The Addition of Xanthan Gum to Enteral Nutrition Suppresses Postprandial Glycemia in Humans.

The semi-solidified nutrition supplemented with soluble dietary fiber, xanthan gum (XG), inhibited postprandial glycemia in rats. The purpose of the present study is to examine whether XG exerts the same effects in humans. Subjects fasted for 12 h and then ingested the enteral nutrient, Meibalance with or without XG at 9 AM. Blood glucose levels were measured 0, 20, 40, 60, and 120 min after its ingestion. Postprandial blood glucose levels were lower in the XG group than in the control group. At 20 min, postprandial blood glucose levels were significantly lower in the XG group (84±5.3 mg/dL) than in the control group (107±7.8 mg/dL) (p<0.05). A significant difference was also observed in ΔAUC between the two groups. These results demonstrate that XG exerts inhibitory effects on glucose excursion in humans.

Lipopolysaccharide inhibits hepatic gluconeogenesis in rats: The role of immune cells.

AIMS/INTRODUCTION: Bacterial septicemia has diverse clinical symptoms including severe hypoglycemia. However, sepsis-induced hypoglycemia has not yet been examined in detail. The aim of the present study was to investigate the mechanisms underlying hypoglycemia in sepsis. MATERIALS AND METHODS: We induced endotoxin shock in rats using lipopolysaccharide (LPS). After an intraperitoneal injection of LPS, we measured gluconeogenesis using the pyruvate tolerance test. The effects of LPS on glucose metabolism were investigated in perfused livers and isolated hepatocytes. Furthermore, its effects on the production of inflammatory cytokines were examined in isolated splenocytes. The interaction between splenocytes and hepatocytes in response to LPS was investigated in vitro using a co-culture of splenocytes and hepatocytes. RESULTS: In the pyruvate tolerance test, the pretreatment with LPS decreased gluconeogenesis. The in vivo pretreatment of rats with LPS did not inhibit glucose production in perfused livers. The in vitro treatment of isolated hepatocytes with LPS did not decrease hepatic gluconeogenesis. Although LPS increased the production of inflammatory cytokines (tumor necrosis factor-α, interferon-γ, interleukin-1ß, interleukin-6 and interleukin-10) and nitric oxide in isolated splenocytes, only nitric oxide significantly inhibited gluconeogenesis in isolated hepatocytes. When splenocytes and hepatocytes were co-cultured in medium containing LPS, the messenger ribonucleic acid expression of glucose-6-phosphatase in hepatocytes was suppressed. CONCLUSIONS: LPS reduced hepatic gluconeogenesis, at least in part, by stimulating the production of nitric oxide in splenocytes. This effect could contribute to the mechanisms responsible for septicemia-induced hypoglycemia.

Tetrahydrobiopterin activates brown adipose tissue and regulates systemic energy metabolism.

Brown adipose tissue (BAT) is a central organ that acts to increase energy expenditure; its regulatory factors could be clinically useful in the treatment of obesity. Tetrahydrobiopterin (BH4) is an essential cofactor of tyrosine hydroxylase and nitric oxide synthase (NOS). Although BH4 regulates the known regulatory factors of BAT, such as noradrenaline (NA) and NO, participation of BH4 in BAT function remains unclear. In the present study, we investigate the role of BH4 in the regulation of BAT. Hph-1 mice, a mouse model of BH4 deficiency, exhibit obesity, adiposity, glucose intolerance, insulin resistance, and impaired BAT function. Impaired BAT function was ameliorated together with systemic metabolic disturbances by BAT transplantation from BH4-sufficient mice (control mice) into BH4-deficient mice, strongly suggesting that BH4-induced BAT has a critical role in the regulation of systemic energy metabolism. Both NA derived from the sympathetic nerve and NO derived from endothelial NOS in the blood vessels participate in the regulation of BH4. In addition, a direct effect of BH4 in the stimulation of brown adipocytes via NO is implicated. Taken together, BH4 activates BAT and regulates systemic energy metabolism; this suggests an approach for metabolic disorders, such as obesity and diabetes.

Okara ameliorates glucose tolerance in GK rats.

