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What is diabetes mellitus?
the inability of the body to regulate blood glucose levels
What is T1DM?
Lack of insulin production that results in elevated blood glucose levels
Increased urination, thirst, and hunger + weight loss
What is T2DM?
Insulin resistance (reduced uptake of glucose in cells)
T2DM patients have a reduced incretin effect, meaning they don't adequately stimulate insulin secretion when bindingdecreased glucose levels between meals or while sleeping -> to specific receptors on beta cells
In the pancreas, alpha cells secrete...
glucagon (increases plasma glucose, catabolic)
In the pancreas, beta cells secrete...
insulin (decreases plasma glucose, anabolic)
amylin (decreases plasma glucose, slows gastric emptying)
Structure of insulin
active insulin is composed of A and B chain C-peptide is the connecting peptide and it is co-secreted with insulin
Insulin release is stimulated by
hyperglycemia (GLUT-2)
byproducts of food/nutrient ingestion (amino acids, K+, free fatty acids)
parasympathetic activation
hormones (GIP, CCK, GLP-1)
sulfonylurea drugs
Insulin release is inhibited by
hypoglycemia
exercise
sympathetic activation (alpha-2 receptor inhibition)
somatostatin
Function of GLUT2
stimulate insulin release from BETA-CELL (pancreas)
Function of GLUT4
allows glucose entry into cell (adipose tissue and skeletal muscle cells)
What is the action of insulin?
binds to insulin receptor on muscle, liver and fat cells
in muscle and fat cells, causes translocation of GLUT-4 to cell surface, which leads to uptake of glucose
promotes glucose uptake, glycogenesis, lipogenesis
Define glycogenesis (Does insulin/glucagon increase or decrease?)
formation of GLYCOGEN and storage in liver and muscle
insulin: increased
glucagon: decreased
Define glycogenolysis (Does insulin/glucagon increase or decrease?)
breakdown of GLYCOGEN from storage
insulin: decreased
glucagon: increased
Define glycolysis (Does insulin/glucagon increase or decrease?)
breakdown of GLUCOSE to release ATP (cellular respiration)
insulin: increased
glucagon: decreased
Define gluconeogenesis (Does insulin/glucagon increase or decrease?)
formation of GLUCOSE from non-glucose sources
insulin: decreased
glucagon: increased
Define ketogenesis (Does insulin/glucagon increase or decrease?)
production of KETONE bodies during metabolism of fats
insulin: decreased
glucagon: increased
Define lipogenesis (Does insulin/glucagon increase or decrease?)
conversion of FATTY ACIDS and glycerol into fats (storage fats)
insulin: increased
glucagon: decreased
Define lipolysis (Does insulin/glucagon increase or decrease?)
breakdown of stored FATS to release fatty acids
insulin: decreased
glucagon: increased
Define protein degradation (Does insulin/glucagon increase or decrease?)
breakdown of PROTEIN into amino acids
insulin: decreased
glucagon: increased
Define protein synthesis (Does insulin/glucagon increase or decrease?)
creation of polypeptides by amino acids
insulin: increased
glucagon: decreased
Major physiologic action of glucagon in regulating blood glucose levels
decreased glucose levels between meals or while sleeping -> decreases insulin -> glucagon secretion stimulation -> hepatic glycogenolysis, gluconeogenesis -> increase blood glucose levels
Pathophysiologic events resulting in T2DM
can be due to multiple defects
impaired insulin secretion
deficiency and resistance to incretin hormones
insulin resistance (skeletal muscle, adipose tissue, liver)
excess glucagon secretion
increased hepatic glucose production (liver)
upregulation of SGLT (kidney)
What are the main symptoms of T1DM?
polyuria (frequent urination) polydipsia (excessive thirst) polyphagia (excessive hunger) others: weight loss, DKA, dehydration, fatigue
Pathophysiologic events resulting in T1DM
autoimmune destruction of beta-cells of the pancreas (do not make insulin)
Risk factors for T2DM
> 45years old
family history
overweight/obese
HTN
dyslipidemia
history of GDM
What are the main symptoms of T2DM?
polyuria (frequent urination) polydipsia (excessive thirst) polyphagia (excessive hunger) others: weight gain, fatigue, risk of infections, CV complications may be asymptomatic
What is gestational diabetes mellitus (GDM)?
hormone changes during pregnancy results in increased insulin resistance
Ultra rapid acting insulin onset
15 min (take 15-30 min before meals - POSTPRANDIAL)
What is the leading cause of death in diabetes?
