Chizumi Yamada

Pancreatic and Extrapancreatic Effects of Gastric Inhibitory Polypeptide

The hormonal factor(s) implicated as transmitters of signals from the gut to pancreatic β-cells is referred to as incretin, and gastric inhibitory polypeptide (GIP) is identified as one of the incretins. GIP is a gastrointestinal peptide hormone of 42 amino acids that is released from duodenal endocrine K-cells after absorption of glucose or fat and exerts its effects by binding to its specific receptor, the GIP receptor. By generating and characterizing mice with a targeted mutation of the GIP receptor gene, we have shown that GIP has not only an insulinotropic role, but also physiological roles on fat accumulation into adipose tissues and calcium accumulation into bone. We here propose a new acronym, GIP, for gut-derived nutrient-intake polypeptide.

Effect of corosolic acid on gluconeogenesis in rat liver

Corosolic acid (CRA), an active component of Banaba leaves (Lagerstroemia speciosa L.), decreases blood glucose in diabetic animals and humans. In this study, we investigated the mechanism of action of CRA on gluconeogenesis in rat liver. CRA (20-100 microM) dose-dependently decreased gluconeogenesis in perfused liver and in isolated hepatocytes. Fructose-2,6-bisphosphate (F-2,6-BP), a gluconeogenic intermediate, plays a critical role in hepatic glucose output by regulating gluconeogenesis and glycolysis in the liver. CRA increased the production of F-2,6-BP along with a decrease in intracellular levels of cAMP both in the presence and in the absence of forskolin in isolated hepatocytes. While a cAMP-dependent protein kinase (PKA) inhibitor inhibited hepatic gluconeogenesis, the drug did not intensify the inhibitory effect of CRA on hepatic gluconeogenesis in isolated hepatocytes. These results indicate that CRA inhibits gluconeogenesis by increasing the production of F-2,6-BP by lowering the cAMP level and inhibiting PKA activity in isolated hepatocytes. Furthermore, CRA increased glucokinase activity in isolated hepatocytes without affecting glucose-6-phosphatase activity, suggesting the promotion of glycolysis. These effects on hepatic glucose metabolism may underlie the various anti-diabetic actions of CRA.

Optimal reference interval for homeostasis model assessment of insulin resistance in a Japanese population

The aim of the present study was to establish a reference interval for homeostasis model assessment of insulin resistance (HOMA‐IR) in a Japanese population based on the C28‐A3 document from the Clinical and Laboratory Standards Institute (CLSI). We selected healthy subjects aged 20–79 years, with fasting plasma glucose < 100 mg/dL, body mass index < 25 kg/m2 and alanine aminotransferase < 31 U/L. HOMA‐IR values were log transformed, values beyond mean ± 3 standard deviations (SD) were truncated, and the mean ± 2 SD of log HOMA‐IR values were taken as the upper and lower reference limits of HOMA‐IR. We selected 2173 subjects as reference individuals, and 2153 subjects were used for analysis. The reference interval for HOMA‐IR was established as between 0.4 and 2.4. This represents the first reference interval study for HOMA‐IR that applies the stringent CLSI C28‐A3 document. HOMA‐IR ≥ 2.5 should be considered a reasonable indicator of insulin resistance in Japanese. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00113.x, 2011)

Association between insulin resistance and plasma amino acid profile in non‐diabetic Japanese subjects

Elevation of the branched‐chain amino acids (BCAAs), valine, leucine and isoleucine; and the aromatic amino acids, tyrosine and phenylalanine, has been observed in obesity‐related insulin resistance. However, there have been few studies on Asians, who are generally less obese and less insulin‐resistant than Caucasian or African‐Americans. In the present study, we investigated the relationship between homeostasis model assessment of insulin resistance (HOMA‐IR) and plasma amino acid concentration in non‐diabetic Japanese participants.

Self-rated health as a comprehensive indicator of lifestyle-related health status

ObjectivesTo evaluate the usefulness of self-rated health (SRH) as a comprehensive indicator of lifestyle-related health status by examining the relationships between SRH and: (1) history of cancer and cardiovascular disease; (2) treatment of hypertension, diabetes, and dyslipidemia; (3) abnormalities in clinical parameters including blood pressure, fasting glucose, and lipids; and (4) lifestyle habits.Methods3744 health-check examinees at Tokai University Hachioji Hospital seen between April 2009 and March 2010 were enrolled. SRH was graded as “good,” “relatively good,” “relatively poor,” or “poor.” For statistical comparison, the differences among “healthy” (=good), “relatively healthy” (=relatively good), and “unhealthy” (=relatively poor plus poor) groups were examined. Mantel–Haenszel odds ratios were calculated to remove the confounding effect of age, using the healthy group as the reference. The Mantel-extension method was used as a trend test.Results1049 subjects rated their health as good, 2194 as relatively good, 428 as relatively poor, and 73 as poor. The prevalence of all diseases showed significant odds ratios and trends as SRH deteriorated. Obesity, blood pressure, glucose metabolism, and lipids deteriorated significantly as SRH became poorer, and a trend was observed in all parameters. Weight change, exercise, smoking, and rest showed significant odds ratios and trends as SRH deteriorated.ConclusionSRH appears useful as a comprehensive indicator of lifestyle-related health status.

Exendin-4 protects pancreatic beta cells from the cytotoxic effect of rapamycin by inhibiting JNK and p38 phosphorylation.

