Abstract
BackgroundUndercarboxylated osteocalcin (ucOC) is a secreted protein produced by osteoblasts that regulates insulin secretion and insulin sensitivity in rodents. However, the significance of these effects on glucose metabolism in human remains unknown. Moreover, the pathophysiological roles of ucOC on varying degrees of glucose intolerance, including diabetes need to be elucidated. In the present study, correlations between ucOC and indices of insulin secretion and sensitivity were analyzed in normal glucose tolerance (NGT), impaired glucose metabolism (IGM), and diabetes mellitus (DM) groups.MethodsBased on 75 g OGTT data in Japanese individuals without diabetic medication, or medications which may affect ucOC levels, individuals were classified as having normal glucose tolerance (NGT), impaired glucose metabolism (IGM), or diabetes (DM). In each group, 25 individuals were consecutively recruited [total 75 individuals, age: 65 ± 11 (mean ± SD); BMI: 24.9 ± 3.8 kg/m2]. QUICKI and Matsuda index (MI) were calculated as insulin sensitivity indices. Homeostasis model assessment (HOMA)-β and insulinogenic index (IGI) were calculated as insulin secretion indices. UcOC was measured using ECLIA. Normally-distributed loge-transformed (ln-) values were used for ucOC, HOMA-β, IGI, and MI.ResultsThe ucOC was not significantly different among the three groups. The results of multiple regression analysis showed that ln-ucOC did not significantly correlate with age, sex, BMI, waist circumference, fasting plasma glucose, plasma glucose 120 min after glucose loading, fasting plasma immunoreactive insulin, ln-HOMA-β, QUICKI, or ln-MI in any of the three groups. Interestingly, ln-ucOC correlated with ln-IGI (r = 0.422, P = 0.0354) and HbA1c (r = − 0.574, P = 0.0027) only in the DM group. There was no significant correlation between ln-IGI and age, sex, BMI, or HbA1c in the DM group. Further, the results of multiple regression analysis showed that ln-IGI could be independently predicted by BMI (β = 0.598, P = 0.0014) and ln-ucOC (β = 0.641, P = 0.0007) in the DM group (R2 = 0.488, P = 0.0006).ConclusionIn our study, ucOC positively correlated with insulin secretion independently of BMI in Japanese individuals with diabetes. These results suggest that ucOC plays more important roles in insulin secretion than in insulin sensitivity in individuals with diabetes.
Highlights
Undercarboxylated osteocalcin is a secreted protein produced by osteoblasts that regulates insulin secretion and insulin sensitivity in rodents
Laboratory examinations and anthropometric data Based on 75 g oral glucose tolerance test (75gOGTT) data, individuals were either classified as normal glucose tolerance (NGT), impaired glucose metabolism (IGM), or diabetes mellitus (DM) according to the 2006 World Health Organization (WHO) criteria [11] [NGT, fasting plasma glucose (FPG) < 110 mg/dL and 2-h plasma glucose (2-h PG) < 140 mg/dL; IGM, either impaired fasting glucose (IFG, FPG ≥ 110 and < 126 mg/dL) and/or impaired glucose tolerance (IGT, 2-h PG ≥ 140 and < 200 mg/dL); DM, FPG ≥ 126 mg/dL and/or 2-h PG ≥ 200 mg/dL].Fasting serum levels of Undercarboxylated osteocalcin (ucOC) were measured using a ucOC electro-chemiluminescence immunoassay (ECLIA) Kit (Picolumi ucOC, Eidia Co., Ltd., Tokyo)
Indices of insulin secretion including AUCins/gluc and insulin secretion-sensitivity index-2 (ISSI-2) differed among the NGT, IGM, and DM groups (Table 1)
Summary
Undercarboxylated osteocalcin (ucOC) is a secreted protein produced by osteoblasts that regulates insulin secretion and insulin sensitivity in rodents. Funakoshi et al Diabetol Metab Syndr (2020) 12:72 biomarker of bone turnover which is a unique protein synthesized by osteoblasts [2], plays important roles in glucose metabolism, since OCN-deleted mice exhibited hypoinsulinemia, hyperglycemia, glucose intolerance and insulin resistance [1]. In murine studies, these function of OCN are fulfilled by its undercarboxylated form, namely undercarboxylated osteocalcin (ucOC) [2]. UcOC promotes proliferation via GPRC6A and increases insulin secretion [2, 4]. UcOC promotes β cell proliferation and insulin secretion in human pancreatic islets [5]. It is revealed that OCN signaling via GPRC6A favors glucose uptake and utilization by myofibers [6]
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