and making acetyl CoA • C’s in the fatty acid can’t go all the way around the cylcle and make glucose because they’re being lost as CO2 x2

Answer 113

o If we fast for a really long time, you can use ketone bodies make from acetyl CoA into ketones to feed brain via HMG-CoA synthase (key step) o Ketones are an alternative fuel source for brain and to a lesser extent muscle acetyl CoA--> ketone bodies

Answer 114

o Acetyl CoA can also be made into cholesterol through anabolic rxn o Happens in cytosol o Key regulated enzyme is HMG CoA reductase (statins inhbit this enzyme) acetyl CoA--> HMG CoA--> Mevalonate --> cholesterol

Answer 115

acetyl CoA via pyruvate (glycolysis, proteins, AAs) acetyl CoA turns into OAA and citrate in the MITO leaves mito into cytosol as citrate ♣ ATP can inhibit TCA cycle which can allow citrates to accumulate and cross mito membrane, I think he said ♣ In cytosol, citrate can be converted to OAA again or into acetyl CoA via ♣ OAA can be oxidized back into malate, then pyruvate, then back into mito ♣ Acetyl CoA can turn into malonyl CoA via acetyl CoA carboxylase (rate limiting rxn) rate limiting step: acetyl CoA --> malignly CoA via acetyl CoA carboxylase ACC ♣ Malonyl CoA will be substrate for fatty acid synthase to make palmitic acid- final product of fatty acid synthesis; 16 C saturated regulate via ACC final products: palmitate palmitate can go to ER or mito for elongation, or exclusively to ER for desaturation ♣ Malonyl CoA will be substrate for fatty acid synthase to make palmitic acid- final product of fatty acid synthesis; 16 C saturated used in lipid membranes, or triacyl glycerides TAGs

Answer 116

o Hydrophobic hydrocarbon chain CH3(CH2)n o Hydrophilic carboxyl group (ionized at pH 7) COO- o Consists of hydrophobic hydrocarbon chain w/ terminal carboxyl group o Longer chain = more insoluble in water o Usually esterified (ex triacylglycerols) o Plasma fatty acids are transporterd by serum album o Structural components of membrane lipids, precursors of the hormone-like prostaglandins o Can also be conjugated on proteins o Saturated vs unsaturated fatty acids ♣ Double bonds in unsat FAs are nearly always in cis config- kink at that position ♣ Double bonds dec melting temp ♣ Membrane lipids usually contain long fatty acids (>=16 C’s) • Presence of double bonds helps maintain membrane fluidity

Answer 117

A: C’s numbered starting w/ carboxyl C as C1 • Number before colon = C’s in the chain • After the colon= numbers and position of double bonds o Ex. 20:4(5,8,11,14) = arachidonic acid B: C atoms are numbered beginning w/ 2nd C as alpha, beta, gamma, etc. • The C AFTER the carboxyl group ♣ C of the terminal methyl group is called the omega carbon regardless of chain length • The double bonds in a fatty acid can also be counted beginning at the omega end ♣ Omega 3 and omega 6 fatty acids • Linoleic acid (omega 6) and linolenic acid (omega 3) are 2 dietary essential FAs o Human cells don’t have enzymes to introduce double bonds between C 9 and the omega end of FAs o Linoleic acid is precursor of arachidonic acid, the substrate for prostaglandin synthesis Linolenic acid is precursor of other omega-3 FAs important for growth/dev

Answer 118

♣ Major hydrophobic components of all cell membranes ♣ Major storage form of metabolic E, 70-80% of caloric reserve is triacylglycerols ♣ Essential precursors for eicosanoids (paracrine hormones: prostaglandins, leukotrienes, thromboxanes)

Answer 119

♣ Biosynthesis from small molec intermediates derived from metabolic breakdown of sugars, AAs, and fats ♣ Diet essential FAs (linoleic and linolenic acid) • Linoleic acid: the precursor of arachidonic acid, the substrate for prostaglanding synthsesis) • Linolenic acid: the precursor of other omega-3 FAs important for growth/dev

Answer 120

♣ Occurs when dietary calories are excess ♣ Carbs- glucose – pyruvate- Acetyl CoA + CO2 palmitic acid C16 other fatty acids ♣ Proteins AAs Pyruvate and acetyl CoA (ketogenic AAs) in the above process too Producing the substrates for FA synthesis ♣ Pyruvate goes into mito membrane; turns into citrate ♣ Citrate then goes out and can become acetyl CoA for FA synthesis