It has been reported that the immunosuppressant rapamycin decreases the viability of pancreatic beta cells. In contrast, exendin-4, an analogue of glucagon-like peptide-1, has been found to inhibit beta cell death and to increase beta cell mass. We investigated the effects of exendin-4 on the cytotoxic effect of rapamycin in beta cells. Incubation with 10 nM rapamycin induced cell death in 12 h in murine beta cell line MIN6 cells and Wistar rat islets, but not when coincubated with 10 nM exendin-4. Rapamycin was found to increase phosphorylation of c-Jun amino-terminal kinase (JNK) and p38 in 30 minutes in MIN6 cells and Wistar rat islets while exendin-4 decreased their phosphorylation. Akt and extracellular signal-regulated kinase (ERK) were not involved in the cytoprotective effect of exendin-4. These results indicate that exendin-4 may exert its protective effect against rapamycin-induced cell death in pancreatic beta cells by inhibiting JNK and p38 signaling.

Optimal cut-off point for homeostasis model assessment of insulin resistance to discriminate metabolic syndrome in non-diabetic Japanese subjects.

We have recently established a ‘health‐associated’ reference interval of homeostasis model assessment of insulin resistance (HOMA‐IR) between 0.4 and 2.4. In the present study, the aim was to establish a ‘decision‐based’ limit of HOMA‐IR for the discrimination of metabolic syndrome (MetS) in non‐diabetic Japanese subjects. The receiver–operating characteristic curve of HOMA‐IR for detecting MetS was developed using data from 6868 non‐diabetic subjects (3727 men, 3141 women). The optimal cut‐off point was determined based on the point that yielded the minimum value of the square root of [(1 – sensitivity)2 + (1 – specificity)2]. HOMA‐IR = 1.7 was determined as the optimal cut‐off value, with a sensitivity and specificity of 73.4% and 70.5% for men, and 81.5% and 77.0% for women, respectively. In conclusion, the optimal cut‐off value for HOMA‐IR to discriminate MetS in non‐diabetic Japanese subjects appears to be 1.7. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00194.x, 2012)

Impact of endogenous and exogenous insulin on basal energy expenditure in patients with type 2 diabetes under standard treatment

BACKGROUND Factors that affect resting energy expenditure or basal energy expenditure (BEE) in patients with type 2 diabetes under standard treatment have not been evaluated in detail. OBJECTIVE We determined the clinical factors that affected BEE in addition to body composition in patients with type 2 diabetes under standard treatment. DESIGN BEE was measured by using indirect calorimetry under a strict basal condition in 58 Japanese patients with type 2 diabetes after >7 d as inpatients under management of diabetes with medical nutrition therapy and medications. Insulin secretion was measured with a glucagon test. Stepwise regression was applied to explore determinants of BEE. RESULTS In the stepwise estimation, insulin secretion (P = 0.015), insulin therapy (P = 0.012), and pulse rate (P = 0.011) were selected in addition to fat-free mass (FFM) (P < 0.001) and fat mass (P = 0.006) as significant independent determinants of BEE. Standardized partial regression coefficients of the additional 3 factors were -0.16, -0.15, and 0.15, respectively, whereas those for FFM and fat mass were 0.82 and 0.19, respectively. The additional 3 factors explained another 3.9% of the variability of BEE, and the adjusted coefficient of determination was 83.4%. Age, sex, other medications, and parameters of glycemic control were not significant determinants beyond the combined contribution of body composition, endogenous and exogenous insulin, and pulse rate. CONCLUSION Endogenous insulin secretion and exogenous insulin administered in treatment have significant independent effects in the lowering of BEE in patients with diabetes under standard management with medical nutrition therapy and medications.

Effects of long-term dipeptidyl peptidase-IV inhibition on body composition and glucose tolerance in high fat diet-fed mice.

AIM Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are major incretins associated with body weight regulation. Dipeptidyl peptidase-IV (DPP-IV) inhibitor increases plasma active GLP-1 and GIP. However, the magnitude of the effects of enhanced GLP-1 and GIP signaling by long-term DPP-IV inhibition on body weight and insulin secretion has not been determined. In this study, we compared the effects of long-term DPP-IV inhibition on body composition and insulin secretion of high fat diet (HFD)-fed wild-type (WT) and GLP-1R knockout (GLP-1R(-/-)) mice. MAIN METHODS HFD-fed WT and GLP-1R(-/-) mice were treated with or without DPP-IV inhibitor by drinking water. Food and water intake and body weight were measured during 8 weeks of study. CT-based body composition analysis, Oral glucose tolerance test (OGTT), batch incubation study for insulin secretion and quantitative RT-PCR for expression of incretin receptors in isolated islets were performed at the end of study. KEY FINDINGS DPP-IV inhibitor had no effect on food and water intake and body weight, but increased body fat mass in GLP-1R(-/-) mice. DPP-IV inhibitor-treated WT and GLP-1R(-/-) mice both showed increased insulin secretion in OGTT. In isolated islets of DPP-IV inhibitor-treated WT and GLP-1R(-/-) mice, glucose-induced insulin secretion was increased and insulin secretion in response to GLP-1 or GIP was preserved, without downregulation of incretin receptor expression. SIGNIFICANCE Long-term DPP-IV inhibition may maintain body composition through counteracting effects of GLP-1 and GIP while improving glucose tolerance by increasing glucose-induced insulin secretion through the synergistic effects of GLP-1 and GIP.

Association between insulin resistance and metabolic syndrome risk factors in Japanese.

Aims/Introduction:  It is important to identify individuals at risk of metabolic syndrome (MetS), namely those with insulin resistance. Therefore, the aim of the present study was to find anthropometric and metabolic parameters that can better predict insulin resistance.