Glucose Metabolism In Type Research Articles

Consumption of a Diet Low in Advanced Glycation End Products for 4 Weeks Improves Insulin Sensitivity in Overweight Women

OBJECTIVE High-heat cooking of food induces the formation of advanced glycation end products (AGEs), which are thought to impair glucose metabolism in type 2 diabetic patients. High intake of fructose might additionally affect endogenous formation of AGEs. This parallel intervention study investigated whether the addition of fructose or cooking methods influencing the AGE content of food affect insulin sensitivity in overweight individuals. RESEARCH DESIGN AND METHODS Seventy-four overweight women were randomized to follow either a high- or low-AGE diet for 4 weeks, together with consumption of either fructose or glucose drinks. Glucose and insulin concentrations-after fasting and 2 h after an oral glucose tolerance test-were measured before and after the intervention. Homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity index were calculated. Dietary and urinary AGE concentrations were measured (liquid chromatography tandem mass spectrometry) to estimate AGE intake and excretion. RESULTS When adjusted for changes in anthropometric measures during the intervention, the low-AGE diet decreased urinary AGEs, fasting insulin concentrations, and HOMA-IR, compared with the high-AGE diet. Addition of fructose did not affect any outcomes. CONCLUSIONS Diets with high AGE content may increase the development of insulin resistance. AGEs can be reduced by modulation of cooking methods but is unaffected by moderate fructose intake.

Autocrine role of interleukin-13 on skeletal muscle glucose metabolism in type 2 diabetic patients involves microRNA let-7

Low-grade inflammation associated with type 2 diabetes (T2DM) is postulated to exacerbate insulin resistance. We report that serum levels, as well as IL-13 secreted from cultured skeletal muscle, are reduced in T2DM vs. normal glucose-tolerant (NGT) subjects. IL-13 exposure increases skeletal muscle glucose uptake, oxidation, and glycogen synthesis via an Akt-dependent mechanism. Expression of microRNA let-7a and let-7d, which are direct translational repressors of the IL-13 gene, was increased in skeletal muscle from T2DM patients. Overexpression of let-7a and let-7d in cultured myotubes reduced IL-13 secretion. Furthermore, basal glycogen synthesis was reduced in cultured myotubes exposed to an IL-13-neutralizing antibody. Thus, IL-13 is synthesized and released by skeletal muscle through a mechanism involving let-7, and this effect is attenuated in skeletal muscle from insulin-resistant T2DM patients. In conclusion, IL-13 plays an autocrine role in skeletal muscle to increase glucose uptake and metabolism, suggesting a role in glucose homeostasis in metabolic disease.

Effects of RNA interference targeting angiotensin-converting enzyme on glucose metabolism in type 2 diabetic rats

Objective To investigate the effects of RNA interference (RNAi) targeting angiotensinconverting enzyme (ACE) on blood glucose,insulin resistance,as well as oxidative stress in type 2 diabetic rats.Methods Type 2 diabetic rats were divided into diabetes control group (caudal intravenation with control adenovirus named Ad5),gene treatment group (caudal intravenation with recombinant adenoviral vectors named Ad5-ACE-shRNA,expressing ACE gene-specific shRNA),and enalapril group (intragastric administration with enalapril every day).At the same time,the normal blood glucose control group was set up.All rats were injected two times during the experiment period.Blood glucose was measured before and after the intervention.At the third day of the experiment,expressions of ACE mRNA and protein in pancreas were evaluated by RT-PCR and Western blot,and serum concentrations of ACE and Ang Ⅱ were measured by ELISA.By the end of the experiment,insulin sensitivity index was calculated and expressions of glucose transporter 4 (GLUT4) protein of epididymal adipose tissue and NAD (P) H (p22phox) protein of pancreas were measured.Results Blood glucose levels in the gene treatment group [(17.8 ±1.1) mmol/L] and the enalapril group [(17.9 ± 1.2) mmol/L] were lower than that in the diabetes control group [(24.9 ± 1.3) mmol/L] when the experiment was finished.ACE mRNA and protein expressions in pancreas of the gene treatment group were significantly decreased compared with the diabetes control group (P ＜ 0.05).Serum concentrations of ACE and Ang Ⅱ in the gene treatment group were (16.37 ± 3.01) ng/ml and (18.24 ± 3.69)pg/ml,significantly lower than those of the diabetes control group [(46.67 ± 3.92) ng/ml and (44.93 ± 4.12) pg/ml respectively,both P＜0.05].Insulin sensitivity indexes of the gene treatment group and the enalapril group were (-5.14 ± 0.41) and (-5.17 ± 0.38),being all significantly higher than that of the diabetes control group (-6.18 ±0.46,both P＜0.05).Expressions of GLUT4 protein in epididymal adipose tissue were higher and expressions of p22phox protein in pancreas were lower in the gene treatment group and the enalapril group than those of the diabetes control group (both P＜0.05).Conclusions RNAi targeting ACE gene may delay the progress of hyperglycaemia and improve the situation of insulin resistance and oxidative stress.The RNAi technology may be used as a new strategy of gene therapy for diabetes mellitus. Key words: Angiotensin-converting enzyme; RNA interference; Diabetes mellitus ; Rats

