Insulin Area Under Curve Research Articles

Effects and plasma proteomic analysis of GLP-1RA versus CPA/EE, in combination with metformin, on overweight PCOS women: a randomized controlled trial

PurposePolycystic ovary syndrome (PCOS) is characterized by reproductive dysfunctions and metabolic disorders. This study aims to compare the therapeutic effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) + Metformin (Met) versus cyproterone acetate/ethinylestradiol (CPA/EE) + Met in overweight PCOS women and identify potential proteomic biomarkers of disease risk in women with PCOS.MethodsIn this prospective, open-label randomized controlled trial, we recruited 60 overweight PCOS women into two groups at a 1:1 ratio to receive CPA/EE (2 mg/day: 2 mg cyproterone acetate and 35-μg ethinylestradiol,) +Met (1500 mg/day) or GLP-1 RA (liraglutide, 1.2–1.8 mg/day) +Met (1500 mg/day) for 12 weeks. The clinical effectiveness and adverse effects were evaluated, followed by plasma proteomic analysis and verification of critical biomarkers by ELISA.ResultsEighty(80%) patients completed the study. Both interventions improved menstrual cycle, polycystic ovaries, LH(luteinizing hormone) and HbA1c(hemoglobin A1c) levels after the 12-week treatment. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI (Body Mass Index), and waist circumference, FBG(fasting blood glucose), AUCI(area under curve of insulin),TC (Total Cholesterol), IL-6(Interleukin-6) and improving insulin sensitivity, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in improving hyperandrogenemia, including T(total testosterone), LH, LH/FSH(Luteinizing hormone/follicle-stimulating hormone), SHBG(sex hormone-binding globulin) and FAI (free androgen index). By contract, GLP-1RA+Met group only improved LH. Plasma proteomic analysis revealed that the interventions altered proteins involved in reactive oxygen species detoxification (PRDX6, GSTO1, GSTP1, GSTM2), platelet degranulation (FN1), and the immune response (SERPINB9).ConclusionsBoth CPA/EE+Met and GLP-1RA + Met treatment improved reproductive functions in overweight PCOS women. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI, and waist, and improving metabolism, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in reducing hyperandrogenemia. The novel plasma biomarkers PRDX6, FN1, and SERPINB9, might be indicators and targets for PCOS treatment.Trial registration ClinicalTials.gov Trial No:NCT03151005. Registered 12 May, 2017, https://clinicaltrials.gov/ct2/show/NCT03151005.

Identification of markers that distinguish adipose tissue and glucose and insulin metabolism using a multi-modal machine learning approach

The study of metabolomics has improved our knowledge of the biology behind type 2 diabetes and its related metabolic physiology. We aimed to investigate markers of adipose tissue morphology, as well as insulin and glucose metabolism in 53 non-obese male individuals. The participants underwent extensive clinical, biochemical and magnetic resonance imaging phenotyping, and we also investigated non-targeted serum metabolites. We used a multi-modal machine learning approach to evaluate which serum metabolomic compounds predicted markers of glucose and insulin metabolism, adipose tissue morphology and distribution. Fasting glucose was associated with metabolites of intracellular insulin action and beta-cell dysfunction, namely cysteine-s-sulphate and n-acetylgarginine, whereas fasting insulin was predicted by myristoleoylcarnitine, propionylcarnitine and other metabolites of beta-oxidation of fatty acids. OGTT-glucose levels at 30 min were predicted by 7-Hoca, a microbiota derived metabolite, as well as eugenol, a fatty acid. Both insulin clamp and HOMA-IR were predicted by metabolites involved in beta-oxidation of fatty acids and biodegradation of triacylglycerol, namely tartrate and 3-phosphoglycerate, as well as pyruvate, xanthine and liver fat. OGTT glucose area under curve (AUC) and OGTT insulin AUC, was associated with bile acid metabolites, subcutaneous adipocyte cell size, liver fat and fatty chain acids and derivates, such as isovalerylcarnitine. Finally, subcutaneous adipocyte size was associated with long chain fatty acids, markers of sphingolipid metabolism, increasing liver fat and dopamine-sulfate 1. Ectopic liver fat was predicted by methylmalonate, adipocyte cell size, glutathione derived metabolites and fatty chain acids. Ectopic heart fat was predicted visceral fat, gamma-glutamyl tyrosine and 2-acetamidophenol sulfate. Adipocyte cell size, age, alpha-tocopherol and blood pressure were associated with visceral fat. We identified several biomarkers associated with adipose tissue pathophysiology and insulin and glucose metabolism using a multi-modal machine learning approach. Our approach demonstrated the relative importance of serum metabolites and they outperformed traditional clinical and biochemical variables for most endpoints.

