Moa of all anti diabetics

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I now have comprehensive information on all antidiabetic drug classes. Let me compile the full answer.

Mechanism of Action of All Antidiabetic Drugs

Here is a systematic breakdown of every major class, based on Lippincott Illustrated Reviews: Pharmacology and Tintinalli's Emergency Medicine.

1. Insulin

Insulin binds to its receptor (a tyrosine kinase receptor) on target cells (liver, muscle, fat), triggering a signaling cascade that:

Stimulates glucose uptake into muscle and adipose tissue (via GLUT-4 translocation)
Promotes glycogen synthesis and inhibits glycogenolysis in the liver
Inhibits gluconeogenesis
Promotes lipogenesis and inhibits lipolysis
Promotes protein synthesis

Key preparations by onset/duration:

Type	Examples	Onset	Duration
Rapid-acting	Lispro, Aspart, Glulisine	5-15 min	3-5 hr
Short-acting	Regular insulin	30-60 min	6-10 hr
Intermediate	NPH	1-2 hr	16-24 hr
Long-acting	Glargine, Detemir	1-4 hr	20-24 hr
Ultra long-acting	Degludec	1 hr	>42 hr

2. Biguanides - Metformin

MOA: Activates AMP-activated protein kinase (AMPK), which reduces hepatic insulin resistance. This leads to:

Decreased gluconeogenesis and hepatic glucose production (primary effect)
Some improvement in peripheral insulin sensitivity
Does NOT stimulate insulin secretion - therefore no hypoglycemia risk as monotherapy
Also reduces intestinal glucose absorption

Key point: Contraindicated in eGFR <30 mL/min due to lactic acidosis risk.

Lippincott Illustrated Reviews: Pharmacology, p. 821

3. Sulfonylureas

MOA: Bind to the sulfonylurea receptor (SUR1), a subunit of the ATP-sensitive K+ channel on pancreatic beta-cell membranes.

Binding → K+ channel closes → membrane depolarizes → voltage-gated Ca²+ channels open → Ca²+ influx → insulin granule exocytosis

Stimulate insulin secretion regardless of blood glucose level (hence hypoglycemia risk)
1st generation: Chlorpropamide, tolbutamide, tolazamide
2nd generation (preferred): Glipizide, glyburide, glimepiride, gliclazide

ADRs: Hypoglycemia (most common with this oral class), weight gain

4. Meglitinides (Glinides)

MOA: Same as sulfonylureas - close ATP-sensitive K+ channels on beta cells → insulin secretion. However, they bind at a different site on the SUR receptor.

Faster onset, shorter duration - act postprandially (taken with meals)
Drugs: Repaglinide, Nateglinide
Lower hypoglycemia risk vs. sulfonylureas due to short action
Useful in patients with irregular meal schedules

5. Thiazolidinediones (TZDs / Glitazones)

MOA: Bind to and activate Peroxisome Proliferator-Activated Receptor-gamma (PPAR-γ) in the nucleus of muscle, fat, and liver cells.

PPAR-γ activation → modulates gene transcription → increases expression of GLUT-4 and other genes involved in glucose and lipid metabolism → decreased insulin resistance in peripheral tissues (muscle > adipose)

Also lowers free fatty acid levels by promoting their storage in adipocytes.

Drugs: Pioglitazone, Rosiglitazone
No hypoglycemia risk (insulin sensitizers, not secretagogues)
ADRs: Weight gain, fluid retention, bone fractures, risk of HF; contraindicated in liver disease

6. DPP-4 Inhibitors (Gliptins)

MOA: Inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), which normally rapidly degrades incretin hormones (GLP-1 and GIP).

By blocking DPP-4 → increased circulating GLP-1 and GIP levels → glucose-dependent insulin release from beta cells and suppression of glucagon from alpha cells

Effect is glucose-dependent: only active when glucose is elevated, so very low hypoglycemia risk
Drugs: Sitagliptin, Saxagliptin, Alogliptin, Linagliptin (does not need renal adjustment), Vildagliptin
Do NOT combine with GLP-1 receptor agonists (overlapping mechanism)
ADRs: Pancreatitis risk, nasopharyngitis, urinary tract infections

7. GLP-1 Receptor Agonists (Incretin Mimetics)

MOA: Mimic the action of Glucagon-Like Peptide-1 (GLP-1), an incretin hormone released from intestinal L-cells after meals. They activate GLP-1 receptors to:

Stimulate glucose-dependent insulin secretion from beta cells
Suppress glucagon secretion from alpha cells
Slow gastric emptying → reduce postprandial glucose
Promote satiety → reduce appetite and body weight
Have cardioprotective and renoprotective effects (especially dulaglutide, liraglutide, semaglutide)

