SUMMARY
Both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) affect the bone metabolism at the cellular and biochemical levels. This affects the normal bone homeostasis and turnover which in turn alters the microarchitecture of the bone. There is decreased differentiation of the osteoblastic precursor cells into mature osteoblasts. Rather these cells are converted more into adipocytes. The osteoclastic resorption is also affected in both types of diabetes. Low insulin levels or insulin resistance and hyperglycemia also affect the normal bone metabolism by several mechanisms.
NORMAL BONE METABOLISM IN BRIEF
The normal composition of the bone is as follows (Flowchart 1):
- Collagen found in bone is predominantly of type I variety. It is arranged in an interconnecting manner which provides the bone tensile strength and the power to counteract the shear stresses.
- Osteoblasts are the bone forming cells and are responsible for the formation of the osteoid (unmineralized organic matrix).
- Osteoclasts are the bone cells responsible for bone resorption.
- Osteoblasts produce receptor activator of nuclear factor kappa beta ligand (RANKL) and osteoprotegerin.
- Osteocytes produce sclerostin and FGF23.
- RANKL is receptor activator of nuclear factor kappa beta (NFkB) ligand. It binds to the RANK on the osteoclasts and functions as an important factor in the activation and differentiation of osteoclasts.
- Osteoprotegerin is a decoy factor for RANKL and thus prevents the differentiation of osteoclasts.
- Wnt/beta-catenin pathway is involved in osteoblastogenesis.
- Runx2 is also involved in osteoblastogenesis.
- Sclerostin inhibits the Wnt/beta-catenin pathway and thus inhibits osteoblastogenesis.
- Dickkopf-related protein 1 (DKK-1) is an inhibitor of the Wnt/beta-catenin pathway.
- FGF23 is a phosphatonin whose main role is to inhibit renal reabsorption of phosphate.
- Mesenchymal stem cells (MSCs) can get differentiated into osteoblasts, adipocytes, or chondrocytes (Fig. 1).
Impact of Diabetes on Bone Metabolism
Type 1 diabetes mellitus is characterized by failure of the beta cells of the pancreas to secrete insulin while in T2DM there is predominantly insulin resistance leading to ineffectiveness of the insulin. Both T1DM and T2DM affect the normal bone metabolism but in somewhat different ways. It is a long standing process and not a single pathophysiological mechanism can explain the detrimental effect of diabetes on the bone metabolism.3
Effect of Insulin Signaling on Bone Metabolism
Insulin is an anabolic hormone. It plays a pivotal role in substrate metabolism in many of the major organs. Insulin receptor is expressed on osteoblasts as well as osteoclasts. It helps in proliferation and differentiation of osteoblasts and also promotes the formation of osteoclasts but overall it has a net bone formation effect.1 Osteoblasts also express the insulin-like growth factor 1 (IGF-1) receptor.2 IGF-1 has the capability that it can bind both to the IGF-1 receptor as well as the insulin receptor. By binding to these receptors, just like insulin, it exerts anabolic action on the bone.
Type 1 diabetes mellitus is characterized by low levels of insulin as well as IGF-1. This hampers the differentiation of the MSCs into osteoblasts,3 and other anabolic actions on the bone. Thus, at a very young age the patient skeletal metabolism is affected and the patient has an inadequate accrual of peak bone mass. This makes the patient susceptible for osteoporosis and fragility fractures.
In T2DM, the bone health is usually affected at a later age because of multiple factors such as chronic inflammation, hyperglycemia, lack of insulin action, etc.
Effect on Bone Architecture
The architecture of the bone is such that it is meant to withstand tensile, compressive, and shear stresses. It is very tightly regulated by very biochemical and cellular mechanisms. Once these regulatory mechanisms are affected in diabetes, the normal architecture of the bone gets distorted and it is thus affected adversely.4
The changes in the bone microarchitecture have been extensively studied with the help of magnetic resonance imaging (MRI), bone histomorphometric analysis, peripheral high-resolution quantitative computed tomography (HRpQCT), trabecular bone score (TBS), etc. A study done in the patients of T2DM showed an increase in the intracortical porosity.4 Increased bone marrow adiposity and increase in the amount of saturated fat in the bone marrow of diabetes patients has also been seen.5,6
Figure 2 summarizes the effect of various mechanisms which affect the bone metabolism, architecture, and turnover.7 Increased levels of glucose promotes the conversion of MSCs into the adipocyte while inhibits its conversion into 5osteoblasts. Hyperglycemia also affects vitamin D and parathyroid hormone (PTH) metabolism and glycosuria also increases calcium excretion into urine.8 Increased formation of adipocytes leads to increased production of reactive oxygen species (ROS) and of inflammatory cytokines which again leads to increased formation of adipocytes by stimulating the PPAR-γ and inhibits osteoblasts formation by inhibiting the Wnt pathway. It also leads to the apoptosis of the already formed osteoblasts. Increased production of the advanced glycation end products (AGEs) leads to the cross linking of the collagen fibrils.7
BONE CELLS IN TYPE 1 DIABETES MELLITUS
Osteoblasts
The transcription of the Runx2 gene and of the Wnt/beta-catenin gene is down regulated which lead to a decreased differentiation of the MSCs into osteoblasts.9–11 As already discussed, insulin deficiency, low IGF-1, and hyperglycemia also decreases this differentiation. The already formed osteoblasts are forced to undergo apoptosis.
Osteoclasts
The RANKL derived from osteoblasts bind to the RANK receptor present on the surface of the osteoclasts which leads to the differentiation and activation of these cells. Osteoblasts also produce osteoprotegerin which binds to the RANKL and thus prevents the activation of osteoclasts. It has been found in studies that in patients with T1DM there is a decreased sensitivity to the action of the osteoprotegerin.12 Thus more of osteoclastic bone resorption is seen in these patients.
BONE CELLS IN TYPE 2 DIABETES MELLITUS
Osteoblasts
In T2DM also, lack of insulin action and hyperglycemia affects the osteoblasts in a similar way as in T1DM. Apart from these increased inflammatory cytokines and AGEs also affects the osteoblastic differentiation. It has been found in some studies that in patients with T2DM there is more number of immature osteoblasts. Moreover, increased levels of DKK-1 are also seen in these patients.13 DKK-1 is an inhibitor of the Wnt/beta-catenin pathway. Thus, here also, there is decreased osteoblastic activity along with more number of immature osteoblasts.
Osteoclasts
The bone mineral density (BMD) in patients with T2DM can paradoxically be high. This has been supported by the fact that there are more number of immature osteoclasts seen in these patients which decreases the bone resorption and thus increases the BMD.136
CONCLUSION
- The microarchitecture of the bone is affected in diabetes mellitus which makes the bone susceptible to osteoporosis and fragility fractures.
- There is decreased differentiation of MSCs into osteoblasts.
- Low levels of insulin and IGF-1 in T1DM and insulin resistance in T2DM also affects the formation of osteoblasts.
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