macrovascular complications (CHD, ASCVD, PAD)
Ultra rapid acting insulin
Lispro (Humalog) Aspart (Novolog)term-122 Glulisine (Apidra)
Rapid-acting/Short-acting insulin
Regular insulin (Humulin R, Novolin R)
Rapid-acting/Short-acting insulin onset
30 min (take 30-60 min before meals - POSTPRANDIAL)
Intermediate acting insulin
Neutral Protamine Hagedorn (NPH) - Humulin N, Novolin N (MAINTANENCE)
Long-acting insulin
Levemir (detemir) Lantus (glargine) (MAINTANENCE)
Ultra long acting insulin
Tresiba (degludec) (MAINTANENCE)
Sulfonylureas
Glyburide Glipizide Glimepiride
Sulfonylureas MOA
Bind to and close K+ ATP channel on pancreatic β-cell → depolarization of β-cell opens Ca2+ channel → Insulin release
Sulfonylureas major side effects
Weight gain
SE: Hypoglycemia
Meglitinides
Repaglinide Nateglinide
Meglitinides MOA
Bind to and close K+ ATP channel on pancreatic β-cell → depolarization of β-cell opens Ca2+ channel → Insulin release
Meglitinides major side effects
Weight gain
SE: GI upset, nausea, hypoglycemia
Biguanides
Metformin
Biguanides MOA
Decreases hepatic glucose production by INHIBITING GLUCONEOGENESIS: metformin indirectly activates AMP-dependent kinase (AMPK) which is normally activated when cellular energy ATP/AMP ratio is low (i.e.,decreased energy reserves). Activated AMPK phosphorylates and activates transcription factors which inhibit the expression of hepatic gluconeogenic genes
Biguanides major side effects
Weight neutral
SE: Lactic acidosis, ↓B12, Metallic taste, diarrhea
Metformin doses
500mg QD or BID
850mg QD
max effective dose: 1000mg BID
Alpha Glucosidase Inhibitors
Acarbose Miglitol
Alpha Glucosidase Inhibitors MOA
Competitive, reversible inhibition of alpha-glucosidase to prevent breakdown of carbohydrates into glucose. This delays digestion of carbs and therefore delays glucose absorption
Thiazolidinediones (TZD)
Rosiglitazone Pioglitazone
Thiazolidinediones (TZD) MOA
Increases tissue insulin sensitivity → enhances the insulin dependent uptake of fatty acids and glucose from plasma into fat/muscle
Thiazolidinediones (TZD) major side effects
Weight gain
SE: Fluid retention, bone fractures
GLP-1 Agonists
Exenatide Lixisenatide Liraglutide Semaglutide Dulaglutide
GLP-1 Agonists MOA
Enhance secretion of insulin in the presence of glucose. Slow the rate of absorption of glucose and other nutrients by delaying gastric emptying
GLP-1 Agonists major side effects
Weight loss
SE: Acute pancreatitis, Black box (thyroid cancer), acute renal failure
Liraglutide brand name
Victoza
Semaglutide brand names
Ozempic, Rybelsus
Exenatide brand name
Byetta, Bydureon
Dulaglutide brand name
Trulicity
Tirzepatide brand name
Mounjaro
Frequency = SUBQ QW
Exenatide, Tirzepatide, Semaglutide, Dulaglutide (frequency)
Frequency = SUBQ QD
Liraglutide (for frequency)
Frequency = PO QD
Semaglutide (Rybelsus) frequency
Dipeptidyl-peptidase-4 (DPP4) Inhibitors
Sitagliptin Saxagliptin Linagliptin Alogliptin
DPP4 MOA
Inhibit the metabolism of endogenous GLP-1 and GIP, thereby increasing their duration of effectiveness
DPP4 major side effects
Weight neutral
SE: Severe joint pain, Nasopharyngitis, Acute pancreatitis
Sitagliptin brand name
Januvia
Sitagliptin (Januvia) doses
100mg PO QD
Renal adjustment:
<30 mL/min: 25 mg QD
30-49 mL/min: 50mg QD
Amylin agonist
Pramlintide
Amylin MOA
Slow gastric emptying. Suppress post-prandial glucagon concentration
Amylin side effects
Weight loss
SE: Nausea
SGLT2 Inhibitors
Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin
SGLT2 MOA
Inhibition of SGLT2 inhibits transport of glucose from the renal tubule back into the bloodstream → glucose remains in the urine until it is excreted by urination
SGLT2 major side effects
Weight loss
SE: UTI, Bone fractures, Volume depletion (hypotension, dehydration, thirst)
Canagliflozin brand name
Invokana
Dapagliflozin brand name
Farxiga
Empagliflozin brand name
Jardiance
Canagliflozin (Invokana) doses
100-300mg before main meal
Dapagliflozin (Farxiga) doses
5-10mg QD
Empagliflozin (Jardiance) doses
10-25mg QD
Prediabetes classification
FPG: 100-125 mg/dL HbA1c: 5.7-6.4%
T2DM Diagnosis
FPG: >126 mg/dL HbA1c: >6.5% Random BG: >200 mg/dL
T2DM: HbA1C, FBG and 2 hour PPF goals?