Effect of thymoquinone on high fat diet and STZ-induced experimental type 2 diabetes: A mechanistic insight by in vivo and in silico studies.

The aim was to investigate whether thymoquinone (TQ) attenuates hyperglycemia-induced insulin resistance in experimental type 2 diabetes. Type 2 diabetes mellitus (T2DM) was induced by injection of streptozotocin (STZ, 40mg/kg) in high fat diet (HFD) rats. The levels of glucose, insulin, area under curve (AUC) of glucose, lipid profile parameters, homeostasis model assessment of insulin resistance (HOMA-IR), peroxisome proliferator-activated receptor-γ (PPARγ), and dipeptidyl peptidase peptidase-IV (DPP-IV) were evaluated in HFD + STZ-induced type 2 diabetic rats. TQ treatment significantly reduced elevated levels of glucose, AUC of glucose, insulin, and DPP-IV in diabetic-treated groups. In addition, TQ treatment significantly reduced high levels of triglycerides (TG) and cholesterols (total, low-density and very low-density lipoprotein) accompanied by significant augmentation in high-density lipoprotein (HDL) levels in diabetic-treated groups. However, TQ treatment significantly improved insulin sensitivity in diabetic-treated groups, which was confirmed by increased level of PPARγ and decreased level of HOMA-IR. Molecular docking of TQ exhibited substantial binding affinity with PPARγ and DPP-IV target proteins, which is supported by in vivo results. These results demonstrate that TQ attenuates hyperglycemia-induced insulin resistance by counteracting hyperinsulinemia, improving lipid profile, insulin sensitivity, and inhibiting DPP-IV. PRACTICAL APPLICATIONS: T2DM results in relentless hyperglycemia which eventually progress to a state of insulin resistance. TQ is an active principle compound found in Nigella sative seed, having myriad of traditional medicinal values. Administration of TQ significantly prevented hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, and inhibited DPP-IV in experimental type 2 diabetes. The in vivo results are also supported by molecular docking study of PPARγ and DPP-IV target proteins. Thus, we hypothesize that TQ can be used as an alternative natural drug in the management of hyperglycemia-induced insulin resistance in T2DM.

Association of circulating CEACAM1 levels and insulin sensitivity in gestational diabetes mellitus

BackgroundThe aim of this study was to estimate the levels of circulating carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in subjects with gestational diabetes mellitus (GDM) and investigate the relationships between CEACAM1 and GDM.MethodsCirculating CEACAM1 levels were measured by ELISA kit in 70 women with GDM and 70 normal glucose tolerance (NGT) pregnant women. Blood samples were collected to detect fasting plasma glucose (FPG), fasting insulin (FINS) and glycosylated hemoglobin (HbA1c) levels in all participants. Insulin sensitivity index (ISOGTT) was calculated to assess insulin sensitivity. Correlation analysis was performed between serum CEACAM1 levels and other parameters.ResultsCirculating CEACAM1 levels were higher in the GDM group than that in the NGT pregnant group, however, the difference showed no statistical significance (1889.82 ± 616.14 vs 1758.92 ± 433.15 pg/ml, p > 0.05). In GDM group, CEACAM1 was positively correlated with ISOGTT (R = 0.39, P = 0.001), while negatively with 1 h post-meal plasma insulin level (1hPINS) (R = -0.32, P = 0.008), 2 h post-meal plasma insulin level (2hPINS) (R = -0.33, P = 0.006) and area under curve of insulin (AUCI) (R = -0.36, P = 0.002) when adjusting for maternal age and gestational age.ConclusionsThe present study showed that circulating CEACAM1 levels did not differ in both GDM and NGT groups. However, we found a significant positively correlation between CEACAM1 and insulin sensitivity in the GDM group.