Okara, a food by-product from the production of tofu and soy milk, is rich in three beneficial components: insoluble dietary fiber, ß-conglycinin, and isoflavones. Although isoflavones and ß-conglycinin have recently been shown to improve glucose tolerance, the effects of okara have not yet been elucidated. Therefore, we herein investigated the effects of okara on glucose tolerance in Goto-Kakizaki (GK) rats, a representative animal model of Japanese type 2 diabetes. Male GK rats were fed a 10% lard diet with or without 5% dry okara powder for 2 weeks and an oral glucose tolerance test was performed. Rats were then fed each diet for another week and sacrificed. The expression of genes that are the master regulators of glucose metabolism in adipose tissue was subsequently examined. No significant differences were observed in body weight gain or food intake between the two groups of GK rats. In the oral glucose tolerance test, increases in plasma glucose levels were suppressed by the okara diet. The mRNA expression levels of PPARγ, adiponectin, and GLUT4, which up-regulate the effects of insulin, were increased in epididymal adipose tissue by the okara diet. These results suggest that okara provides a useful means for treating type 2 diabetes.

Effect of nutritional counseling and long term isomaltulose based liquid formula (MHN-01) intake on metabolic syndrome.

The isomaltulose based liquid formula (MHN-01), suppresses postprandial plasma glucose and insulin levels in healthy persons and patients with impaired glucose tolerance (IGT) or type 2 diabetes. MHN-01 intake as a part of breakfast also suppresses glucose and insulin levels after lunch, suggesting second meal effect. The objective of this study was to investigate the effects of nutritional counseling and long-term (24 weeks) MHN-01 ingestion on biomarkers of metabolic syndrome. Forty-one subjects with criteria of metabolic syndrome participated in this study composed with the control period (0-12 week) followed by nutritional counseling and the experimental period (12-36 week) followed by 200 kcal (837 kJ) of MHN-01 or dextrin-based standard balanced liquid formula (SBF) loading as a part of breakfast. In 16 of 41 subjects became to out of criteria for liquid formula loading study during control period (unqualified group). In the unqualified group, several biomarkers were improved. In experimental period, serum HbA1c levels significantly increased in SBF group (n = 12) but did not change in MHN-01 group (n = 10). Thus, intake of 837 kJ MHN-01 as a part of breakfast may be effective for suppression of deteriorating glucose metabolism in metabolic syndrome.

DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells.

Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti-cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosome protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR-dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy.

Circulating TNF receptor 2 is closely associated with the kidney function in non-diabetic Japanese subjects.

AIM: Chronic kidney disease (CKD) is associated with cardiovascular events. Tumor necrosis factor (TNF) and/or its receptors have been postulated to be involved in renal pathophysiology. It is unclear whether an increased TNF system activity is present before the development of apparent CKD. METHODS: Four hundred and twenty non-diabetic Japanese subjects with an estimated GFR (eGFR) greater than 60 ml/min/1.73 m(2) were recruited for measurement of the HbA1c, insulin, TNF system activity (TNF-α, soluble TNF receptor 1 (sTNF-R1) and sTNF-R2) levels and various parameters, including the lipid, high-sensitivity C-reactive protein (hsCRP), high-molecular-weight (HMW) adiponectin and leptin levels. The subjects were stratified according to the eGFR: the G1 level (eGFR ≧90 ml/min/1.73 m(2)) and the G2 level (90 ＞eGFR ≧60 ml/min/1.73 m(2)). RESULTS: Whereas no significant differences were observed in gender, body mass index (BMI), blood pressure, insulin, TNF-α, hsCRP, HMW adiponectin or leptin between the two groups, the values for age, HbA1c, triglycerides, sTNF-R1 and sTNF-R2 were significantly higher in the subjects with a G2 level of eGFR than in those with a G1 level. In contrast, the HDL cholesterol levels were significantly lower in the subjects with a G2 level than in those with a G1 level. Linear negative correlations were also observed between eGFR and age, BMI, HbA1c, triglycerides, sTNF-R1 and sTNFR2, respectively. A multiple logistic regression analysis revealed that only sTNF-R2 was associated with the presence of a G2 level of eGFR (Odds ratio 1.092, 95% CI 1.013-1.177, P=0.021). CONCLUSIONS: The circulating sTNF-R2 level is closely associated with the kidney function in non-diabetic Japanese subjects.