Answer 121

Formation of malonyl CoA is a rate-limiting step in FA biosynthesis Acetyl CoA Carboxylase has three functional regions: the Biotin Carrier Protein, Biotin Carboxylase and the Transcarboxylase that transfers the carboxyl group to acetyl CoA to make malonyl CoA. Biotin moves from one active site to the other via a flexible arm. ♣ The mechanism of hormonal regulation is covalent phosphorylation of acetylCoA carboxylase, the rate-limiting step of FA biosynthesis. ♣ Acetyl CoA carboxylase is inhibited by phosphorylation. ♣ Phosphorylated acetylCoA carboxylase can regain partial activity by allosterically binding citrate. Conversion of malonyl CoA to FA ♣ Malonyl CoA is the substrate for FA synthase (FAS) ♣ FAS (multifunctional enzyme) • 7 enzyme activities • acyl carrier protein (ACP) • performs all the steps to convert malonyl CoA to a FA ♣ the FA molec is synthesized 2 C’s at a time (4 step repeating cycle with the extension of 2 C’s/cycle) ♣ the product of FAS is palmitic acid (16:0) • palmitate is released from FAS by the palmitoyl thioesterase activity and can then undergo separate elongation and/or desaturation to yield other FA molecs synthesis of palmitiate by FAS ♣ 4. Condensation to form acetoacyl ACP ♣ 5. Reduction the Keto group to an alcohol ♣ 6. Dehydration to introduce a double bond ♣ 7. Reduction the double bond ♣ ACP: acyl carrier protein ♣ Repeat these steps ♣ 1st 2 c’s will be from acetyl CoA; the rest of the C’s are from malonyl CoA; he wants us to know that

Answer 122

♣ elongation of palmitate occurs in mito and ER ♣ a family of enzymes designated fatty acid elongases catalyze the initial condensation step for elongation of saturated or polyunsaturated FAs ♣ formation of double bond in FA involves ER membrane proteins in mammalian cells • called mixed-function oxidases ♣ mammalian cells are unable to produce double bonds between carbon 9 and the omega-end of the chain ♣ thus some polyunsaturated FAs are dietary essentials, eg linoleic acid

Answer 123

Diet and Metabolic Conditions • High carbohydrate leads to high pyruvate and acetyl CoA levels in the mitochondrion, which favors production and translocation of citrate from the mitochondrion to the cytosol, thus stimulating fatty acid synthesis. • High fat/low carbohydrate leads to low pyruvate flux in the mitochondrion. Fat metabolism is associated with elevated acyl CoA in the cytoplasm. Both conditions reduce fatty acid biosynthesis. • Hormonal environment: high insulin favors lipogenesis (fatty acid biosynthesis); high glucagon favors lipolysis (-oxidation) and decreased fatty acid biosynthesis. Long-term regulation by gene transcription • Prolonged consumption of a diet containing excess calories causes an increase in acetyl CoA carboxylase and fatty acid synthase synthesis; in contrast, fasting causes a reduction of acetyl CoA carboxylase and fatty acid synthase. Short term regulation of fatty acid biosynthesis ♣ citrate • Availability of cytosolic citrate determines the amount of acetyl CoA available for FA synthesis • Also helps produce NADPH for reducing equivalents used in the rxns • citrate can also activate acetyl CoA carboxylase by causing polymerization of the enzyme (conformational change) and increasing Vmax ♣ Palmitoyl CoA • Acts as inhibitor of Acetyl CoA carboxylase ACC • Cytosolic levels are elevated during starvation or on high fat diets ♣ insulin and glucagon • Insulin promotes fatty acid synthesis indirectly by promoting glucose utilization (increases pyruvate flux), directly by dephosphorylation and activation of acetyl CoA carboxylase. • Glucagon increases intracellular cAMP leading to phosphorylation and inactivation of acetyl CoA carboxylase. ♣ Regulation of Acetyl CoA Carboxylase ACC is the key for regulating fatty acid biosynthesis

Answer 124

Activation of free fatty acids and glycerol for synthesis of TAG ♣ Free FAs must be activated before they can be attached to glycerol 3-phosphate • Via fatty acyl CoA synthetase ♣ Synthesis of glycerol 3-phsophate Storage of fatty acids as TAGs ♣ Synthesis of TAG from glycerol 3-phosphate and fatty acyl CoA includes sequential addition of two fatty acids from fatty acyl CoA, then removal of the phosphate to add the third fatty acid. ♣ The fatty acid on carbon 1 is typically saturated, that on carbon 2 is typically unsaturated and that on carbon 3 can be either. ♣ TAGs are the major storage form of fatty acids. ♣ TAGs synthesized in the liver are packaged with cholesteryl esters, cholesterol, phospholipids and apolipoprotein B-100 to from VLDL for delivery to the body.

Answer 125

Chronic alcoholism causes hyperlipidemia in both liver and serum ♣ Ethanol is oxidized to acetate, primarily in liver acetyl CoA Fatty acids ♣ Inc NADH/NAD slows TCA cycle and fatty acid oxidation, promotes DHAP glycerol 3-P via NADH ♣ Glycerol 3-P + FAs triacylglycerides ♣ The liver secretes abnormally high levels of VLDLs. • However, chronic liver dysfunc impairs protein synthesis, incl ApoB-100. Liver becomes unable to produce and secrete VLDL, increasing hepatic fat buildup

Answer 126

• Fatty acid synthase VLDLs

Answer 127

• Insulin signaling stimulates expression of the ACC gene.

