Role of incretins in glucose homeostasis and diabetes
- Oral intake of food stimulates the intestine to produce incretins (i.e., glucagon-like peptide 1 [GLP-1] and gastric inhibitory peptide).
- These peptides enhance insulin release, reduce glucagon secretion, and delay gastric emptying.
GLP-1 has a short half-life and is degraded within minutes by the enzyme dipeptidyl peptidase 4 (DPP-4). Two new classes of drugs for the treatment of type 2 diabetes were developed based on this mechanism.
- GLP-1 analogues (resistant to DPP-4 degradation)
- B. Dipeptidyl dipeptidase inhibitors (delay GLP-1 degradation)
Noninsulin Antidiabetic Agents
| Drug Class | Mode of Action | Δ (%) HgbA1c Δ Wt. | Hypoglycemia | Side Effects, including GI Symptoms |
|---|---|---|---|---|
| Thiazolidinediones (e.g., pioglitazone) | ↓ peripheral insulin resistance ↑ glucose disposal ↓ HGP | 0.5-1.5↑ | No | Transaminitis, hepatotoxicity, edema, CHF |
| Biguanides (e.g., metformin) | ↓ HGP ↓ peripheral insulin resistance | 1-2↓ | No | Diarrhea, bloating, indigestion, lactic acidosis |
| Sulfonylureas (e.g., glipizide, glyburide) | ↑ pancreatic insulin secretion | 1-2↑ | Yes | Rare symptoms of diarrhea, constipation, etc. |
| Meglitinides (e.g., repaglinide) | ↑ pancreatic insulin secretion | 1-2↑ | Yes | Rare symptoms of diarrhea, constipation, etc. |
| D-phenylalanine derivatives (e.g., nateglinide) | ↑ pancreatic insulin secretion | 1-2↑ | Yes | Rare symptoms of diarrhea, constipation, etc. |
| Incretin mimetics (e.g., exenatide, liraglutide) | ↑ glucose-dependent insulin release ↓ glucagon secretion and HGP ↓ gastric emptying | 0.5-1.5↓ | Yes * | Nausea, vomiting diarrhea, constipation, hyperbilirubinemia, pancreatitis, pancreatic cancer, thyroid c-cell tumors, hypersensitivity reactions |
| DPP-4 inhibitors (e.g., sitagliptin, linagliptin) | ↓ breakdown GLP-1 ↑ incretin effects ↑ insulin release, ↓ glucagon release, ↓ gastric emytying | 0.5-1.5— | Yes * | Pancreatitis, pancreatic cancer, abnormal LFT, nasopharyngitis, URI, headache, hypersensitivity, skin reactions |
| Alpha-glucosidase inhibitors (e.g., acarbose) | ↓ breakdown and absorption carbohydrates in the GI tract | 0.5-1— | No | Abdominal pain, diarrhea, bloating, flatulence |
| Bile acid sequestrants (e.g., colesevelam) | ↓ reabsorption of bile in GI tract | 0.5-1— | No | Indigestion, nausea, constipation |
| Amylin mimetics (e.g., pramlintide) | ↓ glucagon ↓ glucagon & ↓ HGP ↓ gastric emptying ↑ satiety | 0.5-1↓ | Yes | Nausea, indigestion, abdominal pain |
CHF, Congestive heart failure; GI, gastrointestinal; GLP, glucagon-like peptide; HGP, hepatic glucose production; LFT, liver function test; URI, upper respiratory infection.
* Especially in combination with insulin or insulin secretagogues
