Hepatic insulin clearance is increased in patients with high HbA1c type 2 diabetes: a preliminary report

Abstract

IntroductionHepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes. HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. However, hyperglycemia was suggested to enhance HIC, and it is not known whether poorly controlled diabetes increases HIC in patients with type 2 diabetes. We investigated whether HIC was increased in patients with poorly controlled diabetes, and whether HIC was associated with insulin resistance and incretins.Research design and methodsWe performed a meal tolerance test and the hyperinsulinemic–euglycemic clamp in 21 patients with type 2 diabetes. We calculated the postprandial C-peptide area under the curve (AUC)-to-insulin AUC ratio as the HIC; measured fasting and postprandial glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon levels and analyzed serum adiponectin and zinc transporter-8 (ZnT8) gene polymorphism.ResultsThe HIC significantly correlated with glycated hemoglobin (HbA1c) (r_S=0.58, p<0.01). In patients with high HIC above the median of 6.5, the mean HbA1c was significantly higher compared with low HIC below the median. Homeostatic model assessment (HOMA)-beta (r_S=−0.77, p<0.01) and HOMA-IR (r_S=−0.66, p<0.005) were correlated with HIC. The M/I value in the clamp study was correlated with HIC. GLP-1-AUC and GIP-AUC were not correlated with HIC. Glucagon-AUC was negatively correlated with HIC, but there were no significant differences between the high and low HIC groups. Adiponectin was positively correlated with HIC. The ZnT8 gene polymorphism did not affect HIC.ConclusionsThese results suggest that HIC was increased in patients with high HbA1c type 2 diabetes, low insulin secretion, low insulin resistance and high adiponectin conditions.

Hepatic and Extrahepatic Insulin Clearance in Mice with Double Deletion of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Receptors

“…In a previous study, it was shown that glucagon may be inversely related to insulin clearance [36]. It is also worth noting that, in our previous study on incretin hormone single knockouts, we found different glucagon secretion levels depending on the deleted incretin hormone receptor [34].…”

The sodium–glucose cotransporter 2 inhibitor ipragliflozin improves liver function and insulin resistance in Japanese patients with type 2 diabetes

“…The glucose clamp method was performed as we previously reported 8 , 19 . We performed the hyperinsulinemic-euglycemic clamp method to evaluate insulin sensitivity with an artificial endocrine pancreas (STG 55, Nikkiso, Japan).…”

“…One study reported that SGLT2i treatment increased insulin clearance after the meal tolerance test 7 . However, we previously reported that Japanese patients with poorly controlled T2DM showed increased hepatic insulin clearance 8 .…”

Targeting Insulin-Degrading Enzyme in Insulin Clearance

“…Over the past several decades, numerous studies have identified type 2 diabetes mellitus (T2DM) [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ] and obesity [ 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ] as determinant factors associated with impaired insulin clearance. Other metabolic abnormalities, such as non-alcoholic steatohepatitis [ 77 , 92 , 93 , 94 , 95 ], hepatic diseases [ 96 , 97 , 98 , 99 ], polycystic ovarian syndrome [ 100 ], and metabolic syndrome [ 101 , 102 ], as well as aging [ 78 , 103 , 104 ] and ethnicity [ 105 , 106 , 107 , 108 , 109 , 110 , 111 ], have also been linked to reduced insulin clearance.…”