Insulin Response Curve Research Articles

Arepas Made from High Amylose Corn Flour Produce Favorably Low Glucose and Insulin Responses in Healthy Humans

The importance of the amylose: amylopectin ratio in the postprandial glycemic and insulinemic responses to corn was studied in food products that might realistically be consumed. Healthy subjects were given test meals in the form of arepas made from ordinary (25% amylose) or high amylose (70% amylose) corn flour. The ordinary corn meal contained 45 g of potentially available starch. To exclude the possible influence of a lowered content of potentially available starch due to formation of resistant starch in the high amylose product, this product was evaluated at two levels and included either on the basis of potentially available starch (45 g) or total starch (including resistant starch) (45 g, i.e., 29 g potentially available starch), respectively. The rate of starch hydrolysis, measured in vitro employing a method based on chewing, was studied. In addition, the content of in vitro resistant starch was analyzed in all products. The meals containing high amylose corn flour produced lower areas under the glucose and insulin response curves (57 and 42% lower, respectively) than did the meals containing ordinary cornmeal. This could not be explained by a lower amount of potentially available starch. No differences were noted when subjects consumed the two high amylose meals of arepas, despite 36% lower potentially available starch in one of the meals. The rate of starch hydrolysis measured in vitro was slower in the high amylose corn products than in the ordinary corn product. Resistant starch in the ordinary product was 3 g/100 g dry matter, vs. -20 g/100 g dry matter in the high amylose products. We concluded that high amylose corn products have a potential to promote favorably low metabolic responses and high resistant starch contents.

Apple preload increased postprandial insulin sensitivity of a high glycemic rice meal only at breakfast.

The possible impact of preload food on insulin sensitivity has yet been reported. This study aimed to investigate the glycemic and insulinemic effect of an apple preload before breakfast, lunch and early supper, based on high glycemic index (GI) rice meals. Twenty-three healthy participants in Group 1 and 14 participants in Group 2 were served with the reference meal (white rice containing 50g of available carbohydrate) or experimental meals (apple preload and rice, each containing 15 and 35g of available carbohydrate). The meals were either served at 8:00 for breakfast, 12:30 for lunch or 17:00 for early supper to explore the possible effect of time factor. The group 1 assessed the postprandial and subsequent-meal glycemic effect of the test meals by continuous glucose monitoring (CGM), along with subjective appetite; The group 2 further investigated the glycemic and insulin effect by blood collection. The apple preload lowered the blood glucose peak value by 33.5%, 31.4% and 31.0% in breakfast, lunch and supper, respectively, while increased insulin sensitivity by 40.5% only at breakfast, compared with the rice reference. The early supper resulted significantly milder glycemic response than its breakfast and lunch counterparts did. The result of CGM tests was consistent with that of the fingertip blood tests. Apple preload performed the best at breakfast in terms of enhancing the insulin sensitivity. The preload treatment could effectively attenuate postprandial GR without increasing the area under insulin response curve in any of the three meals.

Prenatal stress promotes insulin resistance without inflammation or obesity in C57BL/6J male mice

During gestation, stress exposure increases the risk of developing cognitive and physiological alterations in either the long or short term. Among them, metabolic alterations have been described. Adipose tissue is responsible for the secretion of several factors involved in controlling body weight and energy expenditure, the regulation of insulin sensitivity, and the development of inflammation, among others. Moreover, the liver regulates glucose homeostasis and lipid metabolism, playing an essential role in developing insulin resistance. In this work, we analyzed if prenatal stress leads to alterations in metabolism and the relationship between these alterations and gene expression in the adipose tissue and the liver. Prenatal stress-exposed animals developed disturbances in the glucose and insulin response curve, showing in both tests higher glycemia than the control group. However, they did not exhibit increased body weight. At the same time, in the adipose tissue, we observed an increase in mRNA expression of Leptin and Resistin and a decrease in Adiponectin. In the liver, we observed a lower mRNA expression of several genes involved in glucose metabolism and fatty acid oxidation, such as Sirt1, Pgc1α, Pparα, among others. In both tissues, we observed a lower expression of inflammatory genes. These results suggest that prenatal stress exposure produces insulin resistance at both physiological and molecular levels without pro-inflammatory signaling or obesity.

Amylase-Dependent Regulation of Glucose Metabolism and Insulin/Glucagon Secretion in the Streptozotocin-Induced Diabetic Pig Model and in a Rat Pancreatic Beta-Cell Line, BRIN-BD11.

