PTH and PTHrP: possible links to glucose metabolism?
Creators: name: SAM, Syu Mi
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 320208
subject: Endocrinology
classificationCode: 320220
subject: Pathology (excl. oral pathology)

description: The pancreas is an important organ which plays a vital role in the regulation of glucose in the circulation. Hormones produced by the pancreatic islets are responsible for the homeostasis of blood glucose levels and tissue metabolism. Any alterations to how these hormones, in particular insulin secreted by the ß-cells, can lead to a number of conditions which form part of the metabolic syndrome. Two members of the parathyroid hormone family, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), have recently been implicated in glucose homeostasis and its dysregulation leading to pathological conditions such as metabolic syndrome and type 2 diabetes. Both PTH and PTHrP play imperative roles in the regulation of extracellular calcium. PTH is a classical hormone, that is secreted by the chief cells in the parathyroid gland and its endocrine actions allow it to act on its major target sites, bone and kidney. In contrast, PTHrP is found ubiquitously in the body, thus it is more of a factor rather than a hormone. Its actions are predominantly via an autocrine/paracrine manner. PTH has been suggested to supress glucose uptake and affect insulin signalling whilst PTHrP has been shown to increase ß-cell mass and proliferation in addition to increasing insulin expression. Despite the known functions of PTH and PTHrP, there has been very little research conducted in the area of the pancreas and its possible link to PTH and PTHrP. To date, no studies have localised PTH in human pancreas and PTH is thought to be predominantly produced by the parathyroid glands. 
The overall aim of this thesis was to investigate the potential roles of PTH and PTHrP in the pancreas. The presence of PTH and PTHrP in the pancreas may indicate that these proteins could play a role in glucose metabolism. This may be due to local roles in calcium regulation or they could be members of a growing field of factors that are known to act on bone that are now being implicated in glucose metabolism. The first aim of the study was to localise and examine the presence of PTH, PTHrP and PTH1R in human pancreatic tissue. The second aim was to investigate the receptor functionality and gene expression in insulinoma ß-cell lines. The third aim was to examine the relationship between serum PTH levels and metabolic biomarkers in patients. 
PTH, PTHrP and PTH1R proteins were localised using immunohistochemical (IHC) staining of human pancreatic sections. The IHC staining intensity was semi-quantitated using image analysis recognising the cytoplasmic staining. The receptor, PTH1R, functionality was examined in a mouse insulinoma-derived ß-cell line, MIN6, by measuring the accumulation of cyclic adenosine monophosphate (cAMP) after stimulation with hPTH(1-34) and hPTHrP(1-34). PTH1R mRNA in MIN6 cells and rat insulinoma ß-cell line, INS-1, was also examined using quantitative PCR (qPCR). The association between serum PTH levels and metabolic biomarkers was examined in two different patient cohorts. Patient biochemistry data were obtained from a Diabetes Outpatient Clinic from a tertiary teaching hospital. The pre and post-surgical biochemistry data were also collected from patients undergoing a pancreaticoduodenectomy (Whipple's procedure). 
PTH, PTHrP and PTH1R were localised to the pancreatic islets of human pancreatic tissue sections. PTH1R was shown to be non-functional in mouse MIN6 ß-cells revealed by the lack of change in cellular cAMP content from stimulated and non-stimulated cells when treated with hPTH(1-34) and hPTHrP(1-34). The receptor functionality was further verified when PTH1R mRNA was not detected in MIN6 cells but was shown to be expressed at very low levels in the rat INS-1 cells. 
Serum PTH levels were demonstrated to have a positive association with C-peptide in a diabetic patient cohort, a marker of endogenous insulin production. 
Together, the findings of this research support the emerging field of hormones/factors in bone homeostasis and their possible roles in glucose metabolism. PTH in particular, may be a much more versatile hormone and have more roles than currently understood. Future research should focus on PTH and elucidation of its roles other than being the principal factor regulating serum calcium.