Mapping the Associations of the Plasma Lipidome With Insulin Resistance and Response to an Oral Glucose Tolerance Test.

Insulin resistance (IR) remains a global health challenge. Lipidomics offers an opportunity to identify biomarkers and better understand mechanisms of IR associated with abnormal lipid metabolism. The objective of this article is to determine plasma lipid species associated with indices of IR and evaluate the lipidome response to an oral glucose tolerance test (OGTT). This study was community based and cross-sectional. Plasma samples (collected at 0 and 120 min during an OGTT) from nonobese, young adults age 18 to 34 years (n = 246) were analyzed using liquid chromatography-tandem mass spectrometry. The associations between indices of IR and lipid classes and species (with a sex interaction term), or changes in lipid levels during an OGTT, were tested using linear models (adjusted for age, sex, body mass index, total cholesterol, high-density lipoprotein cholesterol, and triglycerides). Some (213) and (199) lipid species were associated with the homeostatic model assessment of insulin resistance and insulin area under curve (AUC), respectively. Alkylphosphatidylcholine (10), alkenylphosphatidylcholine (23), and alkylphosphatidylethanolamine (6) species were associated with insulin AUC in men only. Species of phosphatidylcholine (7) and sphingomyelin (5) were associated in women only. In response to an OGTT, a perturbation in the plasma lipidome, particularly in acylcarnitine species, was observed; and the changes in many lipid species were associated with insulin AUC. The plasma lipidome and changes in lipid levels during an OGTT were associated with indices of IR. These findings underlie the involvement of molecular lipid species in the pathogenesis of IR and possibly crosstalk between IR and sex-specific regulation of lipid metabolism.

Silencing of Supramammillary Nucleus (SuMN) Dopaminergic Neuronal Activity Induces the Obese Glucose Intolerant State

The “westernized” diet reduces brain dopamine synthesis and low brain striatal dopamine function has been associated with and implicated in potentiation of metabolic syndrome in animals and humans. However, hypothalamic dopamine function may be a more dominant regulator of peripheral fuel metabolism. The hypothalamic SuMN dopaminergic neurons project to the lateral septum, medial preoptic area, and suprachiasmatic nucleus, areas that prominently regulate both peripheral metabolism and striatal dopamine function. However, a causal role for such hypothalamic dopaminergic circuitry in modulating peripheral metabolism under normal feeding conditions has never been explored. This study therefore tested the impact of SuMN-selective knock-down of tyrosine hydroxylase (TH, the rate-limiting enzyme for dopamine synthesis) gene expression using AAV-mediated shRNA targeting TH (AAV-TH shRNA) on peripheral fuel metabolism in 14 weeks old rats fed standard low fat rodent chow (RC). Rats were micro-infused at the SuMN with either AAV-TH shRNA (N=12) or AAV-scrambled shRNA [control] (N=10) and maintained on RC ad lib for 77 days to assess changes in body weight (BW), glucose tolerance and fat metabolism. SuMN-selective TH knock down increased BW gain (54%, p=0.0005), total white adipose tissue mass (43%, p=0.012), feed efficiency (BW gain /g food) (25%, p= 0.048) and cumulative food consumption (15%, p= 0.0001) vs. control. SuMN-selective TH knock down increased glucose tolerance test glucose area under curve (AUC) by 27% (p=0.009) with no change in insulin AUC (p=0.99) vs. control. Such knock down also reduced adipose tissue mitochondrial fatty acid oxidation (FAO) rate (basal oxygen consumption rate 51%, p< 0.0001; endogenous FAO rate 58%, p< 0.0001; and exogenous FAO 54%, p=0.024). These findings indicate that reduced SuMN dopaminergic neuronal activity facilitates dysglycemia and obesity while reducing fat energy expenditure and increasing food consumption. Disclosure Y. Zhang: Employee; Self; VeroScience, LLC. T. Tsai: Employee; Self; VeroScience, LLC. M. Ezrokhi: Employee; Self; VeroScience, LLC. C. Stoelzel: Employee; Self; VeroScience, LLC. A. Cincotta: Employee; Self; VeroScience, LLC.. Stock/Shareholder; Self; VeroScience, LLC..