HbA1c: <7% FBG: 80-130 mg/dL 2 hour PPG: <180 mg/dL
Nonpharmacological treatment/lifestyle changes for DM
physical activity (150 min/week), plate method (vegetables, grains/starch, protein)
First line treatment for T1DM
Insulin Lifelong treatment Basal + bolus insulin
First line treatment for T2DM
Metformin in patients w ASCVD include tx that will reduce CV risk +/- metformin
At what GFR level should you D/C metformin?
When less than 30 mL/min/1.73m
*GFR: >45 (no change) GFR: 30-45 (max TDD: 1000mg)
*do not initiate metformin if GFR <45
SGLT2i are contraindicated when GFR is...
<20-25 mL/min/1.73m2
What are the treatment options to minimize hypoglycemia without established ASCVD, CKD or HF? (+ metformin and lifestyle changes)
GLP-1 RA + SGLT2i + TZD + DPP4
What are the treatment options to minimize weight gain/promote weight loss without established ASCVD, CKD, or HF? (+ metformin and lifestyle changes)
What are the treatment options for patients WITH established ASCVD, high risk ASCVD or LVH?
GLP-1 RA + SGLT2i
GLP-1 RA (lira, sema, gluta) + SGLT2i (empa, cana)
What are the treatment options to minimize cost without established ASCVD, CKD, or HF? (+ metformin and lifestyle changes)
Sulfonylureas TZD
What are the treatment options for patients WITH heart failure?
SGLT2i (empagliflozin or dapagliflozin) Alternative tx: canagliflozin or ertugliflozin
What are the treatment options for patients with CKD?
SGLT2i (empagliflozin, canagliflozin, or dapagliflozin)
If not at goal utilize GLP-1 RA (liraglutide, semaglutide (SQ) or dulaglutide)
What medications have potential cardiovascular benefits?
Metformin + SGLT2i (canagliflozin, empagliflozin, ertugliflozin, dapagliflozin) + GLP-1 RA (liraglutide, semaglutide (SQ) or dulaglutide) + TZD (pioglitazone)
Inhaled insulin
Technosphere insulin (Afrezza)
Insulin delivery devices
Insulin vial and syringe
Insulin pens
Insulin pumps
What are continuous glucose monitors (CGMs)?
Measure interstitial glucose through use of a sensor which is placed below skin
Insulin initiation in T1DM
Initiated with both long-acting and rapid-acting insulin and is based on weight (0.5 units/kg/day)
Convert weight to kg
Find total daily dose (kg x 0.5 units/kg/day)
Divide daily dose (50/50) into long-acting and rapid-acting
Insulin initiation in T2DM
Initiate LONG-ACTING FIRST
dosing 10 units per day (fixed dosing) or 0.1 to 0.2 units/kg/day (weight-based)
Titration: 2 units every 3 days to reach FPG target (80-130 mg/dL)
Start insulin when there are signs of weight loss, symptoms of hyperglycemia, and elevated BG (A1c >10% or BG >300) OR not achieving goal despite use of multiple oral agents +/- GLP-1
Choosing between long-acting insulins
Degludec (Tresiba) - irregular lifestyle and adherence issues
NPH - cost issues (least expensive)
Glargine or detemir - medicare, medicaid
Initiating PRANDIAL insulin
Initiate when basal insulin is adequately titrated to FPG goal and A1c is not controlled OR basal dose is >0.5 units/kg/day and inadequate A1c control
*dosing: 4 units before largest meal (ONE meal) OR 10% or basal dose
Titrate by 1 to 2 units or 10-15% twice weekly
What is the preferred prandial insulin option?
Rapid-acting insulin