Answer 128

Signs and Symptoms*: ♣ Early Failure to Thrive (vomiting with milk) ♣ Hepatomegaly/Cirrhosis ♣ Cataracts/Visual Impairment ♣ Mental Retardation ♣ Diagnosis: Non-glucose reducing substance in the urine while on lactose containing diet: breast milk or infant formula Treatment: Lactose-free diet ♣ N.B.- Galactosemia is part of the Newborn Screening Program in most states

Answer 129

Bypasses PFK-1; enters glycolytic pathway below PFK-1 Hereditary fructose intolerance ♣ Due to deficiency in Aldolase B which splits Fructose 1 P into 3 carbon intermediates that can enter glycolysis. ♣ Effect is accumulation of fructose 1P which has toxic effects on liver, kidney and brain ♣ Symptoms occur with the introduction of fruits and other sources of fructose in the diet in the first year of life (not at birth or in the first few months) ♣ Symptoms: nausea, vomiting, sweating, lethargy, hypoglycemia, hepatomegaly ♣ Increased liver function tests, may progress to severe liver injury. Renal dysfunction may be present ♣ Treatment is avoidance of fructose/sucrose/sorbitol in the diet.

Answer 130

carnitine problems ♣ L-Carnitine- Primary or dietary ♣ Carnitine Palmitoyl-Transferase (CPT)-I ♣ Carnitine/Acylcarnitine Translocase ♣ Carnitine Palmitoyl-Transferase (CPT)-II ♣ overall Fatty acid oxidation problems*** acetyl CoA dehydrogenase deficiencies ♣ MCAD, LCAD, etc (medium and long chains) HMG-CoA synthase/Lyase ♣ Appears in ketone production and cholesterol production pathways dec FA oxidation and ketone formation ♣ Decreased fat oxidation in liver deprives gluconeogenesis of a source of fuel. ♣ Decreased availability of acetyl CoA from fatty acid oxidation and/or ketones makes most tissues obligate glucose utilizers, therefore greatly increasing glucose utilization and predisposing to hypoglycemia.

Answer 131

♣ Decreased fat oxidation in liver deprives gluconeogenesis of a source of fuel. ♣ Decreased availability of acetyl CoA from fatty acid oxidation and/or ketones makes most tissues obligate glucose utilizers, therefore greatly increasing glucose utilization and predisposing to hypoglycemia. Common clinical features • fasting hypoglycemia with low ketones, liver failure, hypotonia. Lab features • hypoglycemia, low ketones, coagulopathy hyperammonemia (from excess AAs coming into the TCA cycle for gluconeogenesis), and elevated CK from exercise-induced rhabdomyolysis • Hypoglycemia • Abnormal urinary organic acids (W-oxidation) • Increase in acylCoA derivatives in blood and urine • Decreased carnitine/Increased acylcarnitines- blood Newborn screening • identified a combined incidence of 1:5000 for FAOD. Most are treatable with a good long term outcome.

Answer 132

Medium Chain [MCAD]- most common (1:9000) Detected on the Newborn Screening Tests MCADD • Enzyme that catalyzes initial setp in B-ox of C10-C6 straight chain acyl-CoAs Clinical Features: o Vomiting, lethargy, hypotonia, +/- seizures o Hypoketotic hypoglycemia o Hepatomegaly, fatty liver o May resemble Reye syndrome (acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction) o Rhabdomyolysis or cardiac symptoms (V fib and cardiac arrest) have been observed Diagnosis: o MS/MS-based acylcarnitine analysis of plasma with increased C8 and C8/ C10/carnitine ratio Treatment: o Avoid fasting and provide a carb-rich diet o In those < 1yr of age, uncooked cornstarch may be needed to avoid decompensation during overnight fasts o Prompt treatment of infections

Answer 133

♣ Newborn screening has been instituted to identify infants before symptoms develop ♣ Definitive diagnosis typically involves • Measuring precursor that is present in excess. • Measuring the activity or expression of the enzyme that is likely defective. ♣ Treatment involves making sure they have enough dietary carbohydrate at all times, or avoiding the offending nutrient (the one that cannot be metabolized).

Answer 134

o Counter-regulatory hormones help maintain glucose during periods of fasting o Insulin should be low or undetectable during fasting ``` hormone dysregulation Hypopituitarism primary adrenal insufficiency hyperinsulinism inc insulin secretion or admin ``` ``` others Salicylate intoxication Ethanol intoxication Diarrhea and malnutrition - Decreased substrates for gluconeogenesis Dumping syndrome - Occurs in children with Gtubes and Nissen Ketotic hypoglycemia Disorders of Amino Acid metabolism Maple syrup urine disease Methylmalonic acidemia Tyrosinemia ```

Answer 135

``` Counterregulatory hormone Defects • Hypopituitarism • Growth Hormone Deficiency • ACTH or cortisol deficiency • Beta-blocker (results in lack of epinephrine) ``` ``` Defects in Insulin Suppression • Congenital Hyperinsulinism • Infant of a diabetic mother • Iatrogenic • Insulinoma ```

Answer 136

multiple hormone deficiencies ♣ ACTH and / or GH deficiency ``` Clinical Features: • Midline defects • Micropenis, undescended testes • Jaundice • nystagmus • Poor growth ``` ``` Causes: • Septo-optic Dysplasia • “Empty Sella” syndrome • Ectopic Pituitary • Pituitary Tumor or Irradiation • Isolated GHD is not commonly associated with hypoglycemia ```

Answer 137