Comparable Effects of Brief Resistance Exercise and Isotime Sprint Interval Exercise on Glucose Homeostasis in Men.

This study compared the effects of a single bout of resistance exercise (RES) on glycemic homeostasis to isotime sprint interval exercise (SIE) using a within-subjects design. Nineteen nondiabetic males (age: 23.3 ± 0.7 yrs; height: 173.1 ± 1.2 cm; weight: 79.1 ± 4.8 kg; % fat: 22.5 ± 2.5%) were studied. RES involved nine exercises of 10 repetitions at 75% 1-RM using a 2 : 2 s tempo and was interspersed with a one-minute recovery; SIE involved four 30 s' all-out cycling effort interspersed with four minutes of active recovery. Plasma glucose and insulin in response to a 75 g oral glucose tolerance test were assessed 12 h after exercise. In comparison to a no exercise control trial (CON), the area under curve (AUC) of plasma glucose was reduced with both RES and SIE (P < 0.05), while insulin AUC was only reduced with RES. Cederholm, Gutt, Matsuda, and HOMA indices were improved (P < 0.05) following RES compared to CON. Corresponding changes following SIE were only found in Cederholm and Gutt indices (P < 0.05). No difference was found in plasma variables and indices between RES and SIE (P > 0.05). Such findings suggest that the RES may represent a potential alternative to the SIE in the development of time-efficient lifestyle intervention strategies for improving diabetes risk factors in healthy populations.

Effects of ketogenic amino acid replacement diet on insulin resistance in mice fed with high fat diet

Objective To investigate the effects of ketogenic amino acid (KAA)replacement diet on insulin resistance in mice fed with high fat diet(HFD) and to analyze the possible mechanism. Methods C57BL mice were fed with a control diet, HFD, and KAA-fortified HFD(HFDKAAR)from the age of 8 weeks, and 8 weeks after HFD initiation, the HFD-fed mice were divided into two groups: one group of mice were fed the same HFD, the other group were fed HFDKAAR (HFD→HFDKAAR). The metabolic evaluations were performed at the end of 16 weeks. Blood glucose levels were measured at 0, 15, 30, 60, 90, and 120 min after the injection of glucose(1 g/kg BW intraperitoneal glucose tolerance test, ipGTT). The insulin, β-hydroxybutyrate, and acetoacetate levels in the plasma were measured via ELISA. The insulin resistance index (IRI)and area under curve (AUC)were calculated. The expression of hepatic LKB1(liver kinase B1), AMP-activated protein kinase(AMPK), and mTOR (Mammalian target of rapamycin)protein, and mcp-1 mRNA were measured by western blot and real-time PCR respectively. Results HFD-fed group of mice displayed significantly heavier body weight, heavier intra-abdominal fat weight, and significant deterioration of glucose tolerance at the end of 16 weeks in addition to higher insulin levels( all P<0.05), HFDKAAR-fed mice exhibited significantly ameliorated high fat diet-induced obesity and glucose intolerance compared to the HFD-fed mice, which was associated with decreased insulin levels, IRI, AUC, and mcp-1 mRNA expression(all P<0.05). HFD suppressed hepatic LKB1 and AMPK phosphorylation expression, and increased mTOR phosphorylation levels compared to the control diet-fed mice(all P<0.05). In contrast, treatment with the HFDKAAR diet increased LKB1and p-AMPK expression, which was associated with suppressed p-mTOR levels compared to the HFD-fed mice(all P<0.05). Conclusion KAA may ameliorate high fat diet-induced obesity, glucose intolerance, via normalizing the hepatic LKB1-AMPK-mTOR nutritional signal passageway. KAA replacement diet seems to be a potential nutritional intervention for the treatment for patients with metabolic defects, such as obesity, glucose intolerance, as well as metabolic syndrome. (Chin J Endocrinol Metab, 2016, 32: 399-404) Key words: Amino acid; Insulin resistance; Metabolic syndrome

