Mihoko Hosoba

The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential.

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that has an antioxidative protective effect on various tissues. Here, we determined whether GLP-1 has a role in the pathogenesis of diabetic nephropathy using nephropathy-resistant C57BL/6-Akita and nephropathy-prone KK/Ta-Akita mice. By in situ hybridization, we found the GLP-1 receptor (GLP-1R) expressed in glomerular capillary and vascular walls, but not in tubuli, in the mouse kidney. Next, we generated C57BL/6-Akita Glp1r knockout mice. These mice exhibited higher urinary albumin levels and more advanced mesangial expansion than wild-type C57BL/6-Akita mice, despite comparable levels of hyperglycemia. Increased glomerular superoxide, upregulated renal NAD(P)H oxidase, and reduced renal cAMP and protein kinase A (PKA) activity were noted in the Glp1r knockout C57BL/6-Akita mice. Treatment with the GLP-1R agonist liraglutide suppressed the progression of nephropathy in KK/Ta-Akita mice, as demonstrated by reduced albuminuria and mesangial expansion, decreased levels of glomerular superoxide and renal NAD(P)H oxidase, and elevated renal cAMP and PKA activity. These effects were abolished by an adenylate cyclase inhibitor SQ22536 and a selective PKA inhibitor H-89. Thus, GLP-1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia, by inhibition of NAD(P)H oxidase, a major source of superoxide, and by cAMP-PKA pathway activation.

Comparisons of the effects of 12‐week administration of miglitol and voglibose on the responses of plasma incretins after a mixed meal in Japanese type 2 diabetic patients

To compare the effects of miglitol [an alpha‐glucosidase inhibitor (AGI) absorbed in the intestine] and voglibose (an AGI not absorbed) on plasma glucagon‐like peptide‐1 (GLP‐1) and gastric inhibitory polypeptide (GIP) levels, 26 and 24 Japanese type 2 diabetic patients were randomly assigned to receive miglitol or voglibose, respectively. After 12‐week administration of both drugs, during 2‐h meal tolerance test, plasma glucose, serum insulin and total GIP were significantly decreased and active GLP‐1 was significantly increased. Miglitol group showed a significantly lower total GIP level than voglibose group. Miglitol, but not voglibose, significantly reduced body weight (BW). In all participants, the relative change in BW was positively correlated with that of insulin significantly and of GIP with a weak tendency, but not of GLP‐1. In conclusion, both drugs can enhance postprandial GLP‐1 responses and reduce GIP responses. The significant BW reduction by miglitol might be attributable to its strong GIP‐reducing efficacy.

Miglitol induces prolonged and enhanced glucagon-like peptide-1 and reduced gastric inhibitory polypeptide responses after ingestion of a mixed meal in Japanese Type 2 diabetic patients.