Characterization of protein glycosylation in skeletal muscle of Type 2 diabetics after aerobic exercise training

Post‐translational modification of proteins play a key role in signal transduction. We hypothesized that skeletal muscle protein glycosylation is a mechanism for explaining impaired glucose metabolism in Type 2 Diabetes Mellitus (T2DM). The aim of this study was: i) to develop a method for large‐scale analysis of N‐linked protein glycosylation in skeletal muscle; and ii) to determine whether aerobic exercise training (AEX) that improved glycemic control in subjects with T2DM would alter muscle protein glycosylation patterns. Older, sedentary T2DM subjects (75±7 yrs; HbA1c 7.1±0.5%) completed 12 mos. of AEX and skeletal muscle biopsy samples were obtained at baseline and 12 mos. training. Muscle biopsy samples were enriched for glycoproteins using lectin affinity columns and then analyzed by tandem mass spectrometry. 87 N‐linked glycoproteins were identified in skeletal muscle. By comparing spectral counts at baseline and after AEX, a decrease in number of glycosylation sites or reduced glycoprotein levels were observed. Five proteins had reduced glycan count, including isoform H17 of myeloperoxidase which was down‐regulated after AEX. This was associated with significant reduction in HbA1c of 0.8±0.1%. Our data support the notion that improved glycemic control is associated with alterations of skeletal muscle protein glycosylation patterns.

The Effect of a Bile Acid Sequestrant on Glucose Metabolism in Subjects With Type 2 Diabetes

We designed an experiment to examine the effect of bile acid sequestration with Colesevelam on fasting and postprandial glucose metabolism in type 2 diabetes. To do so, we tested the hypothesis that Colesevelam increases the disposition index (DI), and this increase is associated with increased glucagon-like peptide-1 (GLP-1) concentrations. Thirty-eight subjects on metformin monotherapy were studied using a double-blind, placebo-controlled, parallel-group design. Subjects were studied before and after 12 weeks of Colesevelam or placebo using a labeled triple-tracer mixed meal to measure the rate of meal appearance (Meal Ra), endogenous glucose production (EGP), and glucose disappearance (Rd). Insulin sensitivity and β-cell responsivity indices were estimated using the oral minimal model and then used to calculate DI. Therapy with Colesevelam was associated with a decrease in fasting (7.0 ± 0.2 vs. 6.6 ± 0.2 mmol/L; P = 0.004) and postprandial glucose concentrations (3,145 ± 138 vs. 2,896 ± 127 mmol/6 h; P = 0.01) in the absence of a change in insulin concentrations. Minimal model–derived indices of insulin secretion and action were unchanged. Postprandial GLP-1 concentrations were not altered by Colesevelam. Although EGP and Rd were unchanged, integrated Meal Ra was decreased by Colesevelam (5,191 ± 204 vs. 5,817 ± 204 μmol/kg/6 h; P = 0.04), suggesting increased splanchnic sequestration of meal-derived glucose.

Comparison of effects of pitavastatin and atorvastatin on glucose metabolism in type 2 diabetic patients with hypercholesterolemia.

