The effects of diabetes on the metabolism of the bone

Authors

Abstract

Mortality and morbidity in diabetic patients are influenced by a multitude of factors, including genetic sus- ceptibility, environmental influences, uncontrolled medical and surgical histories, and the impact of diabetes on bones and fractures. In type 1 diabetes (T1D), bone mineral density (BMD) tends to be low, elevating the risk of fractures. In type 2 diabetes mellitus (T2DM), osteoblast function is impaired, leading to less mature bone formation, and accelerated bone resorption by osteoclasts. Therefore, it is reasonable to assume that some an- tidiabetic medications may affect bone density. It is crucial to have updated screening and prevention programs in all countries where diabetes is increasing.
This paper will discuss the impact of diabetes mellitus on bone health to enhance understanding among stu- dents and healthcare workers.

Keywords

Introduction

Diabetes mellitus (DM) is a chronic non-communicable disease that increases risk of bone fractures and osteoporosis. The consequences of type 1 diabetes on the bones are more severe than those of type 2 diabetes because insulin does not have an anabolic impact on bones. [1]. Testing of bone mineral density (BMD) is the first step in detecting fracture risk and osteoporosis. BMD is a measure of the mineral content in bones that contributes to its strength. Recent studies consistently indicate that total body mineral density (TMD) is higher in type 2 diabetes and lower in type 1 diabetes [1, 2]. Many factors can make bones more likely to break or become weak, including how well you control your blood sugar, the severity and duration of disease, how often you fall, osteopenia, postural hypotension, medication side effects, vascular disease, and poor bone quality [3, 4, 5]. Researchers in Rotterdam found that, compared to healthy controls, diabetics had a 69% higher incidence of fractures [6]. T2DM and osteoporosis are chronic conditions, and the risk of developing either increases with age [7], more than 8.9 million fractures occur each year in women over the age of 50 due to both T2DM and osteoporosis [8]. Lower BMD is a significant indicator of the increased risk of fractures in type 1 diabetes [9].
T1D causes hyperglycemia and early bone fragility as a novel consequence [10]. However, Weber et al. demonstrated that the elevated risk of hip fractures in individuals with type 1 begins in early adulthood [11]. Although fractures in type 2 diabetes are more common than in T1D [12], some possible reasons why people with type 1 diabetes may not have healthy bones include hyperinsulinemia, low levels of insulin-like growth factor-1 and vitamin D, poor metabolic management, vascular problems, and a high lipid profile [13]. Clinical trials conducted on this topic thus far have either used too few patients or failed to record important details like metabolic control, insulin exposure, or hypoglycemia episodes [14]. Due to better medical care, longer life expectancy has contributed to a significant increase in the overall number of people with type 1 diabetes who are in the age group most susceptible to fragility fractures [15]. A study indicated that certain diabetes-related factors, such as the duration of the disease, the presence of neuropathy, and their HbA1c levels, may be used to assess a patient’s risk of fracture. Until recently, the mechanism behind the increased fracture risk was not well known [16].
The obesity epidemic and uncontrolled glycemic levels increase the incidence of type 2 diabetes and diabetic complications such as macrovascular disease, retinopathy, nephropathy, neuropathy, and fragility fractures, even though BMD was shown to be high in diabetic patients[17, 18]. They also sustain fractures even at low-stress levels [19], which could explain the discrepancy between BMD and fracture incidence.
Bone strength is reduced in people with type 2 diabetes [20, 21]. Farr and his colleagues studied the bone quality in 2016 and they found that cortical thickness was thinner in diabetics compared to controls [22]. The literature also showed that bone remodeling in diabetics is impaired, the cortical layer is thin and bone bending strength is low, thereby raising the susceptibility to fragility fractures [23, 24, 25]. Particularly those of Latino and African American cultural heritage [24]. Factors such as aging, corticosteroid use, sensory neuropathy, visual impairment, postural hypotension, and vascular disease are all linked to an increased risk of falls and bone fractures in diabetics, according to some evidence [19, 26, 27].
Why diabetes affects bone