``` Clinical features: • Poor growth/weight gain • Decreased energy • Nausea, vomiting, abdominal pain • Hypotension • Hyperpigmentation • Salt craving • Associated autoimmune diseases ``` ``` Common causes • Congenital adrenal hyperplasia • Adrenal hemorrhage • Addison disease • Adrenoleukodystrophy ```

Answer 138

Neonatal: • Infants of Diabetic Mothers: “Transient” • Congenital hyperinsulinism “permanent” Childhood: • Islet Cell Adenoma • Insulin O.D., Type 1 DM, Child Abuse Adolescents - as above and: • Oral Hypoglycemic Agent Ingestion • Factitious”- hypoglycemic symptoms only Large for Gestational Age Glucose Infusion Rate >10mg/kg/min to sustain normoglycemia Non-ketotic (may see slight ketonuria) Non-suppressed serum insulin Rise in blood glucose >40mg/dL after glucagon (reflects increased storage of liver glycogen)

Answer 139

♣ Infants of Diabetic Mothers ♣ Congenital hyperinsulinism (genetic) ♣ Islet Cell Adenomas ``` ♣ Insulin Overdose • Accidental in Type 1DM • Iagtrogenic or munchausen by proxy o Criminal: child abuse, homicide • Ingestion of oral hypoglycemic agents ```

Answer 140

``` One of the most common causes of hypoglycemia in childhood Diagnosis of exclusion Lack of substrates for gluconeogenesis Hypoglycemia after fasting 14-24 hours Presents at 1-5 years old Spontaneously remits at 8-9 years old ```

Answer 141

13/120 proteins needed for oxidative phosphorylation are coded by mitochondrial DNA Disorders of mitochondrial function are expressed in tissues with the greatest energy requirements - Heart - Skeletal muscle - Brain and nerves Myopathies: exercise induced fatigue and muscle breakdown (rhabdomyolysis) Retinal degeneraton

Answer 142

the critical sample!! CONFIRM BG <50 mg/dl Plasma bicarbonate, ketones (beta-hydroxybutyrate), insulin, cortisol, growth hormone, free fatty acids, lactate, and pyruvate, (c-peptide, total and free carnitine, acyl carnitine profile) Urine ketones and organic acids

Answer 143

acidosis: ``` with high ketones: Normal ketotic hypoglycemia Panhypopituitarism GH deficiency ACTH/cortisol deficiency GSD 3,6,9,10 ``` ``` with high lactate: GSD 0 F-D-Pase deficiency Pyruvate carboxylase deficiency Normal neonates ``` no acidosis, low ketones: with low FFAs Hyperinsulinism Hypopituitarism with high FFAs Fatty acid oxidation disorder Defect in ketogenesis

Answer 144

problem with | glycogen --> G6P

Answer 145

problem with | G6P--> Triose 3-P

Answer 146

problem with | G6P --> glucose

Answer 147

problem with | beta oxidation

Answer 148

problem with carnation transporter CTP1 w/ Acetyl-CoA-->acyl-carnitine translocate w/ acyl-carnitine --> acyl-carnitine CTP2 w/ actyl-carnitine--> acyl-CoA

Answer 149

problem with | galactose to G1P

Answer 150

problem with | fructose to trips 3P

Answer 151

LDL-C Epidemiology +++ Bio plaus +++ clinical trials +++ VLDL-TG Epidemiology ++ Bio plaus + clinical trials +/- HDL-C Epidemiology ++ Bio plaus ++ clinical trials -

Answer 152

Adults 20 y/o and older should have a fasting lipid panel done at least every 4-6 years Obtain complete lipoprotein profile after 8-12 hour fast LDL-C is primary lipoprotein of “interest” Measure: Total Cholesterol, HDL-C, and triglycerides (TG) Calculate LDL-C (Friedewald Formula): In fasted state: Total-C = LDL-C + HDL-C + VLDL-C VLDL-C = TG÷5 when TG are <400 mg/dl Therefore: LDL-C = Total Cholesterol – (HDL-C + TG/5)

Answer 153

Biologic Plausibility LDL is central in the development and progression of atherosclerosis LDL-C lowering with statins stabilizes atherosclerotic plaques Epidemiology LDL-C elevations are associated with an risk of coronary heart disease Randomized Trials LDL-C lowering with statins reduces heart disease related events and deaths

Answer 154

Based on population curves: Average LDL-C in the US is 116 mg/dl Based on “biology”: Other mammalian species have LDL-C ~30-50 mg/dl Hunter gatherer populations have LDL-C ~60-70 mg/dl We’re born with LDL-C ~30 mg/dl Based on morbidity: Majority of CHD occurs with “average” cholesterol CHD can/does occur with “low” cholesterol levels Is there a threshold at which point no atherosclerosis occurs?

Answer 155

Age, male > female African American vs. Caucasian Cigarette smoking - current Hypertension Systolic BP >140 mm or on antihypertensive therapy Higher total cholesterol Implies higher LDL-C Low HDL-C Diabetes other risk factors ``` o Life-Habit Risk Factors:: --Metabolic syndrome --Sedentary Lifestyle --Atherogenic Diet --Pyschosocial Factors o strong family history o emerging risk factors inc apo B inc LDL particle # inc lipoprotein (a) inc homocysteine Subclinical atherosclerosis ``` ``` risk estimator Race Gender Age Total cholesterol HDL cholesterol Blood pressure / Use of BP medicines Diabetes status Smoking status ```

Answer 156

inc production of lipoproteins and/or dec catabolism of lipoproteins

Answer 157

Lifestyle Diet, inactivity, alcohol Medications (steroids) Diabetes/Glucose intolerance: glucose, HbA1C*** Thyroid disease: TSH*** Liver disease: liver function tests*** Kidney disease: creatinine, urine protein***

Answer 158

Most often a defect in the LDL receptor* A decrease in LDL removal ~50% receptor-negative ~50% are receptor-defective ``` Autosomal dominant Gene frequency: 1 in 250-300 Partial (heterozygote): LDL-C 200-300 mg/dl Complete (homozygote) absence of the LDL receptor: LDL-C >500 mg/dl ``` Premature death from atherosclerosis occurring frequently before age twenty in homozygotes

Answer 159

LDL binds to LDL receptor, endocytosed into a clathrin-coated vesicle, moves into lysosome, and LDL receptor is recycled PCSK9-mediated degradation of the LDL receptor- a GOF mutation will result in too much degradation, and hypercholesterolemia because it's not being endocytosed by the liver

Answer 160

marcus corneas: lipid deposits at the limbs of the cornea may reflect hypercholesterolemia, or may be a nl variant more common as people age xanthelasmas: Lipid deposits in the skin of the eyelid. May reflect hypercholesterolemia, or may be a normal variant. tendinous xanthomas: Typically involves the Achilles tendons and extensor tendons of the hands. Indicative of familial hypercholesterolemia.** specific

Answer 161

May promote clotting, may promote vascular endothelial dysfunction, may be directly delivering cholesterol to the vessel wall. Epidemiology Hypertriglyceridemia in the setting of metabolic syndrome, type 2 diabetes (especially in women) has been shown to be associated with CVD risk Severe hypertriglyceridemia is associated with pancreatitis Randomized Trials Triglyceride lowering has *not* been shown to independently reduce CVD related events and deaths

Answer 162