Lack of goal attainment regarding the low-density lipoprotein cholesterol level in the management of type 2 diabetes mellitus.

OBJECTIVE: The management of diabetes mellitus includes controlling the blood glucose level, body weight, blood pressure and serum lipid level. The coexistence of diabetes and a high low-density lipoprotein cholesterol (LDL-C) level promotes atherosclerosis of the coronary arteries and increases the risk of coronary artery disease (CAD). We compared the rates of attainment of LDL-C goals in type 2 diabetes patients receiving primary and secondary prevention therapy, the former without a history of CAD and the latter with a history of CAD. Because patients receiving secondary prevention are at greater risk of coronary events, LDL-C management is especially important in this group. This study was designed to determine how frequently diabetic patients attain their LDL-C goals and identify the reasons for the lack of attainment. METHODS: The groups were distinguished according to the patients' medical records. Contributory factors for the patients not achieving their goals were recorded in a questionnaire filled out by each patient's physician. RESULTS: The overall attainment rate in both groups was 61%. The most frequent impediment in both groups was "an LDL-C level above or below the goal at every hospital visit" followed by "continuously sufficient effects of dietary therapy only" and the "management of LDL-C by other departments or hospitals," the latter reflecting the increasing problems of polydisease and polypharmacy in diabetes care. CONCLUSION: Polydisease and polypharmacy issues in diabetes patients with a history of CAD constitute a growing barrier to medication adherence and the attainment of treatment goals.

Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogenesis in an endothelial nitric oxide synthase-dependent manner in diabetic mice.

Endothelial nitric oxide synthase (eNOS) dysfunction induces insulin resistance and glucose intolerance. Tetrahydrobiopterin (BH4) is an essential cofactor of eNOS that regulates eNOS activity. In the diabetic state, BH4 is oxidized to 7,8-dihydrobiopterin, which leads to eNOS dysfunction owing to eNOS uncoupling. The current study investigates the effects of BH4 on glucose metabolism and insulin sensitivity in diabetic mice. Single administration of BH4 lowered fasting blood glucose levels in wild-type mice with streptozotocin (STZ)-induced diabetes and alleviated eNOS dysfunction by increasing eNOS dimerization in the liver of these mice. Liver has a critical role in glucose-lowering effects of BH4 through suppression of hepatic gluconeogenesis. BH4 activated AMP kinase (AMPK), and the suppressing effect of BH4 on gluconeogenesis was AMPK-dependent. In addition, the glucose-lowering effect and activation of AMPK by BH4 did not appear in mice with STZ-induced diabetes lacking eNOS. Consecutive administration of BH4 in ob/ob mice ameliorated glucose intolerance and insulin resistance. Taken together, BH4 suppresses hepatic gluconeogenesis in an eNOS-dependent manner, and BH4 has a glucose-lowering effect as well as an insulin-sensitizing effect in diabetic mice. BH4 has potential in the treatment of type 2 diabetes.

Circulating TNF receptor 2 is associated with the development of chronic kidney disease in non-obese Japanese patients with type 2 diabetes.

