Altered bone microarchitecture in a type 1 diabetes mouse model Ins2^Akita

Abstract

Type 1 diabetes mellitus (T1DM) has been associated to several cartilage and bone alterations including growth retardation, increased fracture risk, and bone loss. To determine the effect of long term diabetes on bone we used adult and aging Ins2 Akita mice that developed T1DM around 3–4 weeks after birth. Both Ins2 Akita and wild‐type (WT) mice were analyzed at 4, 6, and 12 months to assess bone parameters such as femur length, growth plate thickness and number of mature and preapoptotic chondrocytes. In addition, bone microarchitecture of the cortical and trabecular regions was measured by microcomputed tomography and gene expression of Adamst‐5, Col2, Igf1, Runx2, Acp5, and Oc was quantified by quantitative real‐time polymerase chain reaction. Ins2 Akita mice showed a decreased longitudinal growth of the femur that was related to decreased growth plate thickness, lower number of chondrocytes and to a higher number of preapoptotic cells. These changes were associated with higher expression of Adamst‐5, suggesting higher cartilage degradation, and with low expression levels of Igf1 and Col2 that reflect the decreased growth ability of diabetic mice. Ins2 Akita bone morphology was characterized by low cortical bone area (Ct.Ar) but higher trabecular bone volume (BV/TV) and expression analysis showed a downregulation of bone markers Acp5, Oc, and Runx2. Serum levels of insulin and leptin were found to be reduced at all‐time points Ins2 Akita. We suggest that Ins2 Akita mice bone phenotype is caused by lower bone formation and even lower bone resorption due to insulin deficiency and to a possible relation with low leptin signaling.

<p>Type 1 Diabetes and Bone Fragility: Links and Risks</p>

“…Insulin does not alter the levels of CTX or P1NP in T1D,32 which has been confirmed by Basu et al35 However, insulinopenia in T1D may contribute to a low bone formation as insulin is a bone anabolic agent,36 and bone turnover was decreased in a mouse model of insulinopenia but restored by insulin treatment 37. Another mouse model of insulinopenia reported decreased levels of osteocalcin and RUNX2 with concomitant low insulin levels 38. The low bone turnover caused by insulin deficiency possibly occurs over time and may not be detected in studies with acute changes in insulin levels as described above 32,35…”

Biomechanical Properties and Macroelement Element Composition of Long Tubular Bone of Rats Under Experimental Hyperglycaemia

“…Hyperglycemia is a pathognomonic symptom of diabetes mellitus (DM) -a disease that occurs due to insulin deficiency or insulin resistance and is accompanied by metabolic disorders and the development of pathological changes in bone tissue, resulting in an increased risk of fractures and inhibition of healing [4,5,12].…”

“…First, it should be noted the need for a deeper argumentation of hypotheses about the violation of the process of bone mineralization in diabetes [8,11]. Given the large number of results of clinical and experimental studies on the study of diabetic disorders of the vertebrae and femurs, which underlie the corresponding risk of fractures, it should be noted insufficient study of pathological changes in other loci of the skeleton and areas of individual bones, including in age and gender aspects, which causes a certain problem of adequate justification of the mechanisms of osteopathy in diabetes [2,4,12,13].…”

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

“…(7,8) Extending to the context of T1D, chronically low levels of insulin or frequent hyperglycemia may each slow bone turnover or accrual. (9)(10)(11) Exogenous insulin is generally required to maintain glucose control in T1D, which could have both a direct and indirect role in acutely stimulating or suppressing bone turnover. There is evidence in preclinical models that bone and pancreatic β-cells are linked by a feedback loop by which osteocalcin (OCN) promotes β-cell production and secretion of insulin.…”

“…( 7,8 ) Extending to the context of T1D, chronically low levels of insulin or frequent hyperglycemia may each slow bone turnover or accrual. ( 9–11 )…”