An ADAM17 selective inhibitor promotes glucose uptake by activating AMPK.

AMPK activation promotes glucose and lipid metabolism. Here, we found that our previously reported ADAM17 inhibitor SN-4 activates AMPK and promotes membrane translocation and sugar uptake of GLUT4. AMPK inhibitor dorsomorphin reversed this effect of SN-4, confirming that the effect is mediated by AMPK activation. In addition, SN-4 inhibited lipid accumulation in HepG2 under high glucose conditions by promoting lipid metabolism and inhibiting lipid synthesis. Although lactic acidosis is a serious side effect of biguanides such as metformin, SN-4 did not affect lactate production. Furthermore, SN-4 was confirmed to inhibit the release of TNF-α, a causative agent of insulin resistance, from adipocytes. In diabetes treatment, it is important to not only regulate blood sugar levels but also prevent complications. Our findings reveal the therapeutic potential of SN-4 as a new antidiabetic drug that can also help prevent future complications.

The Amount of Residual Incretin Regulates the Pancreatic ß-cell Function and Glucose Homeostasis.

The gastrointestinal tract is considered an important endocrine organ for controlling glucose homeostasis via the production of incretins. A 21-year-old man emergently underwent total colectomy due to severe ulcerative colitis, and overt diabetes became evident. Weekly administration of a glucagon-like peptide (GLP)-1 receptor agonist (RA) dramatically improved his glucose control. Levels of GLP-1 or gastric inhibitory polypeptide (GIP) were low at the baseline in the duodenum and serum of the patient. After 11 months of GLP-1RA treatment, his HbA1c worsened again, and intensive insulin therapy was necessary to control his glucose levels. Our report may explain the significance of residual incretin for maintaining the pancreatic ß-cell function.