Kenji Kohara

Vildagliptin preserves the mass and function of pancreatic β cells via the developmental regulation and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes

We investigated the molecular mechanisms by which vildagliptin preserved pancreatic β cell mass and function.

Protective effects of pioglitazone and/or liraglutide on pancreatic β-cells in db/db mice: Comparison of their effects between in an early and advanced stage of diabetes.

The aim was to compare the protective effects of pioglitazone (PIO) and/or liraglutide (LIRA) on β-cells with the progression of diabetes. Male db/db mice were treated with PIO and/or LIRA for 2 weeks in an early and advanced stage. In an early stage insulin biosynthesis and secretion were markedly increased by PIO and LIRA which was not observed in an advanced stage. In concomitant with such phenomena, expression levels of various β-cell-related factors were up-regulated by PIO and LIRA only in an early stage. Furthermore, β-cell mass was also increased by the treatment only in an early stage. Although there was no difference in apoptosis ratio between the two stages, β-cell proliferation was augmented by the treatment only in an early stage. In conclusion, protective effects of pioglitazone and/or liraglutide on β-cells were more powerful in an early stage of diabetes compared to an advanced stage.

Ice Cube Tray–Shaped Insulin Lipoatrophy Throughout the Abdomen in a Subject With Type 2 Diabetes

A 71-year-old woman with type 2 diabetes was referred to our hospital because of severe lipoatrophy throughout the whole abdomen induced by insulin therapy. The patient was diagnosed with type 2 diabetes when she was 63 years old and was treated with diet therapy only. When she was 69, her glycemic control became poor and insulin therapy was introduced (before breakfast, 20 units biphasic insulin Novolin 30R). Just after treatment began, she noticed that her abdomen gradually became atrophic, but she left it as it was. HbA1c levels were ∼8–9% (64–75 mmol/mol). She was treated only with biphasic insulin, and other antidiabetes agents were not used. Since her understanding about diabetes was poor, it was possible that she forgot to rotate the insulin injection site. When she was 71 years old, her glycemic control became …

Protective effects of SGLT2 inhibitor luseogliflozin on pancreatic β-cells in obese type 2 diabetic db/db mice

It is well known that Sodium-Glucose Co-transporter 2 (SGLT2) inhibitors, new hypoglycemic agents, improve glycemic control by increasing urine glucose excretion, but it remained unclear how they exert protective effects on pancreatic β-cells. In this study, we examined the effects of SGLT2 inhibitor luseogliflozin on β-cell function and mass using obese type 2 diabetic db/db mice. Ten-week-old male diabetic db/db mice were treated with luseogliflozin 0.0025% or 0.01% in chow (Luse 0.0025% or Luse 0.01%) or vehicle (control) for 4 weeks. Urinary glucose excretion was increased in Luse groups (0.0025% and 0.01%) compared to control mice 3 days after the intervention. Fasting blood glucose levels were significantly lower in mice treated with Luse compared to control mice. Fasting serum insulin concentrations were significantly higher in mice treated with Luse compared to control mice. Triglyceride levels tended to be lower in Luse groups compared to control mice. In immunohistochemical study using pancreas tissues, β-cell mass was larger in Luse groups compared to control group which was due to the increase of β-cell proliferation and decrease of β-cell apoptosis. Furthermore, in gene analysis using isolated islets, insulin 1, insulin 2, MafA, PDX-1 and GLUT2 gene expression levels were significantly higher in Luse groups compared to control group. In contrast, expression levels of fibrosis-related gene such as TGFβ, fibronectin, collagen I and collagen III were significantly lower in Luse groups. In conclusion, SGLT2 inhibitor luseogliflozin ameliorates glycemic control and thus exerts protective effects on pancreatic β-cell mass and function.

Association of GA/HbA1c ratio and cognitive impairment in subjects with type 2 diabetes mellitus

AIMS The aim of this study was to search for factors influencing cognitive impairment and to clarify the association between the fluctuation of blood glucose levels and cognitive impairment in elderly Japanese subjects with type 2 diabetes. METHODS We recruited 88 relatively elderly subjects (≥65years old) with type 2 diabetes who were hospitalized in Kawasaki Medical School from January 2014 to December 2015. We evaluated the fluctuation of blood glucose levels with glycoalbumin (GA)/hemoglobin A1c (HbA1c) ratio, and estimated cognitive impairment with Hasegawa dementia scale-revised (HDS-R) score and mini mental state examination (MMSE) score. RESULTS Multivariate analyses showed that GA/HbA1c ratio and urinary albumin excretion, but not hypoglycemia, were independent determinant factors for cognitive impairment in elderly Japanese subjects with type 2 diabetes. CONCLUSIONS The fluctuation of blood glucose levels per se is closely associated with cognitive impairment in elderly subjects with type 2 diabetes even when hypoglycemia is not accompanied. Since it is very easy to calculate GA/HbA1c ratio, we should check this ratio so that we can reduce the fluctuation of blood glucose levels especially in elderly subjects with type 2 diabetes.

