Acromegaly Cases Exhibiting Increased Growth Hormone Levels during Oral Glucose Loading with Preadministration of Dipeptidyl Peptidase-4 Inhibitor

Abstract

Objective Glucose-dependent insulinotropic polypeptide (GIP) is speculated to worsen growth hormone (GH) hypersecretion in acromegaly and to be a cause of paradoxical increases in GH (PI-GH) during 75-g oral glucose tolerance testing (75-g OGTT). Dipeptidyl peptidase-4 inhibitors (DPP4is), which increase the circulating concentration of active GIP, are frequently administered to diabetic patients, including those with acromegaly. We aimed to determine whether or not the administration of a DPP4i increases GH concentration, especially in patients demonstrating PI-GH during a DPP4i-OGTT, in which a DPP4i was administered immediately before 75-g OGTT. Methods This prospective cross-sectional study was carried out on acromegalic patients admitted to Hokkaido University hospital between June 2011 and May 2018. The participants underwent both 75-g OGTT and DPP4i-OGTT. For those who underwent surgery, immunohistochemical staining and quantitative polymerase chain reaction (PCR) for the GIP receptor (GIPR) were performed on the resected pituitary adenomas. Results Twenty-five percent of the participants had PI-GH confirmed (3 of 12 cases). Two of the three participants who demonstrated PI-GH exhibited higher circulating GH concentrations during DPP4i-OGTT than during OGTT. The increase in plasma glucose was reduced during DPP4i-OGTT compared to during 75-g OGTT, suggesting that the increase in GH during DPP4i-OGTT was due not to high glucose concentrations but instead increased GIP caused by the administration of DPP4i. The adenoma from one participant with PI-GH displayed positive immunostaining for GIPR and a higher GIPR messenger ribonucleic acid (mRNA) expression than the others. Conclusion DPP4i may enhance the GH secretion response during glucose loading, especially in individuals with PI-GH.

Keywords: acromegaly; glucose-dependent insulinotropic polypeptide; growth hormone.

Figure 1.

Immunostaining for cytokeratin, SSTR2, and SSTR5. Representative images of cytokeratin (CAM5.2) and somatostatin receptors type 2 (SSTR2) and type 5 (SSTR5) in immunostained adenoma sections for cases 1 and 2. Scale bar: 100 μm. Case 1: CAM5.2 staining showed a cytoplasmic pattern, suggesting granulated adenoma. SSTR2 reactivity was strongly observed on the cell membrane circumferentially in almost 100% tumor cells, which was compatible with a score of 3 in the immunohistochemical scoring system. SSTR5 reactivity was observed only in cytoplasm, which was compatible with a score of 1. Case 2: CAM5.2 staining showed a cytoplasmic pattern, suggesting granulated adenoma. SSTR2 staining demonstrated partial membranous reactivity in less than 50% of tumor cells, which was compatible with a score of 2 in the immunohistochemical scoring system. SSTR5 reactivity was observed only in the cytoplasm, which was compatible with a score of 1.

Figure 2.

Changes in the GH concentration during 75-g OGTT and DPP4i-OGTT. PI-GH was defined as being present when the peak GH was twice that of the baseline GH during 75-g OGTT. Three of 12 cases showed PI-GH during 75-g OGTT (cases 1-3). In cases 1 and 3, the increase in GH was more marked during DPP4i-OGTT. In case 2, although there was a substantial increase in GH during DPP4i-OGTT, the increment was similar to that during OGTT. In the participants without PI-GH (cases 7, 10, 11, and 12), the increase in GH was higher during DPP4-OGTT than during the 75-g OGTT in three cases but not in one other case. OGTT: oral glucose tolerance testing, DPP4i-OGTT: oral glucose tolerance testing with concurrent oral administration of a dipeptidyl peptidase-4 inhibitor, PI-GH: paradoxical increase in GH

Figure 3.

Immunostaining for GIPR. Representative images of Hematoxylin and Eosin staining, and GH and glucose-dependent insulinotropic polypeptide receptor (GIPR)-immunostained adenoma sections for cases 1, 2, and 7. Scale bar: 100 μm.

Figure 4.

GIPR mRNA expression. A quantitative reverse transcription-PCR analysis of the GIPR gene expression in adenomas from cases 1, 2, 4, 6, 7, 9, 10, 11, and 12. The mRNA expression was normalized to that of GAPDH, and the x-axis values are fold-differences normalized to the mean value of the participants without PI-GH. GIPR: gastric inhibitory polypeptide receptor