The distinct effects of different statins on glycemic control have not been fully evaluated. In this open-label, prospective, cross-over clinical trial, we compared the effects of pitavastatin and atorvastatin on glycemic control in type 2 diabetic patients with hypercholesterolemia. A total of 28 Japanese type 2 diabetics with hypercholesterolemia treated with rosuvastatin (2.5mg/day) for at least 8weeks were recruited to this quasi-randomized cross-over study. At study entry, the patients assigned to sequence 1 received pitavastatin (2mg/day) for 12weeks in period 1 and atorvastatin (10mg/day) for another 12weeks in period 2, whereas patients assigned to sequence 2 received atorvastatin (10mg/day) for 12weeks in period 1 and pitavastatin (2mg/day) for another 12weeks in period 2. Blood samples were collected at three visits (baseline, after 12 and 24weeks). Lipid control was similar in both statins. The difference in glycated hemoglobin between pitavastatin and atorvastatin treatments was -0.18 (95% confidence interval -0.34 to -0.02; P=0.03). Compared with atorvastatin, pitavastatin treatment significantly lowered the levels of glycoalbumin, fasting glucose and homeostasis model assessment of insulin resistance. Our results showed that treatment with pitavastatin had a more favorable outcome on glycemic control in patients with type 2 diabetes compared with atorvastatin. This trial was registered with UMIN (no. 000003554).

Use of dicarboxylic acids in type 2 diabetes

Even-number, medium-chain dicarboxylic acids (DAs), naturally occurring in higher plants, are a promising alternative energy substrate. Unlike the homologous fatty acids, DAs are soluble in water as salts. They are β-oxidized, providing acetyl-CoA and succinyl-CoA, the latter being an intermediate of the tricarboxylic acid cycle. Sebacic acid and dodecanedioic acid, DAs with 10 and 12 carbon atoms respectively, provide 6.6 and 7.2 kcal g⁻¹ each; therefore, their energy density is intermediate between glucose and fatty acids. Dicarboxylic acids have been proved to be safe in both experimental animals and humans, and their use has recently been proposed in diabetes. Studies in animals and humans with type 2 diabetes showed that oral administration of sebacic acid improved glycaemic control, probably by enhancing insulin sensitivity, and reduced hepatic gluconeogenesis and glucose output. Moreover, dodecanedioic acid intake reduced muscle fatigue during exercise in subjects with type 2 diabetes, suggesting an improvement of energy utilization and 'metabolic flexibility'. In this article, we review the natural sources of DAs, their fate in animals and humans and their effect in improving glucose metabolism in type 2 diabetes.

IL-15 expression in skeletal muscle by resistance exercise training in type 2 diabetic rats