The current study was aimed at highlighting the role of blood pancreatic amylase in the regulation of glucose homeostasis and insulin secretion in a porcine model of streptozotocin- (STZ-) induced diabetes and in a rat pancreatic beta-cell line, BRIN-BD11. Blood glucose, plasma insulin, and glucagon levels were measured following a duodenal glucose tolerance test (IDGTT), in four pigs with STZ-induced type 2 diabetes (T2D pigs) and in four pigs with STZ-induced type 1 diabetes (T1D pigs). Four intact pigs were used as the control group. The effect of amylase supplementation on both acute and chronic insulin secretion was determined in a BRIN-BD11 cell line. The amylase infusion had no effect on the glucose utilization curve or glucagon levels in the healthy pigs. However, a significant lowering of insulin release was observed in healthy pigs treated with amylase. In the T2D pigs, the glucose utilization curve was significantly lowered in the presence of amylase, while the insulin response curve remained unchanged. Amylase also significantly increased glucagon release during the IDGTT in the T2D and T1D pigs, by between 2- and 4-fold. Amylase did not affect the glucose utilization curve in the T1D pigs. Amylase supplementation significantly decreased both acute and chronic insulin secretion in the BRIN-BD11 cells. These data confirm our previous observations and demonstrate the participation of pancreatic amylase in glucose absorption/utilization. Moreover, the present study clearly highlights the direct impact of pancreatic blood amylase on insulin secretion from pancreatic beta-cells and its interactions with insulin and glucagon secretion in a porcine model.

Fetal sex and maternal insulin resistance during mid-pregnancy: a retrospective cohort study

BackgroundRecent studies have suggested that fetal sex influences maternal glucose and insulin metabolism during pregnancy. We examined whether fetal sex is associated with maternal insulin resistance and the β-cell function during mid-pregnancy.MethodsThis retrospective study included singleton pregnant women who underwent a 75-g oral glucose tolerance test (OGTT) at 24–34 weeks of gestation due to positive diabetic screening. In addition to plasma glucose (PG), we measured plasma insulin during the OGTT to obtain surrogate indices associated with insulin resistance (IR), including homeostasis assessment model (HOMA) -IR and insulin sensitivity index (IsOGTT), and β-cell function, including insulinogenic index (II), HOMA-β, and area under the curve of insulin response. We compared these indices between women carrying male fetuses to those carrying female fetuses.ResultsThe study population included 617 women (mean age, 32.4 ± 4.9 years) with a mean pre-pregnancy body mass index (BMI) of 22.6±4.5. They underwent the 75g-OGTT at 29.0 ± 2.5 weeks. Two hundred fifty-eight (42%) women were diagnosed with gestational diabetes (GDM). There was no significant difference in maternal age, pre-pregnancy BMI, gestational age at OGTT, PG at OGTT, or the prevalence of GDM between women with a male fetus (n=338) (male group) and those with a female fetus (n=279) (female group). Regarding the indices of IR, IR was significantly higher and insulin sensitivity was lower in the female group than in the male group (HOMA-IR: 7.0 [5-9.6] vs. 6.2 [4.6-8.8], p< 0.05; IsOGTT: 5.86 [4.29-7.83] vs. 6.29 [4.59-8.84], p< 0.01) (median [quartile range]). These differences remained significant after adjustment for maternal age, pre-pregnancy BMI, gestational age and fasting PG at OGTT, and the diagnosis of GDM. In contrast, the β-cell function did not differ between the two groups.ConclusionMaternal IR during mid-pregnancy was significantly higher in women carrying a female fetus than in those with a male fetus. The sex of the fetus may affect maternal insulin sensitivity during mid-pregnancy.

376 Awardee Talk - Prenatal transportation stress alters physiology of suckling Brahman calves as mediated by changes in DNA methylation