AIMS: Chronic low-grade inflammation and/or obesity are suggested to induce chronic kidney disease (CKD) in patients with type 2 diabetes. This cross-sectional study was performed to investigate the relationship between inflammatory biomarkers and CKD in non-obese patients with type 2 diabetes. METHODS: 106 non-obese Japanese patients with type 2 diabetes were recruited for the measurement of GFR, TNF, HMW adiponectin, leptin, hsCRP and some variables including urinary albumin. BMI, serum creatinine, and urinary albumin levels were 22.2 ± 0.2 kg/m(2) (17.1-24.9 kg/m(2)), 0.76 ± 0.02 mg/dl (0.39-1.38 mg/dl), 40.4 ± 4.3mg/gCr (1.6-195.0mg/gCr), respectively. They were stratified into two groups based on the value of eGFR: low eGFR (eGFR<60 ml/min/1.73 m(2)) and normal eGFR (eGFR>60 ml/min/1.73 m(2)). Logistic regression analysis was used for statistical analysis. RESULTS: Whereas univariate logistic regression analysis showed that gender, diabetes duration, triglyceride, HDL cholesterol, uric acid, urinary albumin, and soluble TNF receptors (sTNF-R1, sTNF-R2) are associated with the development of stage 3 CKD, multivariate logistic regression analysis revealed that sTNF-R2 (Odds ratio 1.003, 95% confidence interval 1.000 to 1.005, P=0.030) showed significant associations with the development of stage 3 CKD. CONCLUSIONS: Circulating TNF receptor 2 is an independent risk factor for CKD in non-obese Japanese patients with type 2 diabetes.

The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice.

Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic ß cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [(14)C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [(14)C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin-mediated pathway rather than through a GLP-1-mediated pathway.

Utility of indices using C-peptide levels for indication of insulin therapy to achieve good glycemic control in Japanese patients with type 2 diabetes.

UNLABELLED: Aims/Introduction: Type 2 diabetes is progressive in that therapy must be altered over time, which is partly as a result of the progressive loss of pancreatic ß-cell function. To elucidate the relationship between residual endogenous insulin secretion and the necessity of insulin therapy to achieve good glycemic control, indices using serum C-peptide immunoreactivity (CPR) were analyzed in patients with type 2 diabetes. MATERIALS AND METHODS: The data of 201 Japanese patients with type 2 diabetes who achieved the target of glycemic control during admission were analyzed retrospectively. Indices using CPR including fasting CPR (FCPR), CPR 6 min after intravenous injection of glucagon (CPR-6 min), increment of CPR (ΔCPR), secretory unit of islet in transplantation index (SUIT) and C-peptide index (CPI) were compared between the group requiring insulin (insulin group) and the group not requiring insulin (non-insulin group). A receiver-operator characteristic (ROC) curve was made, and optimal cut-off point and likelihood ratio were determined for each index. RESULTS: All indices of CPR were lower in the insulin group compared with those in the non-insulin group. Likelihood ratios at the optimal point of FCPR, CPR-6 min, ΔCPR, SUIT, and CPI were 2.0, 2.1, 1.6, 2.3 and 2.8, respectively. Optimal cut-off point of CPI was 1.1 ng/mg. Sensitivity and specificity at optimal point of CPI were 61 and 78%, respectively. CONCLUSIONS: The advantage of CPI of the indices of CPR to select insulin therapy to achieve good glycemic control was shown, but limitations of the predictive abilities of the indices using CPR should be taken into account. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00096.x, 2011).

Overexpression of SIRT5 confirms its involvement in deacetylation and activation of carbamoyl phosphate synthetase 1.

SIR2 protein, an NAD-dependent deacetylase, is localized to nucleus and is involved in life span extension by calorie restriction in yeast. In mammals, among the seven SIR2 homologues (SIRT1-7), SIRT3, 4, and 5 are localized to mitochondria. As SIRT5 mRNA levels in liver are increased by fasting, the physiological role of SIRT5 was investigated in liver of SIRT5-overexpressing transgenic (SIRT5 Tg) mice. We identified carbamoyl phosphate synthetase 1 (CPS1), a key enzyme of the urea cycle that catalyzes condensation of ammonia with bicarbonate to form carbamoyl phosphate, as a target of SIRT5 by two-dimensional electrophoresis comparing mitochondrial proteins in livers of SIRT5 Tg and wild-type mice. CPS1 protein was more deacetylated and activated in liver of SIRT5 Tg mice than in wild-type. In addition, urea production was upregulated in hepatocytes of SIRT5 Tg mice. These results agree with those of a previous study using SIRT5 knockout (KO) mice. Because ammonia generated during fasting is toxic, SIRT5 protein might play a protective role by converting ammonia to non-toxic urea through deacetylation and activation of CPS1.

Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients.