Introduction: Interleukin-15 (IL-15) is reported as a myokine that potentially regulates body composition and glucose metabolism. We investigated the effect of 8 weeks of resistance exercise training on endogenous IL-15 expression in skeletal muscle and glucose tolerance with concomitant changes of body composition in type 2 diabetic rats.Methods: 6 week-old Male ZDF (Zucker diabetic fatty) and ZLC (ZDF Lean Control) rats were randomly divided into 4 groups: sedentary ZDF (Con-ZDF), exercised ZDF (Ex-ZDF), sedentary ZLC (Con-ZLC), and exercised ZLC (Ex-ZLC). Ex-ZDF and Ex-ZLC rats were trained (once every 3 days for 8 weeks) to climb a 1.1-m vertical (80° incline) ladder with weights secured to their tail for progressive workload resistance exercise (the training was started at 50% or 70% of maximal weight of the last trial). Body weight, grip strength and intraperitoneal glucose tolerance test (IPGTT) were evaluated at every week. Body composition was analyzed by PET-CT (Positron Emission Tomography – Computed Tomography) and expression of IL-15 was measured using ELISA in extracted soleus muscle and tibialis anterior muscle.Results: After 8 weeks of resistance training, substantial reduction of the body weight was observed in Ex-ZDF compared to Con-ZDF. Grip strength was also significantly increased in Ex-ZDF compared to Con-ZDF after 8 weeks of regular strength exercise indicating the efficacy of resistance training. Glucose tolerance (IPGTT) was significantly improved in Ex-ZDF (p<0.05) compared to Con-ZDF showing more delayed drop in blood glucose level between 90 min and 120 min. Concurrently, the expression of IL-15 was significantly increased (p<0.01) after training especially in soleus muscle of Ex-ZDF compared to Con-ZDF and also there was a tendency of increase in IL-15 expression in tibialis anterior muscle in Ex-ZDF as well. Accordingly, PET-CT scan showed that muscle quality tended to be higher in Ex-ZDF than Con-ZDF while no significant difference between Con-ZLC and Ex-ZLC.Discussion: 8 weeks of progressive resistance exercise significantly improved glucose tolerance with the concomitant increase of IL-15 expression in hind-limb muscles suggesting that increased level of IL-15 in skeletal muscle by resistance exercise might be a potential mediator in glucose regulation of type 2 diabetes. Further study is needed to elucidate the mechanisms by which how increased IL-15 expression in skeletal muscle by resistance exercise exerts a favorable influence on impaired glucose metabolism in type 2 diabetes mellitus. Introduction: Interleukin-15 (IL-15) is reported as a myokine that potentially regulates body composition and glucose metabolism. We investigated the effect of 8 weeks of resistance exercise training on endogenous IL-15 expression in skeletal muscle and glucose tolerance with concomitant changes of body composition in type 2 diabetic rats. Methods: 6 week-old Male ZDF (Zucker diabetic fatty) and ZLC (ZDF Lean Control) rats were randomly divided into 4 groups: sedentary ZDF (Con-ZDF), exercised ZDF (Ex-ZDF), sedentary ZLC (Con-ZLC), and exercised ZLC (Ex-ZLC). Ex-ZDF and Ex-ZLC rats were trained (once every 3 days for 8 weeks) to climb a 1.1-m vertical (80° incline) ladder with weights secured to their tail for progressive workload resistance exercise (the training was started at 50% or 70% of maximal weight of the last trial). Body weight, grip strength and intraperitoneal glucose tolerance test (IPGTT) were evaluated at every week. Body composition was analyzed by PET-CT (Positron Emission Tomography – Computed Tomography) and expression of IL-15 was measured using ELISA in extracted soleus muscle and tibialis anterior muscle. Results: After 8 weeks of resistance training, substantial reduction of the body weight was observed in Ex-ZDF compared to Con-ZDF. Grip strength was also significantly increased in Ex-ZDF compared to Con-ZDF after 8 weeks of regular strength exercise indicating the efficacy of resistance training. Glucose tolerance (IPGTT) was significantly improved in Ex-ZDF (p<0.05) compared to Con-ZDF showing more delayed drop in blood glucose level between 90 min and 120 min. Concurrently, the expression of IL-15 was significantly increased (p<0.01) after training especially in soleus muscle of Ex-ZDF compared to Con-ZDF and also there was a tendency of increase in IL-15 expression in tibialis anterior muscle in Ex-ZDF as well. Accordingly, PET-CT scan showed that muscle quality tended to be higher in Ex-ZDF than Con-ZDF while no significant difference between Con-ZLC and Ex-ZLC. Discussion: 8 weeks of progressive resistance exercise significantly improved glucose tolerance with the concomitant increase of IL-15 expression in hind-limb muscles suggesting that increased level of IL-15 in skeletal muscle by resistance exercise might be a potential mediator in glucose regulation of type 2 diabetes. Further study is needed to elucidate the mechanisms by which how increased IL-15 expression in skeletal muscle by resistance exercise exerts a favorable influence on impaired glucose metabolism in type 2 diabetes mellitus.

Effects of 12 weeks’ treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind prospective placebo-controlled study