Abstract Mechanisms by which prenatal programming alters the developmental trajectory of biological systems in utero is of relevance to animal agriculture. We hypothesized that prenatally stressed (PNS) calves would exhibit altered postnatal phenotype and differential methylation of DNA. Mature Brahman cows (n = 48) were transported for 2-h periods at 60, 80, 100, 120, and 140 (± 5) d of gestation or maintained as non-transported Controls (n = 48). PNS calves exhibited more excitable temperaments and increased circulating concentrations of cortisol. In response to a glucose tolerance test administered to a subset of PNS and Control bulls, PNS calves returned to basal concentrations of insulin more rapidly and exhibited a lower total area under the insulin response curve. In response to a lipopolysaccharide challenge administered to a subset of PNS and Control bulls, PNS calves exhibited greater circulating concentrations of cortisol and a greater change from baseline for IFN-γ and monocytes. Reduced representation bisulfite sequencing was used to assess methylation of DNA from white blood cells in a subset of 28-d-old bull calves. Because increased methylation of DNA in a gene promoter region typically results in decreased transcriptional activity, differentially methylated CG sites located within promoter regions (n = 1,205) were used to predict alterations to canonical pathways using Ingenuity Pathway Analysis software. There were 113 pathways altered (P ≤ 0.05) in PNS calves. Among these were pathways related to behavior, stress response, metabolism, and immune function. In support of our hypotheses, differential methylation in gene regions related to temperament, stress response, metabolism, and immune response corresponded to phenotypic differences observed in PNS calves, suggesting DNA methylation as a mechanistic basis for prenatal programming. The role of the prenatal epigenome in shaping postnatal outcomes provides novel opportunities to improve animal health and production traits.

Preserving β-cell function is the major determinant of diabetes remission following laparoscopic sleeve gastrectomy in Japanese obese diabetic patients

Laparoscopic sleeve gastrectomy has been proven effective in treating obesity-associated type 2 diabetes mellitus (T2DM). However, reports of the effect of laparoscopic sleeve gastrectomy on glucose metabolism in Japanese obese patients with T2DM are rare. The aim of this study was to evaluate the effects of laparoscopic sleeve gastrectomy on glucose tolerance in Japanese obese patients with T2DM, and to analyze factors influencing diabetes remission after surgery. This was a retrospective analysis of data for 24 consecutive patients with T2DM who underwent laparoscopic sleeve gastrectomy. We investigated weight loss and its impact on T2DM 1 year postoperatively. We also compared baseline characteristics and postoperative factors between patients who achieved diabetes remission and patients without remission. Mean body weight loss and percent total weight loss were 23.9 kg and 23.3%, respectively. Mean hemoglobin A1c levels dropped from 7.3 ± 0.3% to 6.1 ± 0.2%, and 18 patients (75%) achieved diabetes remission 1 year postoperatively. Patients achieving remission had significantly lower hemoglobin A1c levels (p = 0.026), higher fasting C-peptide values (p < 0.001), shorter diabetes duration (p < 0.001), lower insulin requirement (p = 0.002), and higher area under the insulin response curve (p < 0.001) and insulinogenic index (p < 0.001) during oral glucose tolerance testing. In conclusion, laparoscopic sleeve gastrectomy is an effective treatment for Japanese obese patients with T2DM. Preserving insulin secretion is the major determinant of diabetes remission.

Disrupted normal ingestion during glucose intake modulates glucose kinetics in humans.

This study aims to reveal the importance of chemical senses in glucose kinetics and autonomic nervous activity by imposing interventions during glucose intake. The glucose-loading test was applied to seven healthy individuals. Three successive oral glucose-loadings induced a gradual downward shift in the blood glucose curves (BGC) together with increased salivary α-amylase activity (s-AMY) and positively correlated with satisfaction scores. On the other hands, adding a pleasant flavor given during the third trial increased the BGC to the same level as that during the first loading with decreased s-AMY value. Direct intragastric delivery of glucose or clipping the nose induced a downward shift in both BGC and serum insulin response curves (IRC), resulting in a decrease of the area under the BGC, positively correlated with the area under the IRC and satisfaction scores, respectively. The present study suggests that disrupted normal ingestion during glucose intake modulates glucose kinetics along with increased s-AMY values, indicating enhanced sympathetic nervous activity and favorable chemical senses are important in maintaining glucose kinetics.

Dominant-negative inhibition of glucose-dependent insulinotropic polypeptide impairs function of β cells in transgenic pigs.