Multidrug and toxin extrusions (MATE1/SLC47A1 and MATE2-K/SLC47A2) play important roles in the renal excretion of metformin. We have previously identified the nonsynonymous MATE variants with functional defects at low allelic frequencies. The purpose of this study was to evaluate the effects of heterozygous MATE variants on the disposition of metformin in mice and humans. Pharmacokinetic parameters of metformin in Mate1(+ or -) heterozygous mice were comparable with those in Mate1(+ or +) wild-type mice. Among 48 Japanese diabetic patients, seven patients carried heterozygous MATE variant and no patient carried homozygous MATE variant. There was no significant difference in oral clearance of metformin with or without heterozygous MATE variants. In addition, creatinine clearance, but not heterozygous MATE variants, significantly improved the model fit of metformin clearance by statistical analysis using the nonlinear mixed-effects modeling program. In conclusion, heterozygous MATE variants could not influence the disposition of metformin in diabetic patients.

Rapamycin impairs metabolism-secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolism.

Rapamycin, an immunosuppressant used in human transplantation, impairs beta-cell function, but the mechanism is unclear. Chronic (24 h) exposure to rapamycin concentration dependently suppressed 16.7 mM glucose-induced insulin release from islets (1.65+/-0.06, 30 nM rapamycin versus 2.35+/-0.11 ng/islet per 30 min, control, n=30, P<0.01) without affecting insulin and DNA contents. Rapamycin also decreased alpha-ketoisocaproate-induced insulin release, suggesting reduced mitochondrial carbohydrate metabolism. ATP content in the presence of 16.7 mM glucose was significantly reduced in rapamycin-treated islets (13.42+/-0.47, rapamycin versus 16.04+/-0.46 pmol/islet, control, n=30, P<0.01). Glucose oxidation, which indicates the velocity of metabolism in the Krebs cycle, was decreased by rapamycin in the presence of 16.7 mM glucose (30.1+/-2.7, rapamycin versus 42.2+/-3.3 pmol/islet per 90 min, control, n=9, P<0.01). Immunoblotting revealed that the expression of complex I, III, IV, and V was not affected by rapamycin. Mitochondrial ATP production indicated that the respiratory chain downstream of complex II was not affected, but that carbohydrate metabolism in the Krebs cycle was reduced by rapamycin. Analysis of enzymes in the Krebs cycle revealed that activity of alpha-ketoglutarate dehydrogenase (KGDH), which catalyzes one of the slowest reactions in the Krebs cycle, was reduced by rapamycin (10.08+/-0.82, rapamycin versus 13.82+/-0.84 nmol/mg mitochondrial protein per min, control, n=5, P<0.01). Considered together, these findings indicate that rapamycin suppresses high glucose-induced insulin secretion from pancreatic islets by reducing mitochondrial ATP production through suppression of carbohydrate metabolism in the Krebs cycle, together with reduced KGDH activity.

Analysis of factors influencing pancreatic beta-cell function in Japanese patients with type 2 diabetes: association with body mass index and duration of diabetic exposure.

AIMS: To elucidate the clinical factors affecting beta-cell function, serum C-peptide immunoreactivity (CPR) levels of patients with type 2 diabetes were analyzed. METHODS: Seven hundred Japanese patients with type 2 diabetes were enrolled. beta-Cell function was evaluated by fasting CPR (FCPR), 6 min after intravenous injection of 1mg glucagon (CPR-6 min), and the increment of CPR (DeltaCPR). Simple regression analysis between FCPR, CPR-6 min, and DeltaCPR and measures of variables and stepwise multiple regression analysis were carried out. RESULTS: Years from diagnosis and BMI were the major independent variables predicting beta-cell function. Years from diagnosis was negatively correlated with CPR-6 min (P<0.0001, r=-0.271), and decrease in CPR-6 min was 0.050 ng/(ml year). BMI was positively correlated with CPR-6 min (P<0.0001, r=0.369). When subjects were divided according to BMI, the decrease in CPR-6 min per year in the high-BMI group (0.068 ng/(ml year)) was greater than that in the low-BMI group (0.035 ng/(ml year)). CONCLUSION: A linear decline in endogenous insulin secretion over more than several decades of diabetes was confirmed by this cross-sectional study. The duration of diabetes exposure and BMI are thus major factors in beta-cell function in Japanese patients with type 2 diabetes.