Recent studies suggest that proton pump inhibitor treatment may increase insulin secretion and improve glucose metabolism in type 2 diabetes. In a randomised double-blind prospective placebo-controlled 2 × 2 factorial study, we examined the effect of esomeprazole on insulin secretion, HbA(1c) and cardiovascular risk factors in type 2 diabetes. Forty-one patients with type 2 diabetes using dietary control or oral glucose-lowering treatment were randomised to receive add-on esomeprazole 40 mg (n = 20) or placebo (n = 21) for 12 weeks. Randomisation was carried out prior to inclusion on the basis of a computer-generated random-number list. The allocation sequence was concealed in sealed envelopes from the researcher enrolling and assessing participants. The study was undertaken at Steno Diabetes Center, Gentofte, Denmark. The primary outcome was change in AUC for insulin levels during a meal test. Secondary outcomes were the levels of HbA(1c) and biochemical markers of cardiovascular risk, including lipids, coagulation factors, inflammation markers, markers of endothelial function and 24 h ambulatory BP measurements. Forty-one participants were analysed. In the esomeprazole-treated group the AUC for insulin did not change (before vs after treatment: 28,049 ± 17,659 vs 27,270 ± 32,004 pmol/l × min (p = 0.838). In the placebo group AUC for insulin decreased from 27,392 ± 14,348 pmol/l × min to 22,938 ± 11,936 pmol/l × min (p = 0.002). Esomeprazole treatment (n = 20) caused a ninefold increase in the AUC for gastrin. HbA(1c) increased from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.3 ± 0.8% (56 ± 6 mmol/mol) in the esomeprazole-treated group and from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.4 ± 0.8% (57 ± 6 mmol/mol) in the placebo group (n = 21) (p for difference in change >0.05). Except for BP, there were no differences between the groups in the markers of cardiovascular risk (p > 0.05). Monitoring of 24 h ambulatory BP showed a significant decrease in daytime systolic BP, daytime diastolic BP and 24 h diastolic BP in the placebo group (p < 0.05). No change in BP was seen in the patients treated with esomeprazole. Treatment with esomeprazole over 12 weeks did not improve insulin secretion, glycaemic control or cardiovascular disease biomarkers in patients with type 2 diabetes.

Kinetic Modeling of Human Hepatic Glucose Metabolism in Type 2 Diabetes Mellitus Predicts Higher Risk of Hypoglycemic Events in Rigorous Insulin Therapy

A major problem in the insulin therapy of patients with diabetes type 2 (T2DM) is the increased occurrence of hypoglycemic events which, if left untreated, may cause confusion or fainting and in severe cases seizures, coma, and even death. To elucidate the potential contribution of the liver to hypoglycemia in T2DM we applied a detailed kinetic model of human hepatic glucose metabolism to simulate changes in glycolysis, gluconeogenesis, and glycogen metabolism induced by deviations of the hormones insulin, glucagon, and epinephrine from their normal plasma profiles. Our simulations reveal in line with experimental and clinical data from a multitude of studies in T2DM, (i) significant changes in the relative contribution of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization; (ii) decreased postprandial glycogen storage as well as increased glycogen depletion in overnight fasting and short term fasting; and (iii) a shift of the set point defining the switch between hepatic glucose production and hepatic glucose utilization to elevated plasma glucose levels, respectively, in T2DM relative to normal, healthy subjects. Intriguingly, our model simulations predict a restricted gluconeogenic response of the liver under impaired hormonal signals observed in T2DM, resulting in an increased risk of hypoglycemia. The inability of hepatic glucose metabolism to effectively counterbalance a decline of the blood glucose level becomes even more pronounced in case of tightly controlled insulin treatment. Given this Janus face mode of action of insulin, our model simulations underline the great potential that normalization of the plasma glucagon profile may have for the treatment of T2DM.

Nerium oleanderDistillate Improves Fat and Glucose Metabolism in High-Fat Diet-Fed Streptozotocin-Induced Diabetic Rats

Diabetes was induced by intraperitoneal injection of streptozotocin (35 mg/kg bw) in all rats of five groups after being fed for 2 weeks high-fat diet. Type 2 diabetic Nerium-oleander- (NO-) administered groups received the NO distillate at a dose of 3.75, 37.5, and 375 μg/0.5 mL of distilled water (NO-0.1, NO-1, NO-10, resp.); positive control group had 0.6 mg glibenclamide/kg bw/d by gavage daily for 12 weeks. Type 2 diabetic negative control group had no treatment. NO distillate administration reduced fasting blood glucose, HbA1c, insulin resistance, total cholesterol, low density lipoprotein, atherogenic index, triglyceride-HDL ratio, insulin, and leptin levels. Improved beta cell function and HDL concentration were observed by NO usage. HDL percentage in total cholesterol of all NO groups was similar to healthy control. NO-10 distillate enhanced mRNA expressions of peroxisome proliferator-activated-receptor- (PPAR-) α, β, and γ in adipose tissue and PPAR-α–γ in liver. The findings from both in vivo and in vitro studies suggest that the considerable beneficial effect of NO distillate administration at a dose of 375 μg/0.5 mL of distilled water may offer new approaches to treatment strategies that target both fat and glucose metabolism in type 2 diabetes.

