Hideaki Kaneto

Involvement of oxidative stress and the JNK pathway in glucose toxicity.

The hallmark of type 2 diabetes is pancreatic beta-cell dysfunction and insulin resistance. Normal beta-cells can compensate for insulin resistance by increasing insulin secretion, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates and insulin resistance becomes aggravated. Such phenomena are collectively called glucose toxicity. Under diabetic conditions, oxidative stress is induced and the JNK pathway is activated, which is involved in glucose toxicity. Activation of the JNK pathway suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of the JNK pathway in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Consequently, the JNK pathway plays a crucial role in the progression of pancreatic beta-cell dysfunction and insulin resistance and thus could be a potential therapeutic target for the glucose toxicity found in diabetes.

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.

Combination of DPP-4 inhibitor and PPARγ agonist exerts protective effects on pancreatic β-cells in diabetic db/db mice through the augmentation of IRS-2 expression.

We investigated the effects of long- and short-term treatment with pioglitazone (Pio) and/or alogliptin (Alo) on β-cells in diabetic db/db mice. Six-week-old male db/db mice received Pio (25xa0mg/kg, oral) and/or Alo (30xa0mg/kg, oral) for 4 weeks and for 2 days. Blood glucose levels were decreased after 4-week intervention, but not after 2-day intervention. Pio increased adiponectin levels, and Alo decreased glucagon levels and increased active GlP-1 levels. Insulin sensitivity was restored by Pio. After 4-week treatment, β-cell mass was increased (over 2-fold increase) and expression levels of various β-cell-related factors were restored. Expression levels of IRS-2 and various downstream factors were up-regulated by Pio and Alo after 2-day and 4-week intervention. In addition, mRNA and protein levels of IRS-2 and various downstream factors were up-regulated in MIN6 cells after 24-h exposure to Pio and exendin-4. These results suggest that Pio and Alo additively up-regulate IRS-2 expression independently of the alteration of glycemic control. Taken together, combination of Pio and Alo exerts protective effects on β-cells in diabetic db/db mice, at least in part, through the augmentation of IRS-2 expression.

Short-term selective alleviation of glucotoxicity and lipotoxicity ameliorates the suppressed expression of key β-cell factors under diabetic conditions.

Alleviation of hyperglycaemia and hyperlipidemia improves pancreatic β-cell function in type 2 diabetes. However, the underlying molecular mechanisms are still not well clarified. In this study, we aimed to elucidate how the expression alterations of key β-cell factors are altered by the short-term selective alleviation of glucotoxicity or lipotoxicity. We treated db/db mice for one week with empagliflozin and/or bezafibrate to alleviate glucotoxicity and/or liptotoxicity, respectively. The gene expression levels of Pdx1 and Mafa, and their potential targets, insulin 1, Slc2a2, and Glp1r, were higher in the islets of empagliflozin-treated mice, and levels of insulin 2 were higher in mice treated with both reagents, than in untreated mice. Moreover, compared to the pretreatment levels, Mafa and insulin 1 expression increased in empagliflozin-treated mice, and Slc2a2 increased in combination-treated mice. In addition, empagliflozin treatment enhanced β-cell proliferation assessed by Ki-67 immunostaining. Our date clearly demonstrated that the one-week selective alleviation of glucotoxicity led to the better expression levels of the key β-cell factors critical for β-cell function over pretreatment levels, and that the alleviation of lipotoxicity along with glucotoxicity augmented the favorable effects under diabetic conditions.

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.