Seizo Okauchi

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.

Beneficial effects of sodium-glucose cotransporter 2 inhibitors for preservation of pancreatic β-cell function and reduction of insulin resistance.

Type 2 diabetes mellitus is characterized by insulin resistance in various insulin target tissues, such as the liver, adipose tissue, and skeletal muscle, and insufficient insulin secretion from pancreatic β‐cells. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, which are newly developed antidiabetic agents, decrease blood glucose levels by enhancing urinary glucose excretion and thereby function in an insulin‐independent manner. Sodium–glucose cotransporter 2 inhibitors exert beneficial effects to reduce insulin resistance and preserve pancreatic β‐cell function. In addition, SGLT2 inhibitors exhibit a variety of beneficial effects in various insulin target tissues, such as amelioration of fatty liver, reduction of visceral fat mass, and increasing glucose uptake in skeletal muscle. Furthermore, SGLT2 inhibitors protect pancreatic β‐cells against glucose toxicity and preserve insulin secretory capacity. Together, these observations indicate that SGLT2 inhibitors are promising newly developed antidiabetic agents that are gaining attention in both clinical medicine and basic research.

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.

Beneficial effects of SGLT2 inhibitors for preservation of pancreatic β-cell function and reduction of insulin resistance

Type 2 diabetes mellitus is characterized by insulin resistance in various insulin target tissues, such as the liver, adipose tissue, and skeletal muscle, and insufficient insulin secretion from pancreatic β‐cells. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, which are newly developed antidiabetic agents, decrease blood glucose levels by enhancing urinary glucose excretion and thereby function in an insulin‐independent manner. Sodium–glucose cotransporter 2 inhibitors exert beneficial effects to reduce insulin resistance and preserve pancreatic β‐cell function. In addition, SGLT2 inhibitors exhibit a variety of beneficial effects in various insulin target tissues, such as amelioration of fatty liver, reduction of visceral fat mass, and increasing glucose uptake in skeletal muscle. Furthermore, SGLT2 inhibitors protect pancreatic β‐cells against glucose toxicity and preserve insulin secretory capacity. Together, these observations indicate that SGLT2 inhibitors are promising newly developed antidiabetic agents that are gaining attention in both clinical medicine and basic research.

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.

Promising Diabetes Therapy Based on the Molecular Mechanism for Glucose Toxicity: Usefulness of SGLT2 Inhibitors as well as Incretin-Related Drugs.

Pancreatic β-cell dysfunction and insulin resistance are the main characteristics of type 2 diabetes. Chronic exposure of β-cells to hyperglycemia leads to the deterioration of β-cell function. Such phenomena are well known as pancreatic β-cell glucose toxicity. MafA, a strong transactivator of insulin gene, is particularly important for the maintenance of mature β-cell function, but its expression level is significantly reduced under diabetic conditions which is likely associated with β-cell failure. Reduction of incretin receptor expression level in β-cells in diabetes is also likely associated with β-cell failure. On the other hand, incretin-related drugs and sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising diabetes therapy based on the mechanism for pancreatic β-cell glucose toxicity. Indeed, it was shown that incretin-related drugs exerted protective effects on β-cells through the augmentation of IRS-2 expression especially in the presence of pioglitazone. It was also shown that incretin-related drug and/or pioglitazone exerted more protective effects on β-cells at the early stage of diabetes compared to the advanced stage. SGLT2 inhibitors, new hypoglycemic agents, also exert beneficial effects for the protection of pancreatic β-cells as well as for the reduction of insulin resistance in various insulin target tissues. Taken together, it is important to select appropriate therapy based on the molecular mechanism for glucose toxicity.

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.

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.

Case of iliopsoas abscess that was markedly recovered after percutaneous and surgical drainage in a patient with poorly controlled type 2 diabetes.

We experienced a case of iliopsoas abscess which was markedly recovered after percutaneous and surgical drainage in a subject with poorly controlled type 2 diabetes. When iliopsoas abscess is suspected, physicians should survey patients by CT scan or MRI and should consider invasive treatment including surgical drainage.