Role of incretins in glucose homeostasis and diabetes

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 ClassMode of ActionΔ (%) HgbA1c Δ Wt.HypoglycemiaSide Effects, including GI Symptoms
Thiazolidinediones
(e.g., pioglitazone)
↓ peripheral insulin resistance
↑ glucose disposal
↓ HGP
0.5-1.5↑NoTransaminitis, hepatotoxicity, edema, CHF
Biguanides
(e.g., metformin)
↓ HGP
↓ peripheral insulin resistance
1-2↓NoDiarrhea, bloating, indigestion, lactic acidosis
Sulfonylureas
(e.g., glipizide, glyburide)
↑ pancreatic insulin secretion1-2↑YesRare symptoms of diarrhea, constipation, etc.
Meglitinides
(e.g., repaglinide)
↑ pancreatic insulin secretion1-2↑YesRare symptoms of diarrhea, constipation, etc.
D-phenylalanine derivatives
(e.g., nateglinide)
↑ pancreatic insulin secretion1-2↑YesRare 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 tract0.5-1—NoAbdominal pain, diarrhea, bloating, flatulence
Bile acid sequestrants
(e.g., colesevelam)
↓ reabsorption of bile in GI tract0.5-1—NoIndigestion, nausea, constipation
Amylin mimetics
(e.g., pramlintide)
↓ glucagon
↓ glucagon
& ↓ HGP
↓ gastric emptying
↑ satiety
0.5-1↓YesNausea, 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

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