Dear Editor: Glucose-dependent insulinotropic polypeptide (GIP) and proglucagon product glucagon-like peptide-1 (GLP-1) and their corresponding receptors promote secretion of glucose-dependent insulin[1] and may be responsible for up to 70% of postprandial insulin secretions[2]. A diminished incretin effect is typical for type 2 diabetes mellitus (T2DM) patients and their normoglycemic first-degree relatives due to reduced insulinotropic action of GIP[3]. Desensitization of the GIP/GIPR axis[4], down-regulation of GIP receptor (GIPR) on β cells[5], and variation in the GIPR gene[6] all contribute to reduced insulinotropic activity of GIP. GIPRdn encodes human GIPR that is modified in the region of the third intracellular loop by a single mutation (Ala340→Glu340) and deletion of eight amino acids (residues 319–326) essential for signal transduction[8]. In this study, we produced porcine transgenic fibroblasts that overexpressed a GIPRdn under the control of rat Ins2 promoter in the pancreas. The study protocol was approved by the local institutional review board and animal study was done in accordance with established national and institutional guidelines. Oral glucose tolerance tests (OGTTs) in 2-month-old GIPRdn pigs and controls revealed no differences in area under the glucose response curve (AUCglucose) between the two groups (P = 0.07, Fig. 1A). However, the postprandial blood glucose declined slowly and the area under the insulin response curve (AUCinsulin) in GIPRdn pigs increased 2.3-fold versus the controls, implying impaired glucose tolerance (P = 0.02; Fig. 1B). OGTTs in 5-month-old GIPRdn pigs and controls showed no significant differences in glucose levels or insulin content between the groups (Fig. 1C, 1D). Additionally, we observed no significant differences in the insulin response profiles between 2-month-old and 5-month-old controls. However, AUCinsulin was reduced by 44% when the transgenic pigs grew from 2 months to 5 months of ages (Fig. 1E, 1F). To clarify the effect of GIPRdn expression on the proliferation of pancreatic cells, we measured insulin and Ki67 expression by immunohistochemistry in 5-month-old GIPRdn pigs and age-matched controls. Compared with the controls, the number and volume of islets in transgenic pigs decreased. Insulin expression in the islets was reduced by 83% (P<0.01) in 5-month-old GIPRdn pigs (Fig. 2A-2C). In addition, Ki67 expression in GIPRdn pigs decreased to 36% of controls, suggesting that GIPRdn expression impaired islet development and reduced insulin secretion (Fig. 2D-2F). Fig. 1 Oral glucose tolerance test in GIPRdn transgenic (Tg) and wild type (wt) pigs. Fig. 2 Insulin and Ki67 expression in the pancreas. Transgenic mice overexpressing a dominant-negative GIPR were found to develop diabetes accompanied by a marked fasting hypoinsulinemia and severe reduction of β-cell mass by 10 days of age[7]. Similarly, transgenic pigs overexpressing a dominant-negative GIPR exhibited a pre-diabetic phenotype of hyperglycemia and hyperinsulinemia in OGTT[8]. However, no transgenic pigs had developed fasting hyperglycemia. In this study, 2-month-old GIPRdn pigs exhibited a slow decline in postprandial blood glucose and an increase in insulin secretion following an oral glucose load. This increase was approximately 2.3 times higher than in the control, thus imitating insulin secretion in the prodromal stage of T2DM. As the pigs grew up, pancreas development was significantly impaired due to the compromised GIP/GIPR axis, which resulted in reduced insulin secretion and islet dysfunction. Studies indicated that GIP and GLP-1 induced the transcription of beta cell proliferation, differentiation, survival and transcription of some genes[9]. GIP was believed to be the mitogen of beta cells, resulting in insulin secretion and inhibiting the apoptosis of beta cells. In this study, there were no significant differences in insulin content between the 5-month-old groups. However, the oral glucose load of 5-month-old transgenic pigs resulted in a 44% decrease in insulin secretion compared with the 2-month-old transgenic pigs. This is consistent with previous studies and implies progression of T2DM. Defective pancreatic proliferation led to fewer and smaller islets, which were excessively activated to produce more insulin by compensatory mechanism. Overload pressure from the compensation mechanism and impaired proliferation for inactivated GIP/GIPR axis further deteriorated islet function. Similar to the previous study[9], the transgenic pigs did not develop diabetes until 2 years of age. Diabetes is caused by many factors; a single gene change would not lead to the occurrence of the disease. In summary, GIPRdn pigs exhibit impaired glucose metabolism and beta cell function and simulated the phenotype of the prodromal stage in diabetes and progression of the disease.

Hyperandrogenemia in polycystic ovary syndrome: exploration of the role of free testosterone and androstenedione in metabolic phenotype.