``` NCEP/ATP III Classification of Triglycerides Normal: <150 mg/dl Borderline High: 150-199 mg/dl High: 200-499 mg/dl Very High: 500 mg/dl ``` ``` causes: behavioral -ethanol, high fat/sugar intake, sedentary lifestyle altered physiology meds (esp oral contraceptives) ``` genetics There are no single genes that explain hypertriglyceridemia. A number of SNPs on known and unknown genes have been identified LPL and apo A5 most relevant ``` severe clinical feats Eruptive xanthomata Lipemia retinalis (white vessels in eye) Hepatosplenomegaly Abdominal pain +/- acute pancreatitis 5% fatality ``` ``` familial LPL deficiency (rare) Apo CII deficiency GPIHBP1 deficiency -doesn't req secondary disorder pancreatitis risk no premature CHD eruptive xanthoma lipemia retinalis ``` goals Severe Hypertriglyceridemia (>500 mg/dl) Primary goal is to prevent pancreatitis Goal is to clear chylomicrons - reduce TG <500 mg/dl Moderate Hypertriglyceridemia: Primary aim of therapy is to focus on lifestyle/statin recommendations. Further treatments need more evidence.

Answer 163

“Broad Beta Disease” Manifest as inc cholesterol and inc TG Autosomal recessive disorder Apo E2 rather than E3 and E4 Results in chylomicron remnant and IDL accumulation Increased risk for premature CHD Diagnosis: Lipoprotein electrophoresis, apo E genotype (Alzheimer's predisposition) presentation planar, palmar, and tuboeruptive xanthomas -extensor surfaces of arms/legs/palms. rare, but indicative of broad beta or remnant disease

Answer 164

Biologic Plausibility Reverse cholesterol transport Anti-oxidant and anti-inflammatory effects Epidemiology Clear association between low HDL-C and increased risk for CVD in many but not all populations. Randomized Trials HDL-C raising has not been clearly shown to reduce CVD related events and deaths

Answer 165

``` ABC is ATP Binding Cassette gene family- relates to reverse cholesterol transport transmembrane proteins transport ligands amino acids nucleotides lipids ``` ABCA1 gene is altered in Tangier disease and familial hypoalphalipoproteinemia Tangier disease- enlarged orange tonsils from accumulation of cholesterol. inc risk of TAD (rare, but telling?) ``` acquired causes of low HDL-C -Diet: High carbohydrate Obesity -Drugs: β-blockers Diuretics Sex steroids – progestins, androgens HIV protease inhibitors -Others: Hypertriglyceridemic disorders Lifestyle – sedentary, smoking ``` tx goals (<40 mg/dL) First reach LDL-C goal, then: -Intensify weight management and increase physical activity -If TG >200 mg/dL, consider drug treatment of TG -Presently, HDL raising drugs are not indicated High levels of LP little "a" correlate w/ inc CHD risk

Answer 166

Advise adults who would benefit from LDL-C or BP lowering to: Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains: includes low-fat dairy products, poultry, fish, legumes, non-tropical vegetable oils and nuts; and limits intake of sweets, sugar-sweetened beverages and red meats. Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions. Recommended dietary patterns include DASH, USDA, AHA, Mediterranean

Answer 167

with statins: benefit on major CVD events and CVD deaths high intensity: atorvastatin (40 and 80mg; generic) Tosuvastatin (20 and 40mg; generic) ``` moderate intensity: Atorvastatin Tosuvastatin Sinvastatin Pravastatin Lovastatin Fluvastatin ``` low intensity: rarely used, except in statin intolerant pts Pravastatin Lovastatin MOA HMG CoA reductase inhibition Decrease hepatic pool of free cholesterol Increase expression of LDL receptors on cell membranes Increase catabolism of VLDL and LDL Decrease LDL-C concentrations 6% rule!! w/ each statin dose doubling, LDL-C falls by 6% downside of statins: abnl AST and ALT (rare) myopathy: any disease of muscles, esp myalgias* but very rarely rhabdomyolysis cognitive impairment (rare) new onset of T2DM (pertinent- 10% inc risk)

Answer 168

