IDM Exam 3

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)

1. Convert weight to kg

2. Find total daily dose (kg x 0.5 units/kg/day)

3. 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