Masashi Shimoda

Molecular mechanism by which pioglitazone preserves pancreatic β-cells in obese diabetic mice: evidence for acute and chronic actions as a PPARγ agonist

Pioglitazone preserves pancreatic β-cell morphology and function in diabetic animal models. In this study, we investigated the molecular mechanisms by which pioglitazone protects β-cells in diabetic db/db mice. In addition to the morphological analysis of the islets, gene expression profiles of the pancreatic islet were analyzed using laser capture microdissection and were compared with real-time RT-PCR of db/db and nondiabetic m/m mice treated with or without pioglitazone for 2 wk or 2 days. Pioglitazone treatment (2 wk) ameliorated dysmetabolism, increased islet insulin content, restored glucose-stimulated insulin secretion, and preserved β-cell mass in db/db mice but had no significant effects in m/m mice. Pioglitazone upregulated genes that promote cell differentiation/proliferation in diabetic and nondiabetic mice. In db/db mice, pioglitazone downregulated the apoptosis-promoting caspase-activated DNase gene and upregulated anti-apoptosis-related genes. The above-mentioned effects of pioglitazone treatment were also observed after 2 days of treatment. By contrast, the oxidative stress-promoting NADPH oxidase gene was downregulated, and antioxidative stress-related genes were upregulated, in db/db mice treated with pioglitazone for 2 wk, rather than 2 days. Morphometric results for proliferative cell number antigen and 4-hydroxy-2-noneal modified protein were consistent with the results of gene expression analysis. The present results strongly suggest that pioglitazone preserves β-cell mass in diabetic mice mostly by two ways; directly, by acceleration of cell differentiation/proliferation and suppression of apoptosis (acute effect); and indirectly, by deceleration of oxidative stress because of amelioration of the underlying metabolic disorder (chronic effect).

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.

Low bilirubin levels are an independent risk factor for diabetic retinopathy and nephropathy in Japanese patients with type 2 diabetes.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since lundi 8 juin 2015

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.

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.

Self-inducible secretion of glucagon-like peptide-1 (GLP-1) that allows MIN6 cells to maintain insulin secretion and insure cell survival.

Based on the hypothesis that MIN6 cells could produce glucagon-like peptide-1 (GLP-1) to maintain cell survival, we analyzed the effects of GLP-1 receptor agonist, exendin-4 (Ex4), and antagonist, exendin-(9-39) (Ex9) on cell function and cell differentiation. MIN6 cells expressed proglucagon mRNAs and produced GLP-1, which was accelerated by Ex4 and suppressed by Ex9. Moreover, Ex4 further enhanced glucose-stimulated GLP-1 secretion, suggesting autocrine loop-contributed amplification of the GLP-1 signal. Ex4 up-regulated cell differentiation- and cell function-related CREBBP, Pdx-1, Pax6, proglucagon, and PC1/3 gene expressions. The confocal laser scanning images revealed that GLP-1 positive cells were dominant in the early stage of cells, but positive for insulin were more prominent in the mature stage of cells. Ex4 accelerated cell viability, while Ex9 and anti-GLP-1 receptor antibody enhanced cell apoptosis. MIN6 cells possess a mechanism of GLP-1 signal amplification in an autocrine fashion, by which the cells maintained insulin production and cell survival.

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.

Appropriate therapy for type 2 diabetes mellitus in view of pancreatic β‐cell glucose toxicity: “the earlier, the better”

Pancreatic β‐cells secrete insulin when blood glucose levels become high; however, when β‐cells are chronically exposed to hyperglycemia, β‐cell function gradually deteriorates, which is known as β‐cell glucose toxicity. In the diabetic state, nuclear expression of the pancreatic transcription factors pancreatic and duodenal homeobox 1 (PDX‐1) and v‐Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA) is decreased. In addition, incretin receptor expression in β‐cells is decreased, which is likely involved in the impairment of incretin effects in diabetes. Clinically, it is important to select appropriate therapy for type 2 diabetes mellitus (T2DM) so that β‐cell function can be preserved. In addition, when appropriate pharmacological interventions against β‐cell glucose toxicity are started at the early stages of diabetes, β‐cell function is substantially restored, which is not observed if treatment is started at advanced stages. These observations indicate that it is likely that downregulation of pancreatic transcription factors and/or incretin receptors is involved in β‐cell dysfunction observed in T2DM and it is very important to start appropriate pharmacological intervention against β‐cell glucose toxicity in the early stages of diabetes.