DM Flashcards
insulin effect
- Increase uptake of glucose, translocate GLUT 4
- GLUT 4: muscle, adipose tissue
- GLUT2: kidney, liver, pancreatic b cell
- GLUT3: neurons
- Glycogenesis
- Glucose –> glycogen (storage in liver muscle)
- Also causes:
○ lipogenesis (FFA–> TG in adipose tissue)
Proteogenesis (aa –> proteins in muscle)
glucagon effect
- Glycogenolysis
- Glycogen –> glucose
- Lipolysis
- TGL –> FFA –> glycerol + ketones
- Proteolysis
- Protein –> aa
- Gluconeogenesis
- Aa –> glucose
Glycerol –> glucose
- Aa –> glucose
DM acute consequences
*Polyuria (excess urine production)
*Polydipsia (extreme thirst)
1) Excess BGL & urine
2) Osmotic diuresis
3) More urine produced
4) Dehydration
a) Decr blood vol –> peripheral circ failure –> renal failure –> death
b) Polydipsia –> cell shrink –> nervous system malfunction
*Polyphagia (appetite)
1) Incr glucose uptake
2) But still poor intake of glucose intracellularly
*Ketosis – rapid breathing
1) Use up other sources for energy
2) Decr TG synthesis & Incr lipolysis
3) Incr blood FA
4) Alternative energy source
5) Ketosis –> metabolic acidosis
a) Incr ventilation
b) Diabetic coma
i) Death (acidosis depress brain)
**fruity breath [acetone as by-product of fat metabolism]
*death
*weightloss
1) Decr aa uptake by cells + incr prot degradation
2) Muscle waste –> weight loss
3) Incr blood aa –> incr gluconeogenesis
4) Aggravates hyperglycemia (body has glucose but cannot use)
Degenerative blood vessels
□ Microvascular: retinopathy, nerve damage, kidney failure
□ Macrovascular: stroke, heart attack, reduce blood circ
Degenerative blood vessels
□ Microvascular: retinopathy, nerve damage, kidney failure
□ Macrovascular: stroke, heart attack, reduce blood circ
sx diabetes
Symptoms:
1) Tired
2) Weight loss
3) Slow wound healing
4) Sexual problems
5) Vaginal infections
6) Numb, tingling in feet
7) Blurry vision
8) Polydipsia,
9) polyphagia, polyuria
Incretins
Grp of metabolic hormones: released after eating
GIP (DPP4i)
GLP-1 (GLP1 Receptor agonist)
function of incretins
Augment secretory insulin released from pancreatic B cells of islets of Langerhans
Glucose-dependent manner – only when hyperglycemia
1) Gastric emptying in stomach
2) Glucose dependent insulin biosynthesis and secretion
i. Decr glucagon
ii. Improve b-cell function
3) Decr food intake (brain signal)
i. NV (common ADR)
Glucose-dependent insulinotropic polypeptide (GIP)
a. Insulin secretion
b. Expansion of pancreatic B cell
Glucagon-like peptide 1 (GLP-1)
a. Satiety
b. Gastric emptying decr
- Decr weight gain
METFORMIN MOA
- Incr glucose uptake into tissues
- Inhibit gluconeogenesis in liver
* Incr AMP-activated protein kinase - Enhance tissue sensitivity to insulin
* Uptake more glucose - Useful for obese pts
Weight loss and improve lipid levels
function of metformin
- Does not cause hyperinsulinemia
- No hypoglycemia
- Weight loss
- T2DM
- Alone/ other oral hypoglycemic agents
PK of metformins
A: PO, (duration 8-12hr)
D: rapidly distributed, minimal plasma protein binding
(T1/2 ~ 3hr)
M: NA
E: excreted unchanged in urine
- avoid in pt w/ renal insuff
- titrate
ADR of metformin
- Anorexia (LOA –> weight loss)
- GI disturbances
- Diarrhea, vomit indigestion, weight loss
- Take with/ after meal
- risk of Vit B12 def
- Malabsorption, more in LDC
CI of metformin
- Renal problems
- Lactic acidosis (hepatic, CVS problem)
Sulphonylurea MOA
- Glipizide
- Insulin secretagogues (2nd gen)
- Pancreatic b cells secrete insulin
1) SU bind to SU receptor proteins (subunit of K ATP channels)
2) Drug binding inhibits K ATP channel mediated K+ efflux
3) Depolarisation, Ca2+ influx
4) Trigger Ca dependent exocytosis of insulin granules
- from pancreatic B cells
glipizide function
Lowers BGL acutely
* Activate release of insulin from pancreas
* Depends on functioning B cells in pancreas islets
K ATP channel:
b cell ATP-sensitive K channel