Effects of Carvedilol as Third-Line Add-On Therapy on Blood Pressure and Glucose Metabolism in Type 2 Diabetic Patients with Chronic Renal Disease Stage 3 and Above

Background: We evaluated the effect of coadministration of β-blocker (carvedilol) as the third agent with angiotensin II receptor blockers (ARB) and calcium channel blockers (CCB) on blood pressure (BP) regulation and glucose metabolism. Methods: Diabetic patients who did not achieve the therapeutic BP goal (140/90 mmHg) by ARB and CCB combination therapy were recruited. This study was designed to compare the BP regulating effects by adding carvedilol (10 mg/day, n=30) and by doubling the dose of either ARB (n=34) or CCB (n=31). Serum glucose metabolism was examined. Results: The carvedilol group showed a decrease (P<0.01) in BP from 166±11/90±8 to 156±9/84±7 mmHg at 12 weeks. In the ARB and CCB groups, BP also decreased (P<0.01) from 164±11/87±8 to 153±10/83±8 and 163±7/87±8 to 153±8/84±9 mmHg at 12 weeks. The rates of achieving therapeutic goal at 12 weeks were 36.7% in the carvedilol, 38.2% in the ARB and 41.9% in the CCB group. Serum glucose metabolism did not change in all groups. Conclusions: These results suggest that adding carvedilol decreased BP as safely as increasing the dose of ARB or CCB in patients with diabetic nephropathy.

Effect of Tacrolimus Versus Cyclosporine on Glucose Metabolism of Pancreas and Kidney Recipients in the Late (> 8 years) Posttransplant Period

Diabetogenic effects of immunosuppressive agents are of great importance in pancreas or islet transplantation. The aim of our study was to compare the glucose metabolism in type 1 diabetic kidney and pancreas recipients on tacrolimus (Tacro) versus cyclosporine-based (Cyclo) immunosuppression in the late posttransplant period. We examined 26 insulin-independent patients with stabile good renal function. They were at least 7 years after simultaneous pancreas and kidney transplantation and with unchanged immunosuppressive therapy for at least 6 years. The mean follow-up in Tacro (n = 13) and Cyclo (n = 13) groups were 9.7 ± 1.9 and 10.9 ± 1.3 years, respectively ( P = .08). Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA 1c), a standard intravenous glucose tolerance test (IVGTT) with coefficient of glucose assimilation (K G) calculation and trough Tacro/Cyclo levels were assessed. Insulin sensitivity and insulin secretion were evaluated using the homeostasis model assessment (HOMA-IR, HOMA-B). Total C-peptide and insulin secretions were calculated as areas under the curves (AUC) from the serum levels during the IVGTT. Tacro and Cyclo groups did not differ in age and body mass index. We did not find any significant difference in any examined parameters of glucose metabolism (fasting glycemia, insulin and C-peptide levels, HbA 1c, IVGTT with K G, HOMA-IR, HOMA-B, AUC of C-peptide and AUC of insulin; P > .05). Two patients in the Tacro group and none in the Cyclo group had K G <0.8%/min. Seven recipients in the Tacro group and eight in the Cyclo group had the normal glucose tolerance with K G ≥ 1.2%/min. Trough Tacro or Cyclo levels did not correlate with any of examined parameters. The use of different types of calcineurin inhibitors in type 1 diabetic pancreas and kidney recipients had no effect on glucose metabolism in the late posttransplant period.