At present, strategies of enhancing glucagon-like peptide-1 (GLP-1) action have received attention as new therapies in Type 2 diabetic patients (T2DM). In experimental studies in high-fat-fed animals, gastric inhibitory polypeptide (GIP) signals are reduced, obesity prevented and glycaemic control improved through reduction of insulin resistance [1]. Administration of α -glucosidase inhibitors (AGIs) simultaneously with nutrient intake leads to reduction of GIP responses and prolonged elevation of GLP-1 in healthy control subjects. These findings can be explained by the fact that AGIs move the absorption site of carbohydrates from the GIP-producing upper portions of intestine to the GLP-1 producing lower intestine. However, in T2DM, only a few studies in obese patients after a mixed meal have reported conflicting effects of AGIs on GLP-1 secretion [2–4] and a consistent finding of reduced GIP secretion [2,4]. Therefore, we measured plasma glucose (PG), insulin, GLP-1 (active and total forms) and GIP periodically for 3 h after ingestion of a mixed meal (56.5 g of carbohydrates, 18 g of protein, 18 g of fat) before and after administration of 50 mg miglitol three times per day for 14 days in nine Japanese T2DM subjects without severe obesity [glycated haemoglobin (HbA 1c ) 6.6 ± 0.16%; body mass index (BMI) 24.1 ± 1.0 kg/m 2 , (mean ± SE )] treated with diet therapy alone ( n = 5) or with oral glucose-lowering agents ( n = 4; glimepiride 1 or 2 mg/day in three cases; pioglitazone 30 mg/day in one case). Active forms of GLP-1 and total GIP levels, and total GLP-1 levels were measured with commercially available ELISA and RIA kits (Linco Research, St Charles, MO, USA), respectively. As seen in Fig. 1, in response to administration of miglitol, PG, insulin and GIP were unchanged at time 0 min, but during the early phase were significantly decreased. However, both active and total GLP-1 levels were significantly higher during the late phase. Our present study and that of Lee et al . [4] have demonstrated consistent enhancing effects of miglitol on GLP-1 responses to a mixed meal in T2DM. This is in contrast to results after treatment with acarbose, where the GLP-1 response to a mixed meal is unchanged [2,3]. Miglitol is absorbed in the upper portion of the intestine, where AGIs have their main effects [5]. In contrast, acarbose cannot be absorbed from the intestine. Accordingly, the relatively higher amount of carbohydrate absorption in the lower intestine with miglitol than with acarbose may explain the strong enhancement of GLP-1 secretion with miglitol treatment in T2DM subjects, although the percentages of miglitol and carbohydrates actually remaining in the lower part of the intestine are unknown. Additionally, the fact that our patients were not severely obese might partially explain the significant enhancement of GLP-1 response after miglitol; the GLP-1 response to carbohydrate is attenuated in obese individuals [6]. It is possible that the enhancement of postprandial active GLP-1 in response to miglitol might be as a result of dipeptidyl peptidase-4 (DPP-4) inhibition. However, enhancement of both active and total GLP-1 in our present study does not support this implication as DPP-4 inhibitors enhance active GLP-1 and reduce total GLP-1 levels [7]. In this 14-day study, we did not observe any change in body weight or determine directly a change in pancreatic B-cell function. A long-term follow-up study to examine the effects of miglitol on these parameters in relation to enhanced GLP-1 and reduced GIP secretion is warranted.

Modulation of renal superoxide dismutase by telmisartan therapy in C57BL/6-Ins2(Akita) diabetic mice.

Renal superoxide excess, which is induced by an imbalance of the superoxide-producing enzyme NAD(P)H oxidase and the superoxide-scavenging enzyme superoxide dismutase (SOD) under hyperglycemia, increases oxidative stress and contributes to the development of diabetic nephropathy. In this study, we treated non-obese and hypoinsulinemic C57BL/6-Ins2Akita (C57BL/6-Akita) diabetic mice with telmisartan (5 mg kg−1 per day), an angiotensin II type 1 receptor blocker, or amlodipine (5 mg kg−1 per day), a calcium channel blocker, for 4 weeks and compared the effects of these two anti-hypertensive drugs on renal NAD(P)H oxidase, SOD and transcription factor Nrf2 (NF-E2-related factor 2), which is known to upregulate several antioxidant enzymes including SOD. Vehicle-treated C57BL/6-Akita mice exhibited higher renal NAD(P)H oxidase and lower renal SOD activity with increased levels of renal superoxide than the C57BL/6-wild-type non-diabetic mice. Interestingly, telmisartan treatment not only reduced NAD(P)H oxidase activity but also enhanced SOD activity in C57BL/6-Akita mouse kidneys, leading to a reduction of renal superoxide levels. Furthermore, telmisartan-treated C57BL/6-Akita mice increased the renal protein expression of SOD and Nrf2. In parallel with the reduction of renal superoxide levels, a reduction of urinary albumin levels and a normalization of elevated glomerular filtration rate were observed in telmisartan-treated C57BL/6-Akita mice. In contrast, treatment with amlodipine failed to modulate renal NAD(P)H oxidase, SOD and Nrf2. Finally, treatment of C57BL/6-Akita mice with apocynin, an NAD(P)H oxidase inhibitor, also increased the renal protein expression of SOD and Nrf2. Collectively, our data suggest that NAD(P)H oxidase negatively regulates renal SOD, possibly by downregulation of Nrf2, and that telmisartan could upregulate renal SOD by the suppression of NAD(P)H oxidase and subsequent upregulation of Nrf2, leading to the amelioration of renal oxidative stress and diabetic renal changes.