- major role in control B cell mem potential
Glipizide: 2nd gen lower risk of hypoglycemia than other SU
PK of glipizide
A: PO
- F>95%, delayed with food intake
- (onset 0.5hr)
- (duration 12-24hr)
D: binds extensively 99% to plasma proteins (albumin)
(T1/2 ~ 4hr)
M: liver (90%)
E: <10% excreted unchanged in urine, feces
Metabolites: urine, feces
- avoid in renal insuff
- titrate
glipizide metabolism
- P1: hydroxylation
- liver disease, titrate
ADR of glipizide
- Hypoglycemia
- Elderly (poorer liver, kidney function)
*Weight gain
Sitagliptin
DPP-4i MOA
1) Binds, inhibit DPP4
2) Decr enzymatic degradation of GLP-1
3) Prolong action of endogenous insulin (by body)
* Stimulate B cells Release insulin (as if there is presence of glucose)
4) Suppress a- cell mediated glucagon release & hepatic glucose production
* Decr BGL (less glucagon)
DPP-4i function
- Incretin-based therapy
- Dipeptidyl peptidase-1 inhibitor
- less break down incretin
Mono: when MET not suitable/ no response
Combi: MET/ SU/ TZD + DPP4i
Triple:
Insulin+MET/
MET+SU/
MET+TZD
DPP4i PK
A: PO
- F ~ 87%
D: (T1/2 ~ 10-12hr)
M: low liver metabolism
E: 80% excreted in urine
- avoid in renal insuff
- titrate
DPP4i ADR
- GI disturbances
- Flu-like symptoms
- Headache, running nose, sore throat
- Skin reactions
DPP4i CI
- Pt with history of pancreatitis
GLP1 inhibited, incr B cell secretion —> Over stimulate pancreas
Liraglutide MOA
GLP-1 agonist
- Activate GLP-1 receptor
- Mem GPCR on Pancreatic B cells (conformational change)
- Activate adenylate cyclase
- Incr cAMP
- Incr PKA
a. Downstream activation - Incr insulin release and Decr glucagon release
- Insulin secretion subsides as blood glucose conc decr
- Approach euglycemia
structure of GLP-1 agonist
LA peptide (DPP-4 resistant form of GLP-1*)
- C16 FA prevents cleavage breakdown, incr t1/2
function of GLP1 agonist (pros and cons)
- Initial rapid release of endogenous insulin
- Suppress glucagon release
- Delay gastric emptying
- Reduce appetite (weight loss) – Manage obese pt
- Reduce risk of CVS death, non-fatal MI, HF among T2DM pt
Adjunct: for pt not achieve glycemic control w/ oral (first-line) anti-hyperglycemic agent - Expensive $$$ ($700/mnth)
PK of GLP1 agonist
A: SC, (OD dose –> 3mg maintenance dose)
F = 55%
D: C16 FA binds to plasma proteins (albumin)
(T1/2 ~ extend to 13hr)
M: endogenous metabolised in similar manner to large proteins w/o specific organ (non-specific catabolism)
E: 60% renal, 5% feces
Empagliflozin
SGLT2i MOA
- Inhibit sodium-glucose co-transporter-2 (SGLT2)
-Decr reabsorption of filtered glucose in Proximal tubules- Decr renal threshold for glucose
- Incr urinary glucose excretion
-Glucosuria
- DM pts have too high BGL, kidney unable to reabsorb , over saturated
*SGLT2i: stop reabsorption all tgt, just excrete as much glucose as possible
SGLT2i function
- Reduced risk of major cardiac event (11% in pt with asCVD)
- Reduce risk of composite endpt
- Worsening renal function
- Renal failure
- Renal death
- Similar benefit in those with OR w/o asth CVD
Dual: MET
Dual: SU
Triple: MET + SF
SGLT2i PK
A: PO
- F~ 60-80%
- Cmax 1-2h
D: (T1/2 ~ 12h) so only OD
- 90% plasma protein binding
M: meta in liver – Phase 2: glucuronidation (incr solubility)
E: 40% feces, 55% urine
SGLT2i ADR
- UTI
- Incr urination
- Female genital mycotic (fungal) infection
- Diabetic ketoacidosis
diabetes classification
metabolic disorder characterised by resistance to action of insulin, insuff insulin secretion or both
- clinical manifestation = HYEPRGLYCEMIA
types of DM
type 1
type 2
gestation DM
others (infection, monogenic DM syndrome, endocrinopathies, pancreatic destruction)
drug – steroids, HIV, immunosupp, Ab
removal of pancreas
T1 definition
Absolute deficiency of pancreatic b-cell function
- Immune mediated destruction
- Positive Ab
○ Islet cells
○ GAD
○ Insulin
○ Tyrosine phosphatases IA-2, 2b, zinc transporters 8 (ZnT8)
