Naoki Shimo

Vitamin D deficiency is significantly associated with retinopathy in young Japanese type 1 diabetic patients.

The aim of this study was to examine the possible association of vitamin D deficiency with diabetic retinopathy in 75 young Japanese type 1 diabetic patients. A multivariate regression analysis, duration of diabetes and vitamin D deficiency were independent determinants of diabetic retinopathy.

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.

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.

Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet α-Cells into β-Cells in Vivo

Among the therapeutic avenues being explored for replacement of the functional islet β-cell mass lost in type 1 diabetes (T1D), reprogramming of adult cell types into new β-cells has been actively pursued. Notably, mouse islet α-cells will transdifferentiate into β-cells under conditions of near β-cell loss, a condition similar to T1D. Moreover, human islet α-cells also appear to poised for reprogramming into insulin-positive cells. Here we have generated transgenic mice conditionally expressing the islet β-cell–enriched Mafa and/or Pdx1 transcription factors to examine their potential to transdifferentiate embryonic pan–islet cell Ngn3-positive progenitors and the later glucagon-positive α-cell population into β-cells. Mafa was found to both potentiate the ability of Pdx1 to induce β-cell formation from Ngn3-positive endocrine precursors and enable Pdx1 to produce β-cells from α-cells. These results provide valuable insight into the fundamental mechanisms influencing islet cell plasticity in vivo.

A case of diabetic ketoacidosis after everolimus treatment.

Mammalian target-of-rapamycin (mTOR) inhibitors are now widely used as immunosuppressants after organ transplantation. Previous studies reported that the agents impair both insulin sensitivity and insulin secretory capacity, leading to an increased risk of hyperglycemia [1]. However, it remains unknown if they can cause lifethreatening severe hyperglycemia such as diabetic ketoacidosis (DKA), even in patients free from other diabetes-related risk factors, such as past history of hyperglycemia, old age, obesity, and family history of diabetes [2], who are less likely to develop diabetes. Here, we report a case of DKA after administration of an mTOR inhibitor, who had none of these clinical risk factors of diabetes. A 17-year-old boy was admitted to our hospital due to DKA. Fourteen months before the current admission, he underwent heart transplantation for end-stage dilated cardiomyopathy. After the transplantation, he kept receiving tacrolimus, prednisolone, and mycophenolate mofetil for immunosuppression. Eleven months after the transplantation (i.e., 3 months before the current admission), followup intravascular ultrasonography revealed the progression of cardiac allograft vasculopathy, and an mTOR inhibitor everolimus was additionally administered. He had never been diagnosed with diabetes or hyperglycemia, and neither did he have family history of diabetes. His casual plasma glucose and hemoglobin A1c levels 1 month before the add-on of everolimus were 111 mg/dl (6.2 mmol/l) and 5.0 % (31 mmol/mol), respectively. He was not obese, with 160 cm in height and 49.6 kg in body weight. Blood everolimus levels never exceeded the normal range. On the current admission, he complained of general fatigue, weight loss (5 kg in 1 month), thirst, polydipsia, and polyuria. Plasma glucose and HbA1c levels reached 500 mg/dl (27.8 mmol/l) and 11.1 % (98 mmol/mol), with insulin level 1.9 lU/ml, arterial pH 7.27, HCO3 level 13.8 mEq/l, anion gap 20.2 mEq/l, and total ketone level 11,088 lmol/l. He lacked any symptoms of an infection. White blood cells were 6490/ll in blood and negative in urine, with serum C-reactive protein level 0.10 mg/dl and urinary nitrite test negative. A chest X-ray also ruled out infectious status. Under the diagnosis with DKA, intravenous fluids and insulin were administered, followed by subcutaneous multiple daily insulin injection. Total ketone levels were decreased to 135 lmol/l 5 days after the treatment. His serum islet-specific autoantibodies, including glutamic acid decarboxylase (GAD), insulinoma antigen 2 (IA-2) and insulin antibodies, were later found to be negative. Since the current episode was suspected to be due to an everolimus-induced deterioration of glucose metabolism, everolimus was thereafter discontinued, while the other immunosuppressants were continued. However, because of a subsequent obvious progression of cardiac allograft vasculopathy, everolimus had to be restarted 8 months later. Under this temporary discontinuation of everolimus, the amelioration of impaired insulin secretion, as well as the decrease in insulin requirements, was observed (Table 1). Islet-specific autoantibodies rechecked right before the restart were again found negative. Total Managed by Antonio Secchi.

Preserving expression of Pdx1 improves β-cell failure in diabetic mice

Pdx1, a β-cell-specific transcription factor, has been shown to play a crucial role in maintaining β-cell function through transactivation of β-cell-related genes. In addition, it has been reported that the expression levels of Pdx1 are compromised under diabetic conditions in human and rodent models. We therefore aimed to clarify the possible beneficial role of Pdx1 against β-cell failure and generated the transgenic mouse that expressed Pdx1 conditionally and specifically in β cells (βPdx1) and crossed these mice with Ins2Akita diabetic mice. Whereas Pdx1 mRNA levels were reduced in Ins2Akita mice compared with their non-diabetic littermates, the mRNA levels of Pdx1 were significantly recovered in the islets of βPdx1; Ins2Akita mice. The βPdx1; Ins2Akita mice exhibited significantly improved glucose tolerance, compared with control Ins2Akita littermates, accompanied by increased insulin secretion after glucose loading. Furthermore, histological examination demonstrated that βPdx1; Ins2Akita mice had improved localization of SLC2A2 (GLUT2), and quantitative RT-PCR showed the recovered expression of Mafa and Gck mRNAs in the islets of βPdx1; Ins2Akita mice. These findings suggest that the sustained expression of Pdx1 improves β-cell failure in Ins2Akita mice, at least partially through the preserving expression of β-cell-specific genes as well as improved localization of GLUT2.

Sustained expression of GLP-1 receptor differentially modulates β-cell functions in diabetic and nondiabetic mice

Glucagon-like peptide 1 (GLP-1) has been shown to play important roles in maintaining β-cell functions, such as insulin secretion and proliferation. While expression levels of GLP-1 receptor (Glp1r) are compromised in the islets of diabetic rodents, it remains unclear when and to what degree Glp1r mRNA levels are decreased during the progression of diabetes. In this study, we performed real-time PCR with the islets of db/db diabetic mice at different ages, and found that the expression levels of Glp1r were comparable to those of the islets of nondiabetic db/misty controls at the age of four weeks, and were significantly decreased at the age of eight and 12 weeks. To investigate whether restored expression of Glp1r affects the diabetic phenotypes, we generated the transgenic mouse model Pdx1(PB)-CreER(TM); CAG-CAT-Glp1r (βGlp1r) that allows for induction of Glp1r expression specifically in β cells. Whereas the expression of exogenous Glp1r had no measurable effect on glucose tolerance in nondiabetic βGlp1r;db/misty mice, βGlp1r;db/db mice exhibited higher glucose and lower insulin levels in blood on glucose challenge test than control db/db littermates. In contrast, four weeks of treatment with exendin-4 improved the glucose profiles and increased serum insulin levels in βGlp1r;db/db mice, to significantly higher levels than those in control db/db mice. These differential effects of exogenous Glp1r in nondiabetic and diabetic mice suggest that downregulation of Glp1r might be required to slow the progression of β-cell failure under diabetic conditions.