Drugs: Semaglutide (oral/SC), Liraglutide, Dulaglutide, Exenatide, Lixisenatide, Tirzepatide (dual GLP-1/GIP agonist)
No hypoglycemia as monotherapy (glucose-dependent action)
ADRs: Nausea, vomiting, diarrhea, pancreatitis risk; contraindicated in medullary thyroid carcinoma history

8. SGLT2 Inhibitors (Gliflozins)

MOA: Inhibit Sodium-Glucose Co-transporter 2 (SGLT2) in the proximal convoluted tubule of the kidney.

Normally, SGLT2 reabsorbs ~90% of filtered glucose. Inhibiting SGLT2 → glucose is not reabsorbed → glucosuria (glucose excreted in urine) → blood glucose falls.

Also causes osmotic diuresis and natriuresis → blood pressure reduction; cardiorenal protective effects independent of glucose lowering (benefit in HFrEF and HFpEF).

Drugs: Empagliflozin, Dapagliflozin, Canagliflozin, Ertugliflozin
No hypoglycemia risk as monotherapy
Avoid in severe renal impairment (eGFR <30)
ADRs: Genital mycotic infections (most common), UTIs, DKA (euglycemic), Fournier's gangrene, bone fractures (canagliflozin)

9. Alpha-Glucosidase Inhibitors

MOA: Reversibly inhibit alpha-glucosidase enzymes in the intestinal brush border, which normally break down complex carbohydrates into absorbable monosaccharides.

Inhibition → delayed carbohydrate digestion → flattened postprandial glucose peak (lower postprandial hyperglycemia)

Drugs: Acarbose, Miglitol
No hypoglycemia as monotherapy (no effect on insulin secretion)
Must be taken at the start of each meal
ADRs: Flatulence, diarrhea, abdominal cramping (limits clinical use)
Important: Hypoglycemia in combination must be treated with glucose (not sucrose - sucrase is also inhibited)

10. Amylin Analog - Pramlintide

MOA: Synthetic analog of amylin, a hormone co-secreted with insulin from beta cells. Mimics amylin's effects:

Delays gastric emptying → slower glucose absorption
Suppresses postprandial glucagon secretion
Increases satiety
Adjunct to mealtime insulin in both Type 1 and Type 2 diabetes
Given SC before meals; reduce mealtime insulin dose by 50% when initiating
ADRs: Nausea, vomiting; contraindicated in gastroparesis

11. Dual GIP/GLP-1 Agonist - Tirzepatide

MOA: Activates both GIP receptors and GLP-1 receptors (dual incretin agonist). Produces stronger glucose-lowering and weight-loss effects compared to GLP-1 agonists alone.

12. Other Agents (modest clinical use)

Drug	Class	MOA
Bromocriptine	Dopamine agonist	Mechanism for glucose lowering unknown; resets hypothalamic circadian rhythms affecting insulin sensitivity
Colesevelam	Bile acid sequestrant	Mechanism for glucose lowering unknown; possibly modulates bile acid signaling affecting glucose metabolism

Quick Reference Summary Table

Class	Example Drugs	MOA	Hypoglycemia Risk
Biguanides	Metformin	Activate AMPK → ↓ hepatic gluconeogenesis	No
Sulfonylureas	Glipizide, Glyburide	Close K-ATP channel → insulin secretion	Yes
Meglitinides	Repaglinide, Nateglinide	Close K-ATP channel (short-acting)	Rarely
TZDs	Pioglitazone	PPAR-γ agonist → ↓ insulin resistance	No
DPP-4 inhibitors	Sitagliptin, Linagliptin	Block DPP-4 → ↑ GLP-1/GIP levels	No
GLP-1 agonists	Semaglutide, Liraglutide	Activate GLP-1R → ↑ insulin, ↓ glucagon, ↓ gastric emptying	No
SGLT2 inhibitors	Empagliflozin, Dapagliflozin	Block renal glucose reabsorption → glucosuria	No
Alpha-glucosidase inhibitors	Acarbose	↓ Intestinal carbohydrate digestion	No
Amylin analog	Pramlintide	Delays gastric emptying, ↓ glucagon, ↑ satiety	No (with insulin: Yes)
Insulin	All types	Activates insulin receptor → ↑ glucose uptake	Yes

Sources: Lippincott Illustrated Reviews: Pharmacology, pp. 807-821; Tintinalli's Emergency Medicine: A Comprehensive Study, pp. 2647-2665

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