ObjectiveTo evaluate the association between androstenedione, testosterone, and free testosterone and metabolic disturbances in polycystic ovary syndrome.MethodsWe analyzed the association between androstenedione, testosterone, and free testosterone and metabolic parameters in a cross-sectional study including 706 polycystic ovary syndrome and 140 BMI-matched healthy women. Polycystic ovary syndrome women were categorized into 4 groups: normal androstenedione and normal free testosterone (NA/NFT), elevated androstenedione and normal free testosterone (HA/NFT), normal androstenedione and elevated free testosterone (NA/HFT), elevated androstenedione and free testosterone (HA/HFT).ResultsPolycystic ovary syndrome women with elevated free testosterone levels (HA/HFT and NA/HFT) have an adverse metabolic profile including 2 h glucose, HbA1c, fasting and 2 h insulin, area under the insulin response curve, insulin resistance, insulin sensitivity index (Matsuda), triglycerides, total and high density lipoprotein cholesterol levels compared to NA/NFT (p<0.05 for all age- and BMI-adjusted analyses). In binary logistic regression analysis adjusted for age and BMI, odds ratio for insulin resistance was 2.78 (1.34–5.75, p = 0.006) for polycystic ovary syndrome women with HA/HFT compared to NA/NFT. We found no significantly increased risk of metabolic disorders in polycystic ovary syndrome women with HA/NFT. In multiple linear regression analyses (age- and BMI-adjusted), we found a significant negative association between androstenedione/free testosterone-ratio and area under the insulin response curve, insulin resistance, and total cholesterol/high density lipoprotein cholesterol-ratio and a positive association with Matsuda-index, and high density lipoprotein cholesterol (p<0.05 for all).ConclusionsPolycystic ovary syndrome women with elevated free testosterone levels but not with isolated androstenedione elevation have an adverse metabolic phenotype. Further, a higher androstenedione/free testosterone-ratio was independently associated with a beneficial metabolic profile.

Faster In and Faster Out: Accelerating Insulin Absorption and Action by Insulin Infusion Site Warming

This study was undertaken to investigate the effect of an insulin infusion site warming device, the InsuPatch(40)(™) (IP(40)) (InsuLine Medical Ltd., Petach-Tikvah, Israel), on insulin aspart pharmacodynamics (PD) and pharmacokinetics (PK) in adolescents with type 1 diabetes. Seventeen subjects with type 1 diabetes (age, 15±1 years; hemoglobin A1c, 7.5±0.2% [58±2.2 mmol/mol]) underwent two euglycemic clamps performed on separate mornings with and without IP(40) activation with warming temperature at 40°C. On both days, the basal infusion was suspended, and glucose levels were maintained between 90 and 100 mg/dL by a variable rate dextrose infusion for up to 5 h after a 0.2 U/kg bolus of insulin aspart. Time to peak insulin action and time to half-maximal action occurred earlier with a greater early glucodynamic effect (area under the curve [AUC] for glucose infusion rate from 0 to 30 min) with IP(40) than without the IP(40), whereas the AUC for the time-action profile and the peak action did not differ with and without infusion site warming. PK parameters were in agreement with PD parameters, namely, a significantly earlier time to reach the maximum increment in insulin concentrations and greater early bioavailability (AUC for the change in insulin concentration from 0 to 30 min) with the IP(40). The tail of the plasma insulin response curve was also shortened with infusion site warming, with the time to reach baseline insulin concentration occurring significantly earlier (P=0.04). Our data demonstrate that skin warming around the infusion site to 40°C with the IP(40) is an effective means to accelerate absorption and action of rapid-acting insulin. These improvements in time-action responses have the potential to enhance the performance of open- and closed-loop insulin delivery systems.

Effects of Exercise Intensity on Postprandial Improvement in Glucose Disposal and Insulin Sensitivity in Prediabetic Adults

A single bout of exercise improves postprandial glycemia and insulin sensitivity in prediabetic patients; however, the impact of exercise intensity is not well understood. The present study compared the effects of acute isocaloric moderate (MIE) and high-intensity (HIE) exercise on glucose disposal and insulin sensitivity in prediabetic adults. Subjects (n=18; age 49±14 y; fasting glucose 105±11 mg/dL; 2 h glucose 170±32 mg/dL) completed a peak O2 consumption/lactate threshold (LT) protocol plus three randomly assigned conditions: 1) control, 1 hour of seated rest, 2) MIE (at LT), and 3) HIE (75% of difference between LT and peak O2 consumption). One hour after exercise, subjects received an oral glucose tolerance test (OGTT). Plasma glucose, insulin, and C-peptide concentrations were sampled at 5- to 10-minute intervals at baseline, during exercise, after exercise, and for 3 hours after glucose ingestion. Total, early-phase, and late-phase area under the glucose and insulin response curves were compared between conditions. Indices of insulin sensitivity (SI) were derived from OGTT data using the oral minimal model. Compared with control, SI improved by 51% (P=.02) and 85% (P<.001) on the MIE and HIE days, respectively. No differences in SI were observed between the exercise conditions (P=.62). Improvements in SI corresponded to significant reductions in the glucose, insulin, and C-peptide area under the curve values during the late phase of the OGTT after HIE (P<.05), with only a trend for reductions after MIE. These results suggest that in prediabetic adults, acute exercise has an immediate and intensity-dependent effect on improving postprandial glycemia and insulin sensitivity.