Glycemic instability in type 1 diabetic patients: Possible role of ketosis or ketoacidosis at onset of diabetes.

AIMS: In type 1 diabetic patients, some have glycemic instability while others glycemic stability. We have developed criteria for evaluating glycemic instability and investigated the factors responsible. METHODS: Glycemic instability in 52 type 1 diabetic patients was assessed by the mean amplitude of glycemic excursions (MAGE) and M-value, and clinical characteristics of good, fair and poor control groups were compared. RESULTS: The median MAGE and M-value was 6.6mmol/L and 18.7, respectively. Then MAGE >or=6.6mmol/L and M-value >or=18.7 was defined as poor control. In the 32 patients without detectable C-peptide levels, 18 patients (56%) showed poor control. The frequency of ketosis or ketoacidosis at onset of diabetes was dramatically higher in the poor control group not only in the patients as a whole but also in those without detectable C-peptide levels. CONCLUSIONS: A decreased level of C-peptide is a significant factor in glycemic instability. However, some patients have glycemic stability though beta-cell function is completely depleted. The presence of ketosis or ketoacidosis at onset of diabetes may be a factor in later glycemic instability, suggesting the importance of examining patients in detail at onset of diabetes for careful follow-up to prevent progression of acute and chronic complications of diabetes.

Dietary corosolic acid ameliorates obesity and hepatic steatosis in KK-Ay mice.

Corosolic acid (CRA), a constituent of Banaba leaves, has been reported to exert anti-hypertension, anti-hyperinsulinemia, anti-hyperglycemia, and anti-hyperlipidemia effects as well as to induce anti-inflammatory and anti-oxidative activities. The aim of this study was to investigate the inhibitory effects of CRA on the development of obesity and hepatic steatosis in KK-Ay mice, a genetically obese mouse model. Six-week-old KK-Ay mice were fed a high fat diet for 9 weeks with or without 0.023% CRA. Nine-week CRA treatment resulted in 10% lower body weight and 15% lower total fat (visceral plus subcutaneous fat) mass than in control mice. CRA treatment reduced fasting plasma levels of glucose, insulin, and triglyceride by 23%, 41%, and 22%, respectively. The improved insulin sensitivity in CRA-treated mice may be due on part to the increased plasma adiponectin and white adipose tissue (WAT) AdipoR1 levels. In addition, CRA treatment increased the expression of peroxisome proliferator-activated receptor (PPAR) alpha in liver and PPAR gamma in WAT. This is the first study to show that CRA treatment can contribute to reduced body weight and amelioration of hepatic steatosis in mice fed a high fat diet, due in part to increased expression of PPAR alpha in liver and PPAR gamma in WAT.

Short-term intensive glycemic control improves vibratory sensation in type 2 diabetes.

Strict long-term glycemic control has been reported to prevent or improve diabetic peripheral neuropathy, but the effects of short-term glycemic control have not been clarified in patients with type 2 diabetes. To investigate reversibility of impaired vibratory sensation by short-term glycemic control, we used the TM31 liminometer and C64 tuning fork methods to measure peripheral neuropathy. Thirty-one type 2 diabetes patients with poor glycemic control (HbA1c: 10.8+/-0.4%, mean+/-S.E.M., range from 7.9% to 16.2%) were administered strict glycemic control. Vibratory sensation before and after short-term glycemic control was evaluated, and the metabolic profile including plasma glucose, HbA1c, total cholesterol, HDL cholesterol, triglyceride, and free fatty acid (FFA) was measured. After 20.0+/-2.1 days of strict glycemic control, vibratory sensation improved significantly in both upper and lower extremities, assessed by TM31 liminometer and C64 tuning fork. Along with the improved glycemic control, lipid metabolism (total cholesterol, triglyceride and FFA) was significantly improved. Thus, short-term intensive glycemic control can improve vibratory sensation, metabolic changes in glucose and lipid metabolism being the factors responsible for improved of peripheral nerve function.

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.