Enhanced urinary adiponectin excretion in IgA-nephropathy patients with proteinuria.

Adiponectin is secreted specifically by adipose tissue. It was reported that the serum adiponectin level was markedly increased in patients with end-stage renal disease and was positively associated with abnormal renal function in type 2 diabetes. Recently, we found that urinary adiponectin level was significantly increased in type 2 diabetic patients with overt diabetic nephropathy, but not in those without nephropathy. The aim of the present study was to evaluate whether the urinary adiponectin level is increased not only in diabetic patients with macroalbuminuria but also in IgA-nephropathy patients with macroalbuminuria. We measured urinary adiponectin levels in 24 healthy control subjects, 12 IgA-nephropathy patients, and 19 type 2 diabetic nephropathy patients, and they were, in medians, 2.24 µg/g creatinine (ranges of 0.85 ~ 3.70), 59.2 µg/g creatinine (4.95 ~ 186), and 33.1 µg/g creatinine (4.69 ~ 114), respectively. In the two patient groups, urinary adiponectin levels were significantly higher than in control subjects (P < 0.01). Moreover, positive correlations between urinary adiponectin levels and albumin-to-creatinine ratios were observed in IgA-nephropathy (R2 = 0.53, P < 0.01) and diabetic nephropathy patients (R2 = 0.61, P < 0.01), but not in control subjects. Serum adiponectin levels were unchanged in these three groups. These findings suggested that the increase of urinary adiponectin levels partly results from enhanced filtration of circulating adiponectin through the changes of glomerular permselectivity and intraglomerular hydruric pressure. However, clinical implication of urinary adiponectin excretion in healthy control remains to be elucidated.

A case of insulinoma following total gastrectomy--effects of an alpha-glucosidase inhibitor on suppressing GIP and GLP-1 elevations.

A 61-year-old woman with fasting hypoglycemia following total gastrectomy was diagnosed as insulinoma. GIP and GLP-1 levels after a mixed meal were extremely increased. Administration of miglitol, an alpha-glucosidase inhibitor, suppressed the GIP and GLP-1 elevations.

Urinary Excretion of Transferrin and Orosomucoid Are Increased after Acute Protein Loading in Healthy Subjects

Background/Aims: The aim of this study was to elucidate what kind of plasma proteins would change their urinary excretions when the glomerular filtration rate (GFR) was increased. Methods: We measured urinary excretions of three plasma proteins with different molecular radii (MR) and isoelectric points (pI): albumin, orosomucoid (OM) and transferrin (Tf), after acute protein loading in healthy subjects. Results: Urinary excretion of OM with more anioic charge and smaller MR than albumin, and Tf with more cationic charge and slightly larger molecular weight than albumin, significantly increased in parallel with increased creatinine clearances after acute protein loading. These renal responses returned to basal levels 9 h after protein ingestion. In contrast, increases in urinary excretion of albumin were not observed. Conclusion: Because these findings could not be explained by changes in either size or charge selectivity of shunt pores in the glomerular capillary wall, it is suggested that urinary excretion of albumin may have a special property that distinguishes it from other plasma proteins and may be a less sensitive marker to reflect changes in renal hemodynamics than the other plasma proteins.

Efficacy and safety of patient‐directed titration of once‐daily pre‐dinner premixed biphasic insulin aspart 70/30 injection in Japanese type 2 diabetic patients with oral antidiabetic drug failure: STEP‐AKITA study

Aims/Introduction:  To clarify clinical characteristics related to optimal glycemic control achieved after adding once‐daily pre‐dinner biphasic insulin aspart 70/30 (BIAsp 30) in Japanese type 2 diabetic (T2D) patients with oral antidiabetic drug (OAD) failure.