Estimated proinsulin processing activity of prohormone convertase (PC) 1/3 rather than PC2 is decreased in pancreatic β-cells of type 2 diabetic patients.
Type 2 diabetic (T2D) patients exhibit fasting relative hyperproinsulinemia owing to pancreatic β-cell dysfunction. To clarify the mechanism underlying this hyperproinsulinemic state, we evaluated the activities of the endopeptidases prohormone convertase (PC) 1/3 and PC2 in T2D patients. Fasting blood levels of intact proinsulin (IPI), total proinsulin (t-PI) and C-peptide were measured simultaneously, and intravenous glucagon loading was performed to investigate the dynamics of circulating proinsulin-related molecules released from pancreatic β-cells in 12 healthy volunteers and 18 T2D patients. Taking advantage of the 95% cross-reactivity between proinsulin and des-31,32-proinsulin (des-31,32-PI) with the human proinsulin radioimmunoassay kit used in this study, we estimated PC1/3 and PC2 activities using the following formulas: des-31,32-PI = (t-PI-IPI)/0.95; PC1/3 activity = des-31,32-PI/IPI; and PC2 activity = C-peptide/des-31,32-PI. C-peptide responses to glucagon were slightly lower among T2D patients. IPI and the IPI/C-peptide ratio were significantly higher in T2D patients (p<0.05 and p<0.01, respectively). There was no difference in des-31,32-PI levels or PC2 activity between the two groups. However, PC1/3 activity was significantly lower in T2D patients than in the control group (p<0.01). We propose that decreased activity of PC1/3 rather than PC2 in pancreatic β-cells is involved in the impaired proinsulin processing, resulting in elevated IPI levels in T2D patients.
Third Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
Sachihiko
S
Ozawa
Hidenori
H
Katsuta
Kiyoshi
K
Suzuki
Kazuto
K
Takahashi
Toshiaki
T
Tanaka
Yoshikazu
Y
Sumitani
Susumu
S
Nishida
Katsuhiko
K
Yoshimoto
Hitoshi
H
Ishida
D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D002096:C-Peptide / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005934:Glucagon / Q000008:administration & dosage; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008875:Middle Aged; D011384:Proinsulin / Q000378:metabolism*; D045664:Proprotein Convertase 1 / Q000378:metabolism*; D045706:Proprotein Convertase 2 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013223:Statistics as Topic
D002096:C-Peptide; D005934:Glucagon; D011384:Proinsulin; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2