Increased Insulin following an Oral Glucose Load, Genetic Variation near the Melatonin Receptor MTNR1B, but No Biochemical Evidence of Endothelial Dysfunction in Young Asian Men and Women.

AimTo identify biochemical and genetic variation relating to increased risk of developing type 2 diabetes mellitus and cardiovascular disease in young, lean male and female adults of different ethnicities.MethodFasting blood and urine and non-fasting blood following oral glucose intake were analysed in 90 Caucasians, South Asians and South East/East Asians.ResultsThere were no differences in age, birthweight, blood pressure, body mass index, percent body fat, total energy, percentage of macronutrient intake, microalbumin, leptin, cortisol, adrenocorticotropic hormone, nitric oxide metabolites, C-reactive protein, homocysteine, tumor necrosis factor-α, interleukin-6, von Willebrand factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and tissue plasminogen activator. Fasting total cholesterol (P = .000), triglycerides (P = .050), low density lipoprotein (P = .009) and non-fasting blood glucose (15 min) (P = .024) were elevated in South Asians compared with Caucasians, but there was no significant difference in glucose area under curve (AUC). Non-fasting insulin in South Asians (15–120 min), in South East/East Asians (60–120 min), and insulin AUC in South Asians and South East/East Asians, were elevated compared with Caucasians (P≤0.006). The molar ratio of C-peptide AUC/Insulin AUC (P = .045) and adiponectin (P = .037) were lower in South Asians compared with Caucasians. A significant difference in allele frequency distributions in Caucasians and South Asians was found for rs2166706 (P = 0.022) and rs10830963 (P = 0.009), which are both near the melatonin receptor MTNR1B.ConclusionsElevated non-fasting insulin exists in young South Asians of normal fasting glucose and insulin. Hepatic clearance of insulin may be reduced in South Asians. No current biochemical evidence exists of endothelial dysfunction at this stage of development. MTNR1B signalling may be a useful therapeutic target in Asian populations in the prevention of type 2 diabetes mellitus.

Clinical study of exercise on improvement of β-cell function and insulin resistance in non-diabetic young offsprings of diabetic patients

Previous studies have shown that exercise could improve β-cell function in humans or animal models of type 2 diabetes. However, whether it can prevent the progression of pre-diabetes to diabetes remains unclear. To study the effects of exercise on glycolipid metabolism, β-cell function, and insulin resistance in the non-diabetic young offsprings of diabetic patients. One hundred and eighty-two normal glucose tolerance young offsprings of type 2 diabetic parents were enrolled. Individuals with fasting insulin ≥ 12.0 mU/L were assigned to hyperinsulinemia group (n = 72) and those with fasting insulin <12.0 mU/L were assigned to normal group (n = 110). The subjects in hyperinsulinemia group received 12-week exercise intervention. A 75-g oral glucose tolerance test and insulin release test were conducted before and after intervention. The area under curve of glucose (AUCglu), area under curve of insulin (AUCINS), HOMA insulin resistance index (HOMA-IR), HOMA β-cell function (HOMA-β), and early insulin secretion index (ΔI 30/ΔG 30) were calculated. Body composition was measured by dual energy X-ray absorptiometry. At baseline, AUCINS and HOMA-β in hyperinsulinemia group were significantly higher compared with the normal group (P < 0.05). After the 12-week exercise intervention, no significant changes in blood pressure, body mass index, blood glucose, serum lipids, and percentage of body fat were found in hyperinsulinemia group; however, AUCINS, HOMA-β, HOMA-IR (P < 0.05) and ΔI 30/ΔG 30 (P < 0.01) were significantly decreased. Exercise is effective for preventing pre-diabetic insulin resistance and β-cell dysfunction in non-diabetic young offsprings of diabetic patients.