``` plant stanols Inhibition of cholesterol absorption may interfere w/ abs of lipid-soluble vitamins low abs, dose 2-3g/day reduce LDL by 5-10% ``` Ezetimibe Selective cholesterol absorption inhibitors (block Cl abs at intestinal brush border) reduces intrahepatic cholesterol pool size NO side effects BAS (bile acid sequestrates) or resins Cholestyramine Colestipol Colesevelam Not abs, not metabolized - Inhibit reabsorption of bile acids - Decreased reabsorption of bile acids stimulates increased conversion of cholesterol to bile acids -Reduced cholesterol content of hepatic cells 1- Stimulates increased cholesterol synthesis 2- Stimulates LDL receptor synthesis and LDL uptake by the liver** ``` side effects mouth sensation bloating nausea constipation anal irritation ``` ``` inhibits Rx abs Digoxin Warfarin Thiazide diuretics Beta blockers Thyroid hormone ``` Contraindications Dysbetalipoproteinemia Elevated TG (>300 mg/dL)

Answer 169

been approved in past 4 months Alirocumab and Evolocumab to tx adults w/ FH or clinical CAD, who require additional LDL lowering ``` adverse effects injection site rxns- 5% drug-induced Abs <5% allergy neurocognitive events? ```

Answer 170

Maximally tolerated statin + ezetimibe + resin + fenofibrate + niacin If >200 mg/dL on maximum therapy one of two newly approved drugs and/or LDL apheresis.: Mipomersen: targeting Apo B at point of synthesis and secretion MTP inhibition w/ Lomitapide: MOA acts on liver, intestine, and apoB-48 secretion need to lower fat intake otherwise lots of steatorrhea LDL aphaeresis: takes LDL and cholesterol way down, but it will be back up to baseline by 2 weeks

Answer 171

``` fibrates- 20-40% omega-3 fatty acids: 15-35% nicotinic acid: 15-35% statins: 0-35% LOW END- MINIMAL OR NO EFFECT high end: mod to high dose ```

Answer 172

clinical evidence Reduce CVD events in high risk patients not treated with statins Middle-aged men with a non-HDL-C >200 mg/dL Men with CHD and a low plasma HDL-C (32 mg/dL) Relevance now in statin era? Reduction in CVD events in several trials in patients (± statins) with plasma TG >200 mg/dL and low levels of HDL-C adverse rxns ``` fenofibrate skin rash myopathy inc LFTs- rare inc Cr- reversible after drug cessation ``` Gemfibrozil cholelithiasis myopathy GI distress both are contraindicated in severe hepatic and renal disease

Answer 173

fish oil AKA Eicosapentaenoic acid EPA and docoosahexaenoic acid DHA polyunsaturated found naturally in marine sources alpha-linolenic acid (precursor) can't be synthesized by humans and is found in walnuts and flaxseed, soybean, and canola oils ``` MOA dec hepatic triglyceride prod and therefore VLDL-TG secretion 3/4 g/day: dec TG 15-35% inc HDL 5-10% none-inc LDL ``` adverse effect: fishy odor and aftertaste (freezing helps) indicated: fasting TG >500

Answer 174

Nicotinic acid = niacin adipose tissue: binds to inhibitory receptor that inc Gi dec lipolysis (transient effect only) ``` liver: inc AMP kinase inc FFA oxidation dec TG synthesis dec VLDL synthesis and thus, LDL formation ``` lipoprotein effects: inc HDL 10-30% dec TG 15-35% dec LDL 5-25% contraindications Severe skin rash (flushing in most patients) Liver disease – moderate to severe Hyperuricemia and/or gout Active peptic ulcer or inflammatory bowel disease Impaired glucose tolerance (relative contraindication)

Answer 175

``` Niacin 15-35% Fibrates 5-15% Statins 5-10% Resins 5-10% Estrogens – p.o. 10-15% CETP inhibitors 40-200% ``` no evidence, and treating low levels of HDL-C is not a drug indication ``` heart healthy HDL raising therapies exercise sustained weight loss alcohol smoking cessation ```