All Diabetes patients have lower amounts of osteocalcin (OC), which plays an important role in energy metabolism, increases insulin sensitivity in muscle and adipose tissue, and promotes insulin secretion[28, 29, 30]. The literature shows that postmenopausal women with type 2 diabetes had reduced levels of these indicators significantly, compared with controls [29]. Some researchers discussed that people with type 2 diabetes have a lower level of the resorption marker, which is the serum C-terminal telopeptide from type 1 collagen, and high levels of sclerostin, which leads to fractures [30, 31]. Research indicates that high sclerostin levels are positively correlated with the duration of type 2 diabetes mellitus and glycated hemoglobin and negatively correlated with bone turnover marker levels by binding to the low-density lipoprotein receptor-related protein (LPR) 5 or 6, which suppresses the Wnt/ß-catenin pathway and adversely controls bone formation [31]. It appears that hyperglycemia significantly impacts the vitamin D-calcium axis by reducing renal calcium absorption [32]. The high glycemic levels impair the osteoblasts’ capacity to produce osteocalcin in response to 1,25(OH)2D3, which is at least partially explained by the decreased number of 1,25(OH)2D3 receptors on osteoblasts [32]. Until now, it is unclear how vitamin D performs in type 2 diabetes and fracture risk [33]. Diabetics also showed higher levels of circulating advanced glycation end products( AGE) [34]. The interaction between AGEs and immunoglobulin increases vascular inflammation which leads to platelet and macrophage activation [33]. As a result, bones become weak, and easily fractured and the macro- and microangiopathy worsens [35].
Anabolic hormones like growth hormone (GH) and insulin-like growth factor (IGF-1) play an important role in the development of the bone and the maintenance of healthy bones thereafter [36]. Some literature surveys show a higher risk of diabetes and metabolic syndrome in patients with low IGF-I serum levels and resulting in weaker bones in diabetics [37].
IGF-1 plays a role in reducing collagen degradation. There is strong evidence that IGF-1 is positively associated with bone mineral density (BMD) and inversely correlated with hip and vertebral fractures, according to studies [38, 39].
Gut enteroendocrine K-cells in the duodenum secrete GIP, a hormone that regulates glucose levels; L-cells in the colon secrete GLP-1 and GLP-2, two hormones that regulate glucagon levels. The glands secrete GIP and GLP-1 shortly after food is consumed. After entering the bloodstream in an active hormonal state, they attach to specific G protein-coupled receptors located in different cells and target tissues [40]. Dipeptidyl peptidase-4 (DPP-4) an enzyme is present in plasma and a wide range of tissues. It quickly breaks down and inactivates both hormones, which lowers their bioactivity [41]. The incretin hormones GLP-1 and GIP hinder α-cells from releasing insulin by stopping them from producing glucagon [42]. Both osteoblasts and osteoclasts express incretin receptors. These dietary hormones are known to be important in bone turnover because they suppress bone resorption the minute food is ingested. The continuous regulation of bone homeostasis is dependent on the communication between osteoblasts and osteoclasts [43, 44]. The gastrointestinal peptides GIP and, perhaps, GLP-1 and GLP-2, when consumed, may inhibit bone resorption and promote bone formation [45]. Although GIP has dual action as an anabolic and antiresorptive hormone, research indicates that GLP-2, the antiresorptive hormone, may influence bone remodeling through decoupling bone resorption from other processes [46]. Despite this, the precise mechanisms via which GLP-2 and GIP inhibit bone resorption are still a mystery. [47]. Moreover, the effect of GLP-2 is still unknown, but endogenous GIP has an inhibitory impact on bone resorption in diabetic patients. Inconsistent evidence suggests that GLP-1 receptor agonists, which are used to treat obesity and type 2 diabetes, may slow bone loss. In addition to GIP, which is a key physiological regulator of bone loss after a meal, GLP-1 and GLP-2 may also have bone-preserving effects when given by medication. New approaches for treating and preventing skeletal fragility in diabetes could develop from a deeper comprehension of the effects of these gastrointestinal hormones on bone homeostasis in diabetic patients [48].

Figures

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Figure 1. Sclerostin levels are negatively correlated with bone turnover and positively related with diabetes. Figure adapted from P. Ducy (Dia- betologia. 54:1291-7)

Tables

Table 1. Some factors and their effect on bone

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Conclusion

The bone is considered an endocrine organ. There is a crucial link between bone, obesity, and glucose metabolism. High Insulin stimulates the secretion of undercarboxylated osteocalcin and sclerostin, small protein bone cells that respond to mechanical stress and regulate bone remodeling (Figure 1).
Measurements of bone mineral density (BMD) alone cannot predict fracture risk, especially in people with type 2 diabetes. A combination of many variables likely contributes to elevated risk (Table 1). A lower bone production rate, inferior bone quality, and an increased risk of fractures are all consequences of hyperglycemia. Reducing the production of AGEs, vascular damage in bone tissue, and the risk of falls are all possible outcomes of well-managed blood sugar levels, which aid in the prevention of fractures.

Data Availability

The data supporting the findings of this article are available from the corresponding author upon reasonable request, due to privacy and ethical restrictions. The corresponding author has committed to share the de-identified data with qualified researchers after confirmation of the necessary ethical or institutional approvals. Requests for data access should be directed to bmp.eqco@gmail.com

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