Combination of Diane-35 and Metformin to Treat Early Endometrial Carcinoma in PCOS Women with Insulin Resistance

Background: Young women with polycystic ovary syndrome (PCOS) have a high risk of developing endometrial carcinoma. There is a need for the development of new medical therapies that can reduce the need for surgical intervention so as to preserve the fertility of these patients. The aim of the study was to describe and discuss cases of PCOS and insulin resistance (IR) women with early endometrial carcinoma while being co-treated with Diane-35 and metformin.Methods: Five PCOS-IR women who were scheduled for diagnosis and therapy for early endometrial carcinoma were recruited. The hospital records and endometrial pathology reports were reviewed. All patients were co-treated with Diane-35 and metformin for 6 months to reverse the endometrial carcinoma and preserve their fertility. Before, during, and after treatment, endometrial biopsies and blood samples were obtained and oral glucose tolerance tests were performed. Endometrial pathology was evaluated. Body weight (BW), body mass index (BMI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), sex hormone-binding globulin (SHBG), free androgen index (FAI), insulin area under curve (IAUC), and homeostasis model assessment of insulin resistance (HOMA-IR) were determined.Results: Clinical stage 1a, low grade endometrial carcinoma was confirmed before treatment. After 6 months of co-treatment, all patients showed normal epithelia. No evidence of atypical hyperplasia or endometrial carcinoma was found. Co-treatment resulted in significant decreases in BW, BMI, TT, FAI, IAUC, and HOMA-IR in parallel with a significant increase in SHBG. There were no differences in the FSH and LH levels after co-treatment.Conclusions: Combined treatment with Diane-35 and metformin has the potential to revert the endometrial carcinoma into normal endometrial cells in PCOS-IR women. The cellular and molecular mechanisms behind this effect merit further investigation.

Alpha-linolenic acid improves insulin sensitivity in obese patients

To explore the effects of α-linolenic acid on insulin sensitivity in obese patients. From October 2011 to April 2012, 16 patients received an oral dose of α-linolenic acid for 8 weeks.Oral glucose tolerance test (OGTT) and insulin releasing test were performed before and after treatment. Homeostasis model assessment insulin resistance (HOMA-IR) index and area under curve of insulin (AUCI) were calculated to evaluate the insulin sensitivity. The levels of serum triglyceride, free fatty acids (FFA), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were measured after an overnight fast. Obese patients had significantly elevated serum insulin, triglyceride, FFA, IL-6 and TNF-α versus the subjects in normal control group (all P < 0.05). Obese patients were also more insulin-resistant than normal subjects based on a higher HOMA-IR (P < 0.05). Decreased serum insulin, triglyceride, FFA, IL-6 and TNF-α were observed after treatment. With the administration of α-linolenic acid, HOMA-IR and AUCI significantly decreased in obese patients (HOMA-IR: 1.8 ± 0.2 vs 1.2 ± 0.3, P < 0.05; AUCI: 1151 ± 505 vs 768 ± 347, P < 0.05). α-linolenic acid increases peripheral insulin sensitivity in obese patients and it may aid the prevention and treatment of type 2 diabetes mellitus and atherosclerotic vascular diseases.