Melatonin improves metabolic syndrome induced by high fructose intake in rats

In this study, we examined whether melatonin improves metabolic syndrome induced by high fructose intake in male Wistar rats. Feeding of a diet containing 60% fructose (HFD) for 4 or 6 wk caused increased serum insulin, triglyceride, total cholesterol, free fatty acids, uric acid, leptin, and lipid peroxide concentrations as well as hepatic triglyceride and cholesterol concentrations, and relative intra-abdominal fat and liver weights. The 4- or 6-wk HFD feeding reduced serum high-density lipoprotein cholesterol and adiponectin concentrations. The 6-wk HFD feeding increased serum tumor necrosis factor-α concentration and hepatic lipid peroxide concentration and lowered hepatic reduced glutathione concentration. Daily intraperitoneal administration of melatonin (1 or 10mg/kg body weight), starting at 4-wk HFD feeding, attenuated these changes at 6-wk HFD feeding more effectively at its higher dose than at its lower dose. In an oral glucose tolerance test, rats with 4- or 6-wk HFD feeding showed higher serum insulin response curve and normal serum glucose response curve when compared with the corresponding animals that received the control diet. The 4- or 6-wk HFD feeding caused insulin resistance, judging from the scores of HOMR-IR and QUICKI, which are indices of insulin resistance. The daily administered melatonin (1 or 10mg/kg body weight) ameliorated the higher serum insulin response curve in the oral glucose tolerance test and insulin resistance at 6-wk HFD feeding more effectively at its higher dose than at its lower dose. These results indicate that melatonin improves metabolic syndrome induced by high fructose intake in rats.

Apoptotic markers indicate nonalcoholic steatohepatitis in polycystic ovary syndrome

Background: Polycystic ovary syndrome (PCOS) characterized by chronic anovulation and hyperandrogenism is highly associated with obesity and insulin resistance (IR), two key features of nonalcoholic steatohepatitis (NASH). NASH often leads to cirrhosis, including portal hypertension, liver failure, and hepatocellular carcinoma as long-term complications. The caspase 3-cleaved fragment of cytokeratin 18 (CK18) emerging from ongoing cell death during apoptosis process has been established as a serum marker for NASH. This study was conducted to evaluate the prevalence of NASH in PCOS patients by caspase-cleaved CK18 measurement. Methods: In 192 PCOS patients [age, 29.0 ± 6.7 yr; body mass index (BMI), 31.5 ± 8.2 kg/m2] and 73 age-matched controls (age, 28.6 ± 8.0 yr; BMI, 24.1 ± 4.6 kg/m2), obesity and IR were determined by BMI and area under the curve of insulin response (AUCI), respectively. Apoptotic cell death was measured by M30 ELISA detecting caspase-cleaved CK18 only. Results: M30 levels were signifi...

Apoptotic Markers Indicate Nonalcoholic Steatohepatitis in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) characterized by chronic anovulation and hyperandrogenism is highly associated with obesity and insulin resistance (IR), two key features of nonalcoholic steatohepatitis (NASH). NASH often leads to cirrhosis, including portal hypertension, liver failure, and hepatocellular carcinoma as long-term complications. The caspase 3-cleaved fragment of cytokeratin 18 (CK18) emerging from ongoing cell death during apoptosis process has been established as a serum marker for NASH. This study was conducted to evaluate the prevalence of NASH in PCOS patients by caspase-cleaved CK18 measurement. In 192 PCOS patients [age, 29.0 +/- 6.7 yr; body mass index (BMI), 31.5 +/- 8.2 kg/m(2)] and 73 age-matched controls (age, 28.6 +/- 8.0 yr; BMI, 24.1 +/- 4.6 kg/m(2)), obesity and IR were determined by BMI and area under the curve of insulin response (AUCI), respectively. Apoptotic cell death was measured by M30 ELISA detecting caspase-cleaved CK18 only. M30 levels were significantly elevated in PCOS patients after correction for BMI (304.7 +/- 223.1 vs. 86.3 +/- 165.6 U/liter; P < 0.001). M30 correlated significantly with BMI, AUCI, glucose secretion, low-density lipoprotein, low high-density lipoprotein, and free androgen index. AUCI turned out to be the only independent M30-determining factor in the multiple regression analysis with an effect size of 7.9%. Fifty-one of 186 (27.4%) PCOS patients showed M30 levels of at least 395 U/liter, indicating NASH. These data demonstrate elevation of apoptotic cell death, its correlation with IR, and a high prevalence of NASH in PCOS patients. Given this high prevalence, PCOS may be a risk factor for progressive hepatic sequelae. Incidence data are of strong interest.