Answer 176

fed state most inborn errors don't relate to the fed state when eat glucose, it goes to liver, can go through glycolysis, glycogen, HMP pathway, we can get glycerol out of there if we eat a lot of glucose, we can go through Acetyl CoA and make FFAs and make triglycerides adipose- can take up glucose and make fat stored as triglyceride brain- just takes up glucose to keep constant glucose and use it as an oxidative fuel skeletal muscle- serves as cupboard for glucose- can burn it, or store it as glycogen

Answer 177

keep feeding brain- glucose or ketone as an alt deliver nutrients to liver so we can make glucose for brain 2 glucose relieving pathways from liver: glycogenolysis when counter regulatory hormones are high via glycogen phosphorylase is a quick E source shortly after meal gluconeogenesis fro pyruvate as fast goes on longer carbons can come into pyruvate as lactate, AA (alanine), AAs entering in the TCA cycle, glycerol from fat breakdown lipolysis breaks down TGs to give you FFAs to go through beta oxidation to give you acetyl CoA to generate ATP from TCA cycle to generate gluconeogenesis if fast goes on long enough and we have lots of Acetyl CoA it can also be generated to ketones which is an alt fuel for skeletal muscles fat can go to muscle so muscle doesn't have to use glucose so glucose can be preserved for the brain to use (brain can use ketones eventually if you end up in a starved state) cori gives us substrates for gluconeogenesis in muscle, you can't take glycogen and get it out as glucose, but you can take it out as lactate and convert it to glucose in the liver -can also do this in RBCs

Answer 178

``` Whipple’s Triad: classic symptoms (discussed below)-> BG < 50 mg/dl -> resolution with glucose ingestion ``` ``` Laboratory definition Adults: plasma venous sample <50s mg/dl (after 84 hrs fasting) Children: 53 (after 30 hrs fasting) In neonates, controversial Term within first 12 hrs: BG <30 After 12hrs: BG <45 After 48hrs: BG <50 ``` ``` symptoms autonomic NS activation: Sweating Shaky, trembling Tachycardia Anxiety Weakness Hunger Nausea/vomiting ``` ``` Neuroglycopenic symptoms: (looks drunk) Irritable, restless Headache Confusion Visual changes Slurred speech/concentration Behavior changes Somnolence Coma/seizures ```

Answer 179

important to ID and tx Brain relies on glucose (major fuel), ketones, and lactate In infancy and childhood, hypoglycemia can injure the developing brain and result in permanent neurodevelopmental problems

Answer 180

first abs then glycogenolysis then gluconeogenesis then fatty acid oxidation

Answer 181

``` < 4 – 6 hours: Glucose 6 phosphatase deficiency Milder Glycogen Storage Diseases in infants and children Hyperinsulinism Cortisol and GH deficiency in infants ``` > 6-8 hours: Cortisol deficiency and fatty acid oxidation disorders in infants Milder glycogen storage and gluconeogenic diseases Cortisol and GH deficiency in children and adults > 10-12 hours: Fatty acid oxidation disorders in older children and adults Mild disorders of GSD in adults > 12- 24 hours: ketotic hypoglycemia (not enzyme defect, but common) Fatty acid oxidation disorders in older children and adults

Answer 182

Many present as hypoglycemia (<50 mg/dl) May present with accumulation of abnormal amounts of substrate behind block: glycogen, galactose, fructose, lactate, triglycerides Precipitating factors: fasting, illness, exercise, ingestion of dietary galactose or fructose Presence of ketones separates defects in fat oxidation from glucose disorders

Answer 183

Glycogen storage diseases Glycogen synthase, branching enzyme Glycogen phosphorylase, phosphorylase kinase Gluconeogenic Defect: F1,6 bisphosphatase deficiency Glucose 6 phosphatase deficiency Hereditary Fructose Intolerance Galactosemia

Answer 184

Disorder of glucose release Disorders of synthesis Disorders of degradation

Answer 185

(GSD-I Von Gierke) Deficiency of glucose-6-phosphatase: the final common pathway: impairment in glucose release from the liver from glycogenolysis and gluconeogenesis ``` Signs and Laboratory Findings: Hepatomegaly (pronounced) Hypoglycemia: early (<4h) and severe Lactic acidosis Hypertriglyceridemia and hypercholesterolemia Hyperuricemia Short stature, doll-like face ``` ``` tx Constant glucose supply! Frequent feeding Nasogastric drip feeding Uncooked cornstarch: Slow release CHO, lasts 6 h, slow start ``` Any possible hypoglycemia needs prompt iv glucose treatment ``` Results: Normalization of growth Maintaining glucose > need for gluconeogenesis Decrease cholesterol and triglycerides Still hepatomegaly but less pronounced ```

Answer 186

Glycogen Synthase deficiency (GSD 0) Clinical presentation: hyperglycemia after a meal, followed by low blood sugar later, increased lactate, and severe ketotic hypoglycemia No liver enlargement unlike other GSDs Treatment: high protein diet to provide gluconeogenesis substrates and low glycemic index complex carbs to minimize post-prandial hyperglycemia and hyperlactacidemia Branching (1,4---1,6) Enzyme deficiency Abnormal glycogen: associated with tissue damage ``` Symptoms: Progressive liver cirrhosis (transplant by age 4 – 6 YRS) Hepatosplenomegaly, failure to thrive Nonprogressive form: mild mutations Cardiomyopathy Muscle: Neonatal severe hypotonia and muscle weakness Childhood muscle weakness Neuropathy ``` Diagnosis: pathology on muscle biopsy, enzyme assay in liver or fibroblasts, mutation analysis Prognosis: mutation analysis can aid Treatment: supportive

