Glucokinase activation leads to an unsustained hypoglycaemic effect with hepatic triglyceride accumulation in db/db mice.

AIM: To investigate how subchronic administration of a glucokinase activator (GKA) results in attenuation of the hypoglycaemic effect in the diabetic condition. MATERIALS AND METHODS: Six-week-old db/db mice were fed standard chow containing a GKA or the sodium-glucose cotransporter 2 inhibitor ipragliflozin for 1, 6, 14 or 28 days. We performed histological evaluation and gene expression analysis of the pancreatic islets and liver after each treatment and compared the results to those in untreated mice. RESULTS: The unsustained hypoglycaemic effect of GKAs was reproduced in db/db mice in conjunction with significant hepatic fat accumulation. The initial reactions to treatment with the GKA in the liver were upregulation of the gene expression of carbohydrate response element-binding protein beta (Chrebp-b) and downregulation of phosphoenolpyruvate carboxykinase (Pepck) on day 1. Subsequently, the initial changes in Chrebp-b and Pepck disappeared and increases in the expression of genes involved in lipogenesis, including acetyl-CoA carboxylase and fatty acid synthase, were observed. There were no significant changes in the pancreatic ß cells nor in hepatic insulin signalling. CONCLUSIONS: The GKA showed an unsustained hypoglycaemic effect and promoted hepatic fat accumulation in db/db mice. Dynamic changes in the expression of hepatic genes involved in lipogenesis and gluconeogenesis could affect the unsustained hypoglycaemic effect of the GKA despite no changes in pancreatic ß-cell function and mass.

[A Case of Prostate Cancer with Multiple Bone Metastasis with High FGF23 Value Indicated by Intractable Hypocalcemia and Hypophosphatemia].

A 53-year-old man was diagnosed with prostate cancer with multiple bone metastasis. Therefore androgen deprivation therapy was initiated. After treatment with denosumab injection for bone metastasis, hypocalcemia and hypophosphatemia occurred. Despite treatment for hypocalcemia with vitamin D and calcium lactate,his serum calcium and phosphate levels were refractory to treatment. The etiology of hypophosphatemia was investigated,and the level of serum fibroblast growth factor 23 (FGF23) was abnormally elevated. Three months after the first measurement of FGF23,the patient died of prostate cancer. Severe hypophosphatemia is a typical manifestation of tumor-induced hypophosphatemic osteomalacia (TIO),which is a paraneoplastic condition, mediated by FGF23 overexpression in most cases. His osteoblastic metastasis,however,did not meet the disease criteria of osteomalacia. Several reports have suggested that excessive FGF23 may mediate both severe hypophosphatemia and aggressive castrationresistant prostate cancer characteristics. Management of serum FGF23 may be a novel therapeutic strategy for castration-resistant prostate cancer with hypophosphatemia.

Effects of glucokinase haploinsufficiency on the pancreatic ß-cell mass and function of long-term high-fat, high-sucrose diet-fed mice.

AIMS/INTRODUCTION: We previously showed that glucokinase haploinsufficiency improves the glucose tolerance of db/db mice by preserving pancreatic ß-cell mass and function. In the present study, we aimed to determine the effects of glucokinase haploinsufficiency on the ß-cell mass and function of long-term high-fat, high-sucrose (HFHS) diet-fed mice. MATERIALS AND METHODS: Four-week-old male glucokinase haploinsufficient (Gck+/-) mice and 4-week-old male wild-type (Gck+/+) mice (controls) were each divided into two groups: an HFHS diet-fed group and a normal chow-fed group, and the four groups were followed until 16, 40 or 60 weeks-of-age. Their glucose tolerance, glucose-stimulated insulin secretion and ß-cell mass were evaluated. In addition, islets were isolated from 40-week-old mice, and the expression of key genes was compared. RESULTS: Gck+/-HFHS mice had smaller compensatory increases in ß-cell mass and glucose-stimulated insulin secretion than Gck+/+HFHS mice, and their glucose tolerance deteriorated from 16 to 40 weeks-of-age. However, their ß-cell mass and glucose-stimulated insulin secretion did not decrease between 40 and 60 weeks-of-age, but rather, tended to increase, and there was no progressive deterioration in glucose tolerance. The expression of Aldh1a3 in pancreatic islets, which is high in several models of diabetes and is associated with an impairment in ß-cell function, was high in Gck+/+HFHS mice, but not in Gck+/-HFHS mice. CONCLUSIONS: Glucokinase haploinsufficiency prevents the progressive deterioration of pancreatic ß-cell mass/function and glucose tolerance in long-term HFHS diet-fed mice.

Improved time in range and postprandial hyperglycemia with canagliflozin in combination with teneligliptin: Secondary analyses of the CALMER study.

AIMS/INTRODUCTION: We recently reported the beneficial effect of the combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis. MATERIALS AND METHODS: The CALMER study was a multicenter, open-label, prospective, randomized, parallel-group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated. RESULTS: All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2-82.7%, P < 0.001). The extent of the reduction in time above target range was significantly larger in the COMB group compared with the SWITCH group (-14.8% vs -7.5%, P < 0.01). Area under the curve values for glucose at 120 min after all meal tolerance tests were significantly decreased in the COMB group compared with the SWITCH group (P < 0.05). CONCLUSIONS: Sodium-glucose cotransporter 2 inhibitor combined with dipeptidyl peptidase-4 inhibitor improved the quality of glycemic variability and reduced postprandial hyperglycemia compared with each monotherapy.