Effects of raising muscle glycogen synthesis rate on skeletal muscle ATP turnover rate in type 2 diabetes

Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. We hypothesized that any impairment in insulin-stimulated muscle ATP production could merely reflect the lower rates of muscle glucose uptake and glycogen synthesis, rather than cause it. If this is correct, muscle ATP turnover rates in type 2 diabetes could be increased if glycogen synthesis rates were normalized by the mass-action effect of hyperglycemia. Isoglycemic- and hyperglycemic-hyperinsulinemic clamps were performed on type 2 diabetic subjects and matched controls, with muscle ATP turnover and glycogen synthesis rates measured using 31P- and 13C-magnetic resonance spectroscopy, respectively. In diabetic subjects, hyperglycemia increased muscle glycogen synthesis rates to the level observed in controls at isoglycemia [from 19 ± 9 to 41 ± 12 μmol·l−1·min−1 (P = 0.012) vs. 40 ± 7 μmol·l−1·min−1 in controls]. This was accompanied by a modest increase in muscle ATP turnover rates (7.1 ± 0.5 vs. 8.6 ± 0.7 μmol·l−1·min−1, P = 0.04). In controls, hyperglycemia brought about a 2.5-fold increase in glycogen synthesis rates (100 ± 24 vs. 40 ± 7 μmol·l−1·min−1, P = 0.028) and a 23% increase in ATP turnover rates (8.1 ± 0.9 vs. 10.0 ± 0.9 μmol·l−1·min−1, P = 0.025) from basal state. Muscle ATP turnover rates correlated positively with glycogen synthesis rates (rs = 0.46, P = 0.005). Changing the rate of muscle glucose metabolism in type 2 diabetic subjects alters demand for ATP synthesis at rest. In type 2 diabetes, skeletal muscle ATP turnover rates reflect the rate of glucose uptake and glycogen synthesis, rather than any primary mitochondrial defect.

Insulin in podocyte podiatry.

Insulin in podocyte podiatry.

Effect of Exenatide on Splanchnic and Peripheral Glucose Metabolism in Type 2 Diabetic Subjects

Our objective was to examine the mechanisms via which exenatide attenuates postprandial hyperglycemia in type 2 diabetes mellitus (T2DM). Seventeen T2DM patients (44 yr; seven females, 10 males; body mass index = 33.6 kg/m(2); glycosylated hemoglobin = 7.9%) received a mixed meal followed for 6 h with double-tracer technique ([1-(14)C]glucose orally; [3-(3)H]glucose i.v.) before and after 2 wk of exenatide. In protocol II (n = 5), but not in protocol I (n = 12), exenatide was given in the morning of the repeat meal. Total and oral glucose appearance rates (RaT and RaO, respectively), endogenous glucose production (EGP), splanchnic glucose uptake (75 g - RaO), and hepatic insulin resistance (basal EGP × fasting plasma insulin) were determined. After 2 wk of exenatide (protocol I), fasting plasma glucose decreased (from 10.2 to 7.6 mm) and mean postmeal plasma glucose decreased (from 13.2 to 11.3 mm) (P < 0.05); fasting and meal-stimulated plasma insulin and glucagon did not change significantly. After exenatide, basal EGP decreased (from 13.9 to 10.8 μmol/kg · min, P < 0.05), and hepatic insulin resistance declined (both P < 0.05). RaO, gastric emptying (acetaminophen area under the curve), and splanchnic glucose uptake did not change. In protocol II (exenatide given before repeat meal), fasting plasma glucose decreased (from 11.1 to 8.9 mm) and mean postmeal plasma glucose decreased (from 14.2 to 10.1 mm) (P < 0.05); fasting and meal-stimulated plasma insulin and glucagon did not change significantly. After exenatide, basal EGP decreased (from 13.4 to 10.7 μmol/kg · min, P = 0.05). RaT and RaO decreased markedly from 0-180 min after meal ingestion, consistent with exenatide's action to delay gastric emptying. Exenatide improves 1) fasting hyperglycemia by reducing basal EGP and 2) postmeal hyperglycemia by reducing the appearance of oral glucose in the systemic circulation.

Berberine Improves Glucose Metabolism in Diabetic Rats by Inhibition of Hepatic Gluconeogenesis

Berberine (BBR) is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS) was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway.

