Teriparatide Improves Bone and Lipid Metabolism in a Male Rat Model of Type 2 Diabetes Mellitus

Abstract

Osteoporosis is a complication of diabetes mellitus (DM). The pathology of diabetic osteoporosis is distinct from postmenopausal osteoporosis, and there are no specific treatment guidelines for diabetic osteoporosis. In the current study, this issue was addressed by evaluating the effect of osteoporosis medications, such as the anabolic agent PTH [teriparatide (TPTD)] and the antiresorptive agents calcitonin [elcatonin (ECT)] and bisphosphonate [risedronate (RIS)], on bone metabolism as well as on glucose and lipid metabolism in spontaneously diabetic Torii (SDT) fatty rats, which are a model of type 2 DM (T2DM). The medicines were injected subcutaneously into 8-week-old male SDT fatty rats three times weekly for 8 weeks. TPTD treatment in SDT fatty rats increased the osteoblast number and function on trabecular bone in vertebrae, and increased the trabecular bone mass, bone mineral density (BMD), and mechanical strength of vertebrae. Additionally, TPTD improved cortical bone structure and increased BMD. RIS decreased the osteoclast number and function, which led to an increase in vertebral bone mineral content and BMD in the femoral diaphysis, and mechanical strength was increased in the vertebrae. ECT showed no clear effects on bone mass or metabolism. Similar to diabetic lesions, all of the drugs had no effects on hyperglycemia, pancreas morphology, or serum insulin and glucagon levels. However, triglyceride levels and lipid droplets in fatty liver were decreased in the TPTD group. These results suggest that TPTD may be useful for treating fatty liver in addition to osteoporosis in T2DM.

Figure 1.

Bone geometry, mineral density, and mechanical properties of L3 bodies. Geometric parameters are (A) cylinder height and (B) bone volume. (C) BMC; (D) BMD measured by dual X-ray absorptiometry. Mechanical properties include (E) maximum load, (F) stiffness, and (G) energy absorption in a three-point bending test. All measurements were performed at the end of the administration period. The box plot shows the median, lower, and upper quartiles and the minimum and maximum values (n = 7 to 9). **P < 0.01, for difference from the SD group; ^†P < 0.05, ^††P < 0.01, for difference from the Fatty group.

Figure 2.

Bone geometry, mineral density, and mechanical properties of femurs. Geometric parameters include the following: (A) bone length and (B) bone volume. (C) BMC of the femoral shaft measured by dual energy X-ray absorptiometry. (D) BMD of the femoral shaft measured by dual energy X-ray absorptiometry. Mechanical properties include the following: (E) maximum load, (F) stiffness, and (G) energy absorption in a three-point bending test of the femoral diaphysis. All measurements were performed at the end of the administration period. The box plot shows the median, lower, and upper quartiles and the minimum and maximum values (n = 8 to 9). **P < 0.01, for difference from the SD group; ^†P < 0.05, ^††P < 0.01, for difference from the Fatty group.

Figure 3.

The effects of osteoporotic drugs on glucose metabolism. (A) Blood glucose levels and (B) serum insulin levels after fasting at before (0w) and after 2, 4, and 8 wk (2w, 4w, 8w) of administration (n = 3 to 5). (C) H&E staining and immunostaining for cell type–specific markers in rats with β-cells and α-cells indicated by insulin and glucagon, respectively. (a) SD rat (aged 8 wk), (b) SDT fatty rat (aged 8 wk), both before administration. (c–q) All animals were 16 wk old (i.e., at the end of the administration period). (c–e) SD, (f–h) Fatty, (i–k) TPTD, (l–n) ECT, and (o–q) RIS. (D) The insulin-producing cell mass rate in pancreatic islets. Scale bars, 50 µm. The box plot shows the median, lower, and upper quartiles and the minimum and maximum values (n = 3 to 5). *P < 0.05, **P < 0.01, for difference between two groups.

Figure 4.

The effects of osteoporotic drugs on T-cho and TG levels in the serum and liver tissue. (A) Serum T-cho levels and (C) serum TG levels after fasting before administration (0w) and after 2, 4, and 8 wk (2w, 4w, 8w) of administration (n = 3 to 5). (B) Liver T-cho levels and (D) liver TG levels in SD rats and SDT fatty rats after 8 wk of administration (n = 3 to 5). (E) H&E staining of liver sections. (a) SD rat (8 wk old), (b) SDT fatty rat (8 wk old), both before administration. (c–g) All animals were 16 wk old (i.e., at the end of the administration period). (c) SD, (d) Fatty, (e) TPTD, (f) ECT, and (g) RIS. Scale bars, 50 µm. (F) Expression of genes related to lipid metabolism. The mRNA levels were normalized to the housekeeping gene β-actin (n = 3 to 5). (a) Relative SREBP-1c mRNA, (b) relative ACC mRNA, and (c) relative FAS mRNA. The box plot shows the median, lower, and upper quartiles and the minimum and maximum values (n = 3 to 5). *P < 0.05, ** P < 0.01, for difference from the SD group; ^†P < 0.05, for difference from the Fatty group.