Influence of atherosclerosis‐related risk factors on serum high‐sensitivity C‐reactive protein levels in patients with type 2 diabetes: Comparison of their influence in obese and non‐obese patients

Increased levels of high‐sensitivity C‐reactive protein (hs‐CRP) likely leads to the development of atherosclerosis. Therefore, it is very important to know which factors largely influence hs‐CRP levels. In the present study, we examined the influence of various atherosclerosis‐related factors on hs‐CRP levels in patients with type 2 diabetes.

Clinical effects of liraglutide are possibly influenced by hypertriglyceridemia and remaining pancreatic β-cell function in subjects with type 2 diabetes mellitus.

We searched for factors influencing the clinical effects of GLP-1 analogue liraglutide in subjects with type 2 diabetes. Multivariate analyses showed that hypertriglyceridemia and baseline HbA1c levels were independent predictors for the efficacy of liraglutide and that CPR index was an independent predictor for the durability of liraglutide.

Durability of protective effect of dulaglutide on pancreatic β-cells in diabetic mice: GLP-1 receptor expression is not reduced despite long-term dulaglutide exposure

AIMS It is well-known that chronic exposure to large amounts of ligand leads to downregulation of its receptor. It is not known, however, whether a GLP-1R agonist downregulates its receptor. For this reason, our study examined whether GLP-1R expression is reduced after long-term exposure to dulaglutide (Dula) in non-diabetic and diabetic mice. METHODS Seven-week-old male db/db and db/m mice were given either Dula (0.6mg/kg×2/week) or a control vehicle (CTL) for 17 weeks. Various metabolic parameters, such as glucose-stimulated insulin secretion (GSIS), insulin and TG content in islets, were evaluated after the intervention. β-cell-related gene expression was also analyzed by real-time RT-PCR. RESULTS In db/m mice, GLP-1R expression in β-cells did not decrease, not even after long-term administration of Dula, compared with control mice, while GLP-1R expression in 24-week-old db/db mice treated with Dula was augmented, rather than downregulated, compared with 24-week-old CTL db/db mice. This was probably due to improved glycaemic control. In db/db mice treated with Dula, food intake and blood glucose levels were significantly decreased up to 24 weeks of age compared with CTL db/db mice, and their expression levels of various β-cell-related genes, insulin content and GSIS were also enhanced. In contrast, oxidative and endoplasmic reticulum stress, inflammation, fibrosis and apoptosis were suppressed with Dula treatment. CONCLUSION Dula exerts beneficial effects on glycaemic control and has long-lasting protective effects on pancreatic β-cells. GLP-1R expression levels were not reduced at all in non-diabetic as well as diabetic mice despite long-term dulaglutide exposure.

Advanced breast cancer in a relatively young man with severe obesity and type 2 diabetes mellitus

It is known that male breast cancer is extremely rare and obesity is a strong risk factor of breast cancer in both male and female. In general, the prognosis in breast cancer in males is known to be very poor compared to that in females as it tends to be more advanced stage due to delayed initial diagnosis. Therefore, we should be aware of the possibility that breast cancer could be developed even in relatively young males without any specific risk factors especially when the subjects have severe obesity.

Decreased glucagon-like peptide 1 receptor expression in endothelial and smooth muscle cells in diabetic db/db mice: TCF7L2 is a possible regulator of the vascular glucagon-like peptide 1 receptor

Aims: Incretin signalling is known to prevent the development of arteriosclerosis by relaxation response in endothelial cells via the glucagon-like peptide 1 receptor. It remains unclear, however, whether vascular glucagon-like peptide 1 receptor expression is altered under some conditions. The aim of this study is to examine whether vascular glucagon-like peptide 1 receptor expression is altered by diabetic state as reported in pancreatic β-cells. Methods: We used 18-week-old male diabetic db/db mice and control db/m mice. Excised thoracic artery was specifically collected, and vascular endothelial cells were cultured. We compared the glucagon-like peptide 1 receptor expression levels between the db/db and db/m mice. Results: Metabolic parameters were significantly worse in db/db mice. The glucagon-like peptide 1 receptor and transcription factor 7-like 2 expression levels in endothelial and smooth muscle cells were significantly lower in db/db mice. Furthermore, siRNA to transcription factor 7-like 2 decreased the transcription factor 7-like 2 levels and such reduction of the transcription factor 7-like 2 resulted in the downregulation of the glucagon-like peptide 1 receptor expressions in cultured vascular endothelial cells. Conclusion: The glucagon-like peptide 1 receptor expression level was significantly lower under diabetic condition which was accompanied by the reduction of the transcription factor 7-like 2 expression level. Furthermore, the transcription factor 7-like 2 is a possible regulator of the glucagon-like peptide 1 receptor expression in artery as reported in β-cells.