Answer 187

Deficiencies in: Glycogen Phosphorylase (GSD VI) Glycogen Phosphorylase kinase (GSD IX) ``` Debranching Enzyme (GSD III) debranching enzyme: α-1,6-glucosidase GSD-IIIA: deficiency in liver and muscle (85%) GSD-IIIB: deficiency in liver only (15%) ``` Initial presentation: Similar to GSD-I: hypoglycemia, hepatomegaly, growth retardation, mildly elevated cholesterol lactate and uric acid normal Elevation of liver enzymes, fasting ketosis ``` Late presentation: Cardiomyopathy Myopathy (3-4th decade) Polyneuropathy Cirrhosis Abnormal glycogen causes tissue (Liver, heart, muscle) damage ``` Treatment: Continuous glucose, raw cornstarch, to keep BG >70 High protein diet may help myopathy and growth failure

Answer 188

Pyruvate Carboxylase and PEP Carboxykinase: rare- probably lethal Fructose-1,6-bisPO4ase deficiency Hypoglycemia: late and mild Metabolic acidosis: severe lactic acidosis Normal lactate/pyruvate ratio Often acidosis with Kussmaul breathing primary symptom Ketones present and appropriate Mildly elevated liver enzymes, no ammonia TREATMENT: Acute: give glucose -> will correct lactate Give bicarbonate sparingly, acidosis corrects with glucose Prevention: avoid long fasting, uncooked cornstarch at night Prompt treatment of hypoglycemia

Answer 189

Due to deficiency in Aldolase B which splits Fructose 1 P into 3 carbon intermediates that can enter glycolysis. Effect is accumulation of fructose 1P which has toxic effects on liver, kidney and brain Symptoms occur with the introduction of fruits and other sources of fructose in the diet in the first year of life (not at birth or in the first few months) Symptoms: nausea, vomiting, sweating, lethargy, hypoglycemia, hepatomegaly Increased liver function tests, may progress to severe liver injury. Renal dysfunction may be present Treatment is avoidance of fructose/sucrose/sorbitol in the diet.

Answer 190

total E= how many calories you get to eat (related to lean/total body mass) -some % of fat, carb, and protein total E= 25-35 kcal/kg; simply remember 30kcal/kg body weight ex 50kg woman= 1500cal/day 30% fat = 450 cal 9 cal/g fat = 50g fat per day 50% carb = 750 cal 4 cal/g carb = 187.5g carbs per day 20% protein = 300 cal 4 cal/g protein = 75g protein per day

Answer 191

saturated fat- no double bonds stack on e/o easily; solid at room temp unsaturated- double bonds cis bonds typically omega 6 and 3 are essential fatty acids trans fat- a trans double bond "partially hydrogenated" modified by food industry (no kinks)- solid at room temp -don't have enzymes to handle these well; bad for pts

Answer 192

33-37% fat 50% of fat is sat 15% protein- mostly animal 48-52% carbs- almost 1/3 from simple sugars ``` BIGGEST changes in modern diet: inc omega-6 fat (corn oil) trans fat reduced whole grains and fiber inc total E intake (calories), no fasting ``` it's more what type of fat you eat than how much fat you eat -probably want more monounsat fat (olive, canola) than polyunsat (sunflower, corn)

Answer 193

high fat often means high calorie diets- E dense observational studies- suggest all fats aren't equal - type of fat, vs amount of fat - sat fats and trans fats are probably worse for you- higher risk of CAD - omega 3 and omega 6 FAs appear to lessen risk for CAD higher cholesterol levels also gives you higher CAD risk -but DIETARY cholesterol doesn't really affect plasma cholesterol gold standard data- long term, randomized clinical trials in humans

Answer 194

fish/omega-3 fatty acids although controversial, evidence for dec: sudden death arrhythmias triglycerides thrombosis coronary morbidity and mortality in pts w/ CHD plant sterols structurally similar to cholesterol but isolated from plant fats made commercially into margarine-like products inhabit cholesterol abs from the intestine 1-3g/day lowers LDL cholesterol

Answer 195

low carb vs low fat diet: no difference in weight loss at 2 yrs both reasonable diets for weight loss low carb diet may help you lose more weight, but low fat diet may help you lose more fat mass diff in weight, but essentially no diff in fat loss the best predictor of weight loss is compliance!! diet composition doesn't matter much for weight loss no advantage to low carb diets adherence w/ tx plan is most important low carb and mediterranean diet are reasonable options, may be better in some

Answer 196

total calories, positive E balance- most important thing Bessessen thinks - -- weight gain!! and obesity - reversing pos E balance has strong protective effect relative amounts of fat or carbs; types of fat play secondary role, Bessesen thinks ``` high fat diets- cause insulin resistance worse w/ saturated fats omega 6's almost as bad monounsat's and fish oils may be neutral or beneficial ``` "gold standard" approach is low fat diet w/ modest caloric restriction, although Mediterranean diet might be alternative