T2DM

Question 1

composition of islets of Langerhans

Answer 1

1. beta cells produce insulin to lower BG by increasing glucose uptake, marcomolecule synthesis, and inhibition of TG breakdown
2. alpha cells produce glucagon to raise BG via liver glycogenolysis and gluconeogenesis
3. delta cells produce somatostatin
4. F cell produce pancreatic polypeptide

Question 2

diabetes overview

Answer 2

1. diabetes is a group of metabolic disease characterized by hyperglycemia
2. type I is the inability to regulate BG due to deficient insulin secretion from beta cells
3. type II is the inability to reg BG due to lack of insulin sensitivity in normally insulin-sensitive tissues

Question 3

glucose regulation
1. insulin
2. exercise and glucose uptake

Answer 3

1. insulin increases the speed of glucose uptake from blood into cells, with insulin res lose the ability stim translocation of GLUT4 transporter (how majority glucose gets transported), still able to transport glucose through GLUT1 but much slower, BG rises
2. exercise can induce GLUT4 translocation, allowing skeletal muscle to act as a glucose sink

Question 4

T1DM therapeutic intervention
1. monitoring glucose
2. exogenous insulin
3. insulin delivery

Answer 4

1. BG measured throughout day to keep BG in noroglycemic range (70-180 mg/dL)
2. since beta cells cannot produce insulin, deliver exogenous insulin; 4 types: rapid-acting controls spike, short-acting is regular insulin peaking at 2-3 hr, intermediate-acting allows peak in 4-12 hrs, and long-acting with no peaks working over 24 hr
3. insulin injected into subQ fat with needle, modern ver use BG monitor which detects increase in glucose and signal tube under skin to release of rapid-acting insulin from pump

Question 5

diabetes epidemiology
1. overview
2. T2DM risk factors

Answer 5

1. type I and type II affect 15% if pop; with 5-10% T1DM and 90% T2DM; diabetics x3 more likely to be hospitalized with CVD
2. age due to dysreg of cellular functions, POC, family history of T2DM or genetic factors; symptoms of MetS, obesity, poor lifestyle choices

Question 6

T2DM clinical manifestations
1. non-specific clinical manifestation
2. long term manifestation
3. mechanisms and pathogenesis

Answer 6

1. have symptoms of MetS such as overweight, dyslipidemia, hyperinsulinemia, and high BP; fatigue, classical symptoms of polyuria, polydispsia, and polyphagia (too much urination, drinking, and eating); unexplain weight loss due to poor metabolic cycling (glucose cannot be uptaken, fats and proteins are broken down to provide fuel); recurrent infections (high BG breakdown neural and vascular tissue) and poor wound healing (breeding ground for organisms consuming glucose)
2. microvascular and macrovascular complications and steatohepatitis
3. due to B cell dysfunction, insulin res, whole body chronic inflammation

Question 7

insulin resistance and altered beta cell physiology

Answer 7

dysregulation of BG feedback sys begins when too much glucose is in body for long time, beta cells become stressed/overactive and hypertrophy to compensate for high BG; beta cells fail, ratio of alpha to beta cells increase and beta cell sensitivity decrease, dev glucolipotoxicity and insulin res; beta cells then undergo differentiation and death, decreasing beta cell mass by 30-40% leading to diabetes

Question 8

genetic vs. lifestyle factors of T2DM

Answer 8

1. mother > father T2DM risks; SNP in adipocyte TCF7L2 (Wnt signalling pathway) increase risk by 10-20% and in vitro or in vivo inactivation of TCF7L2 increase adipocyte hypertrophy and insulin res; however 55% of people w/o T2DM have risk allele so influence of genetics is less than influence of lifestyle
2. obesity is the single most important predictor; 90% of cases are preventable by following healthy habits

Question 9

multiorgan cause of chronic hyperglycemia: adipose tissue

Answer 9

1. adipose tissue produce leptin and adiponectin, obesity increases leptin decreases leptin sensitivity, gen less satiety
2. decreases adiponectin decrease BG reg high food intake increase BG, increases inflammation and decrease insulin sensitivity
3. adiposity assoc with high amounts of serum (bound to albumin) FFAs, inflammatory cytokine TNF alpha, and decrease insulin receptor density, all of which increase inflammation and insulin sensitivity

Question 10

multiorgan cause of chronic hyperglycemia: pancreas

Answer 10

altered inuslin and glucagon signaling, decrease amylin (beta cell hormone secreted with insulin to increase saitety and decrease glucagon release)

Question 11

multiorgan cause of chronic hyperglycemia: GI tract

Answer 11

Increase ghrelin (stim hunger and food intake) produced in GI cells for insulin res and decrease fasting insulin; decreased beta cell sensitivity to GLP1 and GIP (big moderating factor of insulin secretion)

Question 12

multiorgan cause of chronic hyperglycemia: kidneys

Answer 12

reabsorb glucose from urine using sodium glucose cotransporter 2, high glucose saturates SGLT2 and left over glucose goes into urine but high uptake at kidneys worsens hyperglycemia

Question 13

multiorgan cause of chronic hyperglycemia: brain

Answer 13

manages satiety, insulin, and glucose detection, brain uses 20% of body glucose at rest; high glucose cause neuroinflammation, GLUT1 and GLUT3 have impact on neuro condition such as Alzheimers

Question 14

1. inflammation in dysfunctional adipose cells
2. dev of insulin res

Answer 14

1. functional adipocytes have high amounts of O2, able to produce lots of ATP; dysfunctional addipocyte stores high amt of TG, hypertrophied, less O2 per cell, decrease ATP production leading to cell death and secrete TNF alphha which recruites macrophages to release more inflammatory cytokines
2. TNF alpha inhibit IRS, blocking downstream cascade at the start; cannot uptake FFA to be stored and move FFA to blood thus high serum FFA

