Acute Hyperinsulinemia Alters Bone Turnover in Women and Men With Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) increases fracture risk across the lifespan. The low bone turnover associated with T1D is thought to be related to glycemic control, but it is unclear whether peripheral hyperinsulinemia due to dependence on exogenous insulin has an independent effect on suppressing bone turnover. The purpose of this study was to test the bone turnover marker (BTM) response to acute hyperinsulinemia. Fifty‐eight adults aged 18 to 65 years with T1D over 2 years were enrolled at seven T1D Exchange Clinic Network sites. Participants had T1D diagnosis between age 6 months to 45 years. Participants were stratified based on their residual endogenous insulin secretion measured as peak C‐peptide response to a mixed meal tolerance test. BTMs (CTX, P1NP, sclerostin [SCL], osteonectin [ON], alkaline phosphatase [ALP], osteocalcin [OCN], osteoprotegerin [OPG], osteopontin [OPN], and IGF‐1) were assessed before and at the end of a 2‐hour hyperinsulinemic‐euglycemic clamp (HEC). Baseline ON (r = −0.30, p = .022) and OCN (r = −0.41, p = .002) were negatively correlated with age at T1D diagnosis, but baseline BTMs were not associated with HbA1c. During the HEC, P1NP decreased significantly (−14.5 ± 44.3%; p = .020) from baseline. OCN, ON, and IGF‐1 all significantly increased (16.0 ± 13.1%, 29.7 ± 31.7%, 34.1 ± 71.2%, respectively; all p < .001) during the clamp. The increase in SCL was not significant (7.3 ± 32.9%, p = .098), but the decrease in CTX (−12.4 ± 48.9, p = .058) neared significance. ALP and OPG were not changed from baseline (p = .23 and p = .77, respectively). Baseline ON and SCL were higher in men, but OPG was higher in women (all p ≤ .029). SCL was the only BTM that changed differently in women than men. There were no differences in baseline BTMs or change in BTMs between C‐peptide groups. Exogenous hyperinsulinemia acutely alters bone turnover, suggesting a need to determine whether strategies to promote healthy remodeling may protect bone quality in T1D. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Future studies using histomorphometry in type 1 diabetes mellitus

“…If this acute effect was extrapolated to a chronic effect, this could lead to more brittle, less tough bone. These changes were dependent on insulin but not glucose as glucose levels were maintained in the normal range [13 ▪▪ ].…”

Bone accrual in children and adolescents with type 1 diabetes: current knowledge and future directions

“…Consistent with prior literature, the findings were mixed, but tended to show more consistent decreases in bone formation with less consistent patterns on markers of bone resorption, in T1D participants versus controls. The relationship between glycemic control and bone turnover also remains uncertain, with some studies finding significant associations [29,33 ▪ ] and others reporting no association [44 ▪ ]. Acute hyperinsulinemia under experimental conditions via hyperinsulinemic--euglycemic clamp was found to induce changes in bone turnover markers in adults with T1D, raising questions about how the multiple daily insulin boluses typically needed by patients with T1D might affect bone metabolism [44 ▪ ].…”

“…The relationship between glycemic control and bone turnover also remains uncertain, with some studies finding significant associations [29,33 ▪ ] and others reporting no association [44 ▪ ]. Acute hyperinsulinemia under experimental conditions via hyperinsulinemic--euglycemic clamp was found to induce changes in bone turnover markers in adults with T1D, raising questions about how the multiple daily insulin boluses typically needed by patients with T1D might affect bone metabolism [44 ▪ ]. The relationship between markers of bone turnover and clinically relevant skeletal outcomes has not been well studied.…”

Bone Structure and Turnover in Postmenopausal Women With Long‐Standing Type 1 Diabetes

“…(5) Chronic hyperglycemia and peripheral hyperinsulinemia (mainly in T2D) may lead to suppression of bone formation and resorption. (6)(7)(8) Animal studies using streptozotocin (STZ)-induced insulin deficiency mouse and rat models have reported low bone formation, reduced trabecular bone and osteoid, and decreased mineral apposition rate, where most of these deficits were corrected by insulin administration, suggesting a role of hyperglycemia in suppression of bone turnover. (9)(10)(11)(12) However, data on bone turnover using the gold standard bone histomorphometry technique in people with T1D are scant.…”