While type 1 diabetes mellitus is typically manageable with insulin, diet, and exercise, many complications are still associated with this diabetic condition. A bone fracture is one such complication that is not readily anticipated and can severely hinder quality of life. Moreover, fracture healing in diabetic patients may be suboptimal because diabetes delays the regenerative processes of connective tissues, including bone [43
]. Despite the need to protect persons with diabetes from fractures, there is a paucity of mechanistic information on how insulinopenia and hyperglycemia affect the fracture resistance of bone. The present study provides three possibilities for the effect of diabetes on bone: 1) deterioration of bone structure/architecture, 2) reduction in the capacity of the bone tissue to dissipate energy (i.e., toughness), and 3) perturbation in the relationship between whole bone strength and bone structure.
The deleterious effect of diabetes on bone structure is well established in rodent models of the disease (). As for humans, there is some evidence that diabetics may have smaller bones. Using peripheral quantitative CT (pQCT), Saha et al. [44
] found that the radius and tibia of T1DM adolescents, especially boys, had a smaller cross-sectional area (CSA) than did these bones of appropriately matched non-diabetic adolescents. However, another pQCT study by Bechtold et al. [45
] indicated that as T1DM adolescents reached 14 yr. and 15 yr. of age, their cortical CSA normalized, becoming equivalent to the cortical CSA of non-diabetics at the same age. In recent a report, the deletion of insulin receptor signaling in the osteoblasts of mice resulted in reduced postnatal bone accrual [46
], further supporting the notion that systemic insulin deficiency thus the lack of insulin signaling in osteoblasts can affect bone formation and architecture, thereby increasing risk of fracture.
Given a sufficient duration and intensity of diabetes, the present study suggests that diabetic bone becomes more brittle or less tough. A decrease in bone toughness certainly occurs with aging in humans [47
], and diabetes with hyperglycemia likely accelerates the accumulation of AGEs in bone tissue, thereby prematurely causing brittleness. As animals age, AGEs accumulate in a variety of connective tissues [48
] including bone [50
] even though bone undergoes turnover. Also known as non-enzymatic, glycation-mediated (NEG) collagen crosslinks, AGE concentration in bone was greater for STZ-induced T1DM rats than for normal rats [29
]. While an increase in NEG crosslinks remains to be established as a contributor to bone brittleness in the mouse model of type 1 diabetes, these crosslinks are thought to affect bone quality, leading to an increase in fracture risk [54
]. While more work is needed to strongly establish the causal relationship between AGEs and bone toughness with respect to diabetes and aging, reduced fracture risk among diabetics is quite possibly a problem of inadequate bone toughness as this study suggests.
For the first time, we show a difference in the strength-structure relationship between normal and diabetic bone. As an engineering principle, the distribution of tissue about the neutral axis of bending contributes to the stiffness and peak force experienced by a bone under loading. Differences in this direct relationship between two groups indicate that compositional differences exist in the tissue properties between the groups. In the present study, the slope of the strength-structure relationship was only statistically significant when the regression was performed on combined data from the control and diabetic mice at 21 wk. of age ( and ). As the diabetic condition progresses from 10 wk. to 18 wk, the slope and the y-intercept of the relationship () can be different between T1DM (thin regression line) and CON (solid regression line). This suggests a complex change in the compositional nature of the tissue. Given the observed reduction in Ct.TMD for diabetic bone and the potential for time-dependent alterations to the organize matrix of diabetic bone, this change in the strength-structure relationship for T1DM bone is likely due to a reduced mineralization density interacting with overly-crosslinked collagen fibrils. That is, the contribution of the diabetes-related decrease in mineralization density to material strength is offset by the diabetes-related increase in non-enzymatic collagen crosslinking that may actually strengthen the organic matrix. This would explain why diabetes did not affect the whole bone bending modulus and strength () despite the fact that diabetic bone had a lower Ct.TMD than did control bone ().
There are several conditions of the present mouse model of T1DM that may have indirect effects on the reported differences in bone properties. The diabetic mice weigh less than control mice, and an indirect consequence via mechanical adaptation of this difference could be a reduction in bone size and structural strength. However, insulin has recently been shown to have direct anabolic affects on bone accrual [46
]. Furthermore, a difference in body mass would not necessarily explain the difference in the strength-structure relationship between T1DM and CON as the drop in body mass stabilizes in diabetic mice by 10 weeks following injection of STZ (). The long-term metabolic effects of diabetes prevented some mice from surviving 18 weeks of diabetes as observed by others for DBA/2J mice [56
], so metabolic decompensation could indirectly affect either strength-structure relationship or bone toughness. De-confounding such indirect affects would require complex nutritional and/or genetically modified models in which the affects of blood glucose, insulin production and action, weight loss, lypolysis, acidosis, etc. are independently controlled.
In conclusion, T1DM was associated with complex changes in mouse bone. Early on in the disease process, there was diminished cortical structure and trabecular micro-architecture translating into weakened diabetic bone relative to the non-diabetic bone. As the duration of the diabetic condition increases, further change in these parameters did not occur, suggesting a limit to which insulin-deficiency affects the bone architecture. On the other hand, progression of the diabetic state continuously associates with the post-yield toughness of bone, which may reflect accumulation of AGEs in skeletal tissues. Taken together, the outcomes presented in these studies suggests that the elevated fracture risk among diabetics is impacted by progressive and complex alterations in tissue properties that over time reduce bone toughness and increase the risk to fracture.