Question 15

1. insulin signalling in skeletal muscle on metabolism
2. adiposity on dev of insulin res

Answer 15

1. insulin bind to receptor, IRS trigger signalling cascade to bring in glucose and FFA; conversion of FFA produce ceramides and DAG, DAG converted to TAG (triacylglycerol) for fuel; GLU either converted to glycogen or metabolize by mitocondria
2. bring in high amount of circ FFA, accumulating high amounts of ceramides and DAG, DAG inhibit IRS and thus insulin signalling and ceramides dysregulate AKT and PKB for GLUT4 translocation, less GLU uptake; mitocondria working harder to use up extra E, breakdown due to excessive use due to gen of high amounts of reactive oxidative species

Question 16

assessing and diagnosising T2DM
1. parameter
2. short and long term post prandic response

Answer 16

1. high HbA1c is glycated (chem linked) hgb, high fasting plasma glucose (not able to take in glucose as well due to insulin res), 2 hr plasma OGTT (measure ability to use glucose over 2 hours, homeostatic model assessment for insulin res (HOMA-IR) comp fasted GLU to insulin
2. after OGTT area under the curve (decreasing BG curve) should return to normal after 120 mins, in the long term measure HbA1c at 90 days to see how much hgb is glycated; glycated hgb cause dmg since glucose crystals in blood physically scratch body, increases inflammation

Question 17

metformin for T2DM
1. mechanism
2. risks

Answer 17

1. most commonly prescribed med to decrease hepatic GLU production and HbA1c by decreasing mitochondrial oxidative phosphorylation, decrease liver gluconeogenesis via AMPK activation, decrease ability to use new glucose and force body to use existing GLU
2. induces lactic acidosis to decrease gluconeogenesis

Question 18

glucagonlike pepetide 1 agonist
1. GLP1 function
2. Ozempic mechanism
3. risks of Ozempic

Answer 18

1. GLP1 responds to elevated BG and induces insulin secretion, is broken down by DDP4
2. Ozempic chem identical to GLP1 but is res to DDP4 thus able to mimic the effects of GLP1 to increase insulin secretion, decrease glucagon secretion, and decrease gastric emptying
3. Weight loss of both SM and AT, if gain back as fat, net loss in SM is significant on overall health and glycemic control

Question 19

exercise molecular mechanisms on T2DM

Answer 19

exercise increase Ca2+, increase calmodulin which causes cascade of events inducing exercise induced GLUT4 translocation and increase AMPK which inhibits AS160 allowing GLUT4 translocation

Question 20

T2DM management types
1. diet
2. exercise
3. medications
4. lifestyle vs. medication

Answer 20

1. prevents large spikes in glucose
2. facilitate glucose uptake and promote weight loss (less adiposity less inflammation)
3. increase insulin sensitivity, slow digestion, block renal GLU reabsorption, increase insulin
4. longitudinal study over 5 years, lifestyle intervention has greater decrease in risk of T2DM over metformin, decrease metformin with increase E expenditure per week

Question 21

T2DM management exercise
1. acute changes
2. chronic changes

Answer 21

1. stim increase contraction-induced GLUT4 translocation and increases insulin sensitivity for 24-72 hours to manage BG
2. decrease adiposity by decreasing serum FFA and decrease inflammation by using TG stores, produce less TNF alpha, less use of mitochondria to use up fuel, less reactive O2 species, mitochondria can stay healthy; increase mitochondria and mitochondria enzymes increases efficiency

Question 22

END vs. HIIT on T2DM

Answer 22

1. trad END is well documented in preventing and treating T2DM, usually at lower intensity, better tolerated
2. HIIT can provide great effects for shorter time but may not be tolerated by all, may need start very light and build up
3. both END and HIIT improve VO2max and HbA1c but HIIT shows greater improvement; other variables such as FPG, fasting insulin, insulin res, BP, blood lipid, etc., more research needed

Question 23

creating exercise programming for T2DM
1. ACSM and CSEP recommendations
2. exercise timing

Answer 23

1. primary focus on decreasing adiposity, some exercise is better than none but recommend doing CV, strength, muscular END, and flexibility/balance throughout the week
2. reduce glucose spikes by exercising before meal to increase GLUT4 translocation before, longer durations of aerobic are best for long term glucose management throughout the day but resistance is also effective since it greatly increases Ca2+ to stim GLUT4 and increased muscle mass allows for greater ability to uptake glucose and decrease HbA1c; best performs bouts less than 72 hours apart to maintain level of GLUT4 translocation

Question 24

considerations of exercise and T2DM

Answer 24

1. SNS activity can lead to hyperglycemia but stimuli typically not strong enough, too muscle glucose uptake leads to hypoglycemia but hard to exercise long enough for this to occur, usually more related to poorly timed insulin dosage
2. check that glucose is in normal range and no recent insulin intake or other medications that can affect exercise before starting

Question 25

Insulin signalling in adipose tissue

Answer 25

insulin bind to insulin receptor and IRS trigger casade, activating PI3Kp (p=phos) and PDKp, PDKp activates PKC delta and AKT, PKC delta signals GLUT4 movement and AKT inhibit AS160 (AS160 inhibits translocation) to induce translocation of GLUT4 and FAT CD36 to transport GLU and FFA into cell respectivity, FFA and GLU then be stored as TG in lipid droplet in cell; when need fuel, can breakdown TG into FFA and transport into blood for use