Autoimmune disease
T1 staging
1) Autoimmune (Ab+ve)
-Normoglycemia
- Presymp
2) Autoimmune (Ab+ve)
- Dysglycemia
- Presymp
3) New onset hyperglycemia
- Symptomatic
- (Ab+ve)
(onset is rapid)
NO C-peptide level, no insulin production
presentation in type 1
Young onset, <30yrs
Abrupt clinical presentation (when reach metabolic ketosis – high BGL)
Often thin appearance
type 1 DKA
Diabetic ketosis
* High risk
* Emergency as when BGL too high, insulin too low
* Body breaks down muscle –> ketones produced
* H+: acidity
T2 pathogenesis
- Progressive loss of adequate b-cell insulin secretion (background of insulin resistance)
- Insulin resistance
* Presence of insulin but glucose ultilisation (unable to ab from blood) is impaired* Hepatic glucose output incrs -- not respond to high BGL * Early stage: elevation in both glucose and blood insulin lvls
type 2 onset
(slow onset)
1) Normal insulin release
2) Reduced insulin release
- C-peptide present, remission
- Glucose abnormal –> Overt DM
3) Absent insulin release
- C-peptide absent
C peptide (insulin production)
short aa chain, by-product of insulin
Released into blood when insulin produced by pancreas
clinical presentation of type2
Often >40yrs, incr prevalent in obese children, younger adults
Gradual, still have insulin production
Often overweight appearance (metabolic syndromes)
type 2 metabolic syndrome
Risk of:
- DM, polycystic ovary syndrome, fatty liver
abdominal obesity + 2/4 of factors
- Abdominal obesity (waist circum)
○ M: >90cm
○ F: > 80cm
- TG > 1.7mmol/L , on meds (150mg/dL)
- HDL
- M: <1mmol/L (40mg/dL)
- W: <13 mmol/L (50mg/dL) - BP
- >130/85 mmHg, or on meds - Fasting glucose
- >5.6mmol/L (100mg/dL)
screening for Asx adults
screening at ANY age if risk factors
- metabolic syndrome, obese, gestational, HTN, HDLc/TG, PCOS, CVD
no risk factors = >40yo
- every 3 yrs for annual glucose tolerance
annual for IFG, IGT
hyperglycemia sx
Polydipsia
Polyuria
Polyphagia
Dry skin
Drowsy
Blurred vision
Decr healing
hypoglycemia sx
Shaking
Fast HR
Sweat
Dizzy
Anxious
Hunger
Impaired vision
Weakness, fatigue
Headache
Irritable
shared sx in both HYPER, HYPO
shake
dizzy
drowsy
hungry
fatigue
Parameters to measure DM control
1) Fasting plasma glucose (FPG)
2) Random, casual plasma glucose
3) Postprandial plasma glucose (PPG)
4) Hemoglobin A1c (HbA1c/ A1C)
Fasting plasma glucose (FPG)
No calorie intake for >8hrs
Random, casual plasma glucose
a. Glucose level at any time of the day
Regardless of meals
Postprandial plasma glucose
a. Glucose level measured after meal – 2hrs
b. Measured using standardised 75g oral glucose tolerance test (OGTT)
Hemoglobin A1c (HbA1c/ A1C)
a. Measure average amt of glucose in person’s blood over past 3mnths
b. Glucose stays attached to hemoglobin for lifespan of RBC ~120 days
HbA1c dependent on RBC count
RBC low = hbA1c low
RBC last longer than 120days, anemia = higher hbA1c
RBC shorter lfiespan = decr
vit B12 decr, less erythropoietin = incr
blood loss, incr erythropoietin = decr
blood transfusion (dilute) = decr
renal failure = decr
preg = decr
HbA1c = 3mnths average of _____
i. Fasting (FPG) + postprandial (PPG) combined
- Basal and postprandial contributes to hyperglycemia
- Basal hyperglycemia contributes more to high HbA1c
Use of glucometers
- Monitor hypo/hyperglycemia
○ Adjust meds, diet, exercise - Frequency varies
○ T1DM, preg women, insulin pump users
- >4 times daily
- Before meals/ snacks (3), bed time, 3am
T2DM freq of monitoring
> 3 times daily
-Often at practise setting: pt check before bfast & 2hrs after largest meal = 3times
□ Before fasting, after meal (2hrs after largest meal)
§ for pt: on multiple inj of insulin
§ For pt: less freq insulin inj/ noninsulin therapies/ medical nutrition therapy alone/ self monitor blood glucose (SMBG)
□ Guide for success of therapy
□ Monitor for glucometer use initially and at regular intervals