Oligofructose and inulin modulate glucose and amino acid metabolism through propionate production in normal-weight and obese cats

The effect of dietary oligofructose and inulin supplementation on glucose metabolism in obese and non-obese cats was assessed. Two diets were tested in a crossover design; a control diet high in protein (46 % on DM basis), moderate in fat (15 %), low in carbohydrates (27 %), but no soluble fibres added; and a prebiotic diet, with 2.5 % of a mixture of oligofructose and inulin added to the control diet. Eight non-obese and eight obese cats were allotted to each of two diets in random order at intervals of 4 weeks. At the end of each testing period, intravenous glucose tolerance tests were performed. Area under the glucose curve (AUCgluc) was increased (P = 0.022) and the second insulin peak was delayed (P = 0.009) in obese compared to non-obese cats. Diets did not affect fasting plasma glucose concentrations, blood glucose response at each glucose time-point after glucose administration, AUCgluc, fasting serum insulin concentrations, area under the insulin curve, and height and appearance time of insulin response. Yet, analysis of acylcarnitines revealed higher propionylcarnitine concentrations (P = 0.03) when fed the prebiotic diet, suggesting colonic fermentation and propionate absorption. Prebiotic supplementation reduced methylmalonylcarnitine (P = 0.072) and aspartate aminotransferase concentrations (P = 0.025), both indicating reduced gluconeogenesis from amino acids. This trial evidenced impaired glucose tolerance and altered insulin response to glucose administration in obese compared to non-obese cats, regardless of dietary intervention; yet modulation of glucose metabolism by enhancing gluconeogenesis from propionate and inhibition of amino acid catabolism can be suggested.

Effects Of Exercise Intensity On Post-prandial Glucose Disposal In Abdominally Obese Adults

INTRODUCTION: The effects of acute exercise on post-prandial glucose disposal are equivocal. PURPOSE: To examine the impact of exercise intensity on the blood glucose and insulin responses to an oral glucose tolerance test (OGTT). METHODS: Eleven abdominally obese adults (n=11; age, 25.2 +/- 1.3 yrs; BMI, 38.5 +/- 1.5 kg/m2; % body fat, 43.9 +/- 2.1%; waist circumference, 114.2 +/- 4.1 cm; VO2peak, 17.7 +/- 1.1 ml/kg/min) completed a VO2peak/lactate threshold (LT) protocol plus 4 randomly assigned exercise sessions; 1) rest (C; no exercise); 2) low, (L; 50% of difference between LT and rest), 3) moderate (M; @ LT); and 4) high, (H; 50% of difference between LT and VO2peak). Sessions were calorically equivalent to 200kcal, calculated from min-by-min energy expenditure by open circuit spirometry. One hour after the onset of exercise, subjects received a 75-g OGTT. Glucose and insulin were assayed from blood samples collected before (-30 to 0 min), during (0 to 60min) and after exercise (60 to 240min) at 5-10min intervals. RESULTS: There were no significant differences among conditions in post OGTT 1) area under the glucose concentration curve (mg/dl/180-min; C, 21690 +/- 1288; L, 21691 +/- 1192; M, 22502 +/- 1369; H, 21748+/-1152; p=.80) and 2) area under the insulin response curve (μIU/ml/180-min; C, 9936 +/- 1091; L, 10222 +/- 778; M, 9823 +/- 876; H, 9771 +/- 894; p=.97, n=9). Blood glucose concentrations returned to baseline by 180-min after OGTT in all experimental conditions (mg/dl; baseline, C=89, L=92, M=94, H=93; 180-min, C= 84, L=94, M=90, H=89; p=.887). CONCLUSIONS: In abdominally obese adults a single bout of exercise did not affect post-prandial glucose and insulin responses.