Effect of Fermented Yacon (Smallanthus Sonchifolius) Leaves Tea on Blood Glucose Levels and Glucose Metabolism in High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Mice

The aim of this study was to investigate the hypolgycemic activity of water extract of fermented yacon (Smallanthus sonchifolius) leaves tea (Yacon LWE) in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. Male ICR mice were fed with a HFD (37% calories from fat) for 4 weeks prior to intraperitoneal injection with STZ (100 mg/kg body weight). Diabetic mice were supplemented with two doses of Yacon LWE (0.16% and 0.8%, wt/wt) for 6 weeks. The supplementation of high-dose Yacon LWE significantly lowered blood glucose levels and plasma ALT and AST activities compared with the control group. High-dose Yacon LWE also improved the insulin tolerance without any changes in plasma and pancreatic insulin concentrations in HFD/STZ-induced diabetic mice. Yacon LWE supplementation increased the insulin staining of pancreatic -cells in a dose-dependent manner. Both 0.16% and 0.8% of Yacon LWE significantly elevated plasma leptin concentration, hepatic glucokinase activity and glucokinase/glucose-6-phosphatase ratio compared with the control group. However, glycosylated hemoglobin concentration was not different among the groups. These results suggest that high-dose Yacon LWE lowers the blood glucose level partly by enhancing insulin sensitivity and hepatic glucose metabolism in type 2 diabetic mice.

Effects of water extract and crude polysaccharides from Liriope spicata var. prolifera on InsR/IRS-1/PI3K pathway and glucose metabolism in mice

Aim of the study The present study was designed to investigate the effects of water extract (WE) and crude polysaccharides (CPs) from the tuberous root of Liriope spicata var. prolifer on the InsR/IRS-1/PI3K pathway and glucose metabolism in type 2 diabetic mice. Materials and methods WE and CPs were administered orally at different doses (200 and 100 mg/kg body weight) to streptozotocin (STZ)-induced type 2 diabetic male BABL/c mice, respectively. After 4 weeks of administration, immunohistochemistry and western blot were applied to detect the expression levels of insulin receptor-α (InsR-α), insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI3K) in renal tissues of mice. Moreover, the hepatic glycogen content, glucokinase (GK) and glucose-6-phosphatase (G6Pase) activities were measured to investigate the effect of WE and CPs on glucose metabolism. Results Compared with diabetic control, greater immunostaining for InsR-α, IRS-1 and PI3K was present in the tubulointerstitial regions of WE and CPS groups in renal tissues and the expression levels of these three signal molecules from WE and CPs groups were significantly increased; the glycogen content and GK activity from WE and CPs groups in liver were significantly increased, yet the G6Pase activity was significantly lower. Conclusions It is demonstrated that WE and CPs can ameliorate insulin signaling transduction and glucose metabolism, as a result, lessen IR and hyperglycemia eventually. So, this study has provided more powerful evidences for Liriope spicata var. prolifer to be a potential hypoglycemic agent and insulin sensitizer.

Physical Activity into the Meal Glucose—Insulin Model of Type 1 Diabetes: In Silico Studies

A simulation model of a glucose-insulin system accounting for physical activity is needed to reliably simulate normal life conditions, thus accelerating the development of an artificial pancreas. In fact, exercise causes a transient increase of insulin action and may lead to hypoglycemia. However, physical activity is difficult to model. In the past, it was described indirectly as a rise in insulin. Recently, a new parsimonious model of exercise effect on glucose homeostasis has been proposed that links the change in insulin action and glucose effectiveness to heart rate (HR). The aim of this study was to plug this exercise model into our recently proposed large-scale simulation model of glucose metabolism in type 1 diabetes to better describe normal life conditions. The exercise model describes changes in glucose-insulin dynamics in two phases: a rapid on-and-off change in insulin-independent glucose clearance and a rapid-on/slow-off change in insulin sensitivity. Three candidate models of glucose effectiveness and insulin sensitivity as a function of HR have been considered, both during exercise and recovery after exercise. By incorporating these three models into the type 1 diabetes model, we simulated different levels (from mild to moderate) and duration of exercise (15 and 30 minutes), both in steady-state (e.g., during euglycemic-hyperinsulinemic clamp) and in nonsteady state (e.g., after a meal) conditions. One candidate exercise model was selected as the most reliable. A type 1 diabetes model also describing physical activity is proposed. The model represents a step forward to accurately describe glucose homeostasis in normal life conditions; however, further studies are needed to validate it against data.