Variation In Cortisol Changes And Insulin Sensitivity During Detraining

PURPOSE: To determine whether alteration in insulinemia due to abstention from regular exercise training would be associated with changes in serum dehydroepiandrosterone sulfate (DHEA-S) and cortisol, 18 highly trained badminton players (21.2±0.32 years) were enrolled into a 2-month detraining study. METHODS: Fasting serum insulin, glucose, DHEA-S, and cortisol were determined at trained state and after at day 60 of detraining. Glucose tolerance and insulin sensitivity were assessed by an oral glucose tolerance test (OGTT). RESULTS: The 2-month detraining increased fasting glucose and insulin concentrations and body weight slightly, but did not affect glucose tolerance and insulin response curve, in which 10 subjects had increased and 8 subjects had not increased in the area under curve for insulin (IAUC). In the subjects with IAUC increased, serum cortisol was also increased (from 0.44±0.07 to 0.83±0.26 U/L, P < 0.05) in parallel and serum creatine kinase (CK) was unaltered (from 232±68 to 204±43 U/L, NS) during detraining. Whereas in the subjects without IAUC increased, serum cortisol (from 0.51±0.19 to 0.54±0.14 U/L, no significance) was not changed and serum creatine kinase (from 461± 179 to 151±21 U/L) was decreased during detraining. Two groups of detrained subjects exhibited a similar reduction in serum DHEA-S levels and slight elevation in body weight. CONCLUSIONS: The changes in serum cortisol, but not DHEA-S, were associated with the change in insulin sensitivity during early phase of lifestyle change from physically active to sedentary.

A High Glycemic Meal Suppresses the Postprandial Leptin Response in Normal Healthy Adults

Background/Aims: To evaluate the metabolic effects of meals with varying glycemic index (GI). Methods: We measured the glucose, insulin and leptin responses to two contrasting breakfast cereals in a group of 10 young healthy volunteers. Meals were provided on two separate occasions in random order after a 12-hour overnight fast, and consisted of 50 g of available carbohydrate from either Corn Flakes (Kellogg’s), or Fiber One® (General Mills). Blood samples were obtained at rest, and 30, 60, 90 and 120 min after eating. The GI was calculated from the glucose response to the test meal normalized against a 50 g oral glucose load. Results: The GI for Corn Flakes was 125 ± 17 units and 49 ± 8 units for Fiber One®. These meals were classified as high GI and low GI, respectively, and were significantly different from each other (p < 0.0003). The area under the insulin response curve (AUC) following the low glycemic meal was significantly attenuated compared to the high glycemic meal (14,064 ± 2,694 vs. 6,828 ± 1,182 pmol/l·min, p < 0.02). The leptin AUC revealed that circulating leptin was suppressed by the high glycemic meal compared to the low (3.1 ± 1.5 vs. 9.6 ± 3.6 ng/ml·min, p < 0.04). Conclusions: Lower insulin and higher leptin suggests that low glycemic meals promote a postprandial metabolic milieu that is favorable for reduced food consumption; this may be advantageous in the control of obesity and related disorders including insulin resistance and type 2 diabetes.

Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance

Insulin resistance (IR) and obesity are common features of the polycystic ovary syndrome (PCOS). Insulin-sensitizing agents have been shown to improve both reproductive and metabolic aspects of PCOS, but it remains unclear whether it is also beneficial in lean patients without pre-treatment IR. The aim of this study was to determine the influence of metformin on the clinical and biochemical parameters of PCOS irrespective of the presence of basal obesity and IR. The effect of 6 months of metformin treatment was prospectively assessed in 188 PCOS patients, divided into three groups according to body mass index (BMI; lean: BMI<25 kg/m2, overweight: BMI 25-29 kg/m2, and obese: BMI30 kg/m2). Outcome parameters, which were also assessed in 102 healthy controls, included body weight, homeostasis model assessment for IR (HOMA-IR), fasting glucose and insulin levels, area under the curve of insulin response (AUCI), hyperandrogenism, and menstrual irregularities. In comparison with the respective BMI-appropriate control groups, only obese but not lean and overweight PCOS patients showed differences in fasting insulin and HOMA-IR. Metformin therapy significantly improved all outcome parameters except fasting glucose levels. Subgroup analyses revealed that in the group of lean PCOS patients without pre-treatment IR, metformin significantly improved HOMA-IR (1.7+/-1.0 vs 1.1+/-0.7 micromol/lxmmol/l2) and fasting insulin levels (7.7+/-4.2 vs 5.4+/-3.9 mU/l), in addition to testosterone levels (2.6+/-0.9 vs 1.8+/-0.7 nmol/l), anovulation rate (2.3 vs 59.5%), and acne (31.8 vs 11.6%; all P<0.017). In the overweight and obese PCOS groups, metformin also showed the expected beneficial effects. Metformin improves parameters of IR, hyperandrogenemia, anovulation, and acne in PCOS irrespective of pre-treatment IR or obesity.