Correlation of blood lipids and insulin resistance in patients with impaired glucose tolerance

Blood lipid level and its associations with insulin resistance were studied in patients with impaired glucose tolerance (IGT). Two hundred and twenty first degree relatives of type 2 diabetes mellitus were grouped into normal glucose tolerance (NGT) and IGT groups according to results of oral glucose tolerance test. Compared with the NGT group, the IGT patients had higher serum levels of total triglyceride (TG), total cholesterol (TC), low density lipoprotein-C (LDL-C) but a lower serum level of high density lipoprotein-C (HDL-C). Homeostasis model of assessment for insulin resistance index (HOMA-IR) and area under curve of insulin (AUCI) also increased. A positive relationship was found between TG and HOMA-IR (or AUCI), but a negative relationship existed between HDL-C and HOMA-IR. In conclusion, abnormal blood lipid metabolism is present in IGT patients and it has a close correlation with insulin resistance. Key words: Glucose intolerance; Insulin resistance; Dyslipidemias

Comparison of insulin resistance and pancreatic β cell function between the pregnant women with normal and abnormal glucose metabolism

Objective To observe and compare the variation of insulin resistance and pancreatic β-cell function in pregnant women with abnormal and normal glucose metabolism during the first,second,and third trimesters,and to explore the feasibility of early diagnosis of gestational diabetes mellitus(GDM).Methods This is a prospective study.507 pregnant women with regular antenatal care from February 2009 to March 2010 were included in the study.Based on the results of oral glucose tolerance test,the patients with GDM consisted of 58,86,and 66 subjects respectively in the first,second,and third trimesters.The control group included 72,164,and 66 subjects respectively in the first,second,and third trimesters.Homeostasis model assessment insulin resistance index( HOMA-IR),homeostasis model assessment β-cell function (HOMA-β),area under curve of glucose (AUCG),area under curve of insulin ( AUCI ),30-minute insulin increase to 30-minute glucose increase ( △I30/△G30 ),and insulin sensitivity index composite(ISIcomp) were calculated for the evaluation of insulin resistance and pancreatic β-cell function.Results ( 1 ) AUCG and AUCI in the GDM group were statistically higher than those in control group while △I30/△G30and ISlcomp in the GDM group were statistically lower than those in the control group during the first trimester(P＜0.05),but HOMA-IR showed no statistically significant difference between two groups.In the GDM groups HOMA-IR,AUCG,and AUCI were statistically higher,whereas △I30/△G30 and ISIcomp were statistically lower than those in the control groups during the second and third trimesters (P ＜ 0.05 ). HOMA-β showed no statistically significant differences between the GDM groups and control groups during 3 trimesters.( 2 ) During thefirst,second,and third trimesters,blood glucose reached its peak by 0.5 h in the oral glucose tolerance test,and insulin reached its peak by 0.5-1 h in the control groups; while in the GDM groups the respective figures were 1 h and 2 h.Conclusions The insulin resistance in GDM patients diagnosed during the first,second,and third trimesters was higher than in pregnant women with normal glucose metabolism,and the peaks of blood glucose and insulin reached in oral glucose tolerance test were respectively delayed.The impaired pancreatic β-cell insulin secretion in GDM patients was present from early pregnancy.Thus for high-risk groups,oral glucose tolerance test during early pregnancy will be helpful for screening abnormal glucose metabolism. Key words: Diabetes, gestational; Insulin resistance; Pancreatic β cell function

Postnatal Pancreatic Islet β Cell Function and Insulin Sensitivity at Different Stages of Lifetime in Rats Born with Intrauterine Growth Retardation

Epidemiological studies have linked intrauterine growth retardation (IUGR) to the metabolic diseases, consisting of insulin resistance, type 2 diabetes, obesity and coronary artery disease, during adult life. To determine the internal relationship between IUGR and islet β cell function and insulin sensitivity, we established the IUGR model by maternal nutrition restriction during mid- to late-gestation. Glucose tolerance test and insulin tolerance test(ITT) in vivo and glucose stimulated insulin secretion(GSIS) test in vitro were performed at different stages in IUGR and normal groups. Body weight, pancreas weight and pancreas/body weight of IUGR rats were much lower than those in normal group before 3 weeks of age. While the growth of IUGR rats accelerated after 3 weeks, pancreas weight and pancreas/body weight remained lower till 15 weeks of age. In the newborns, the fasting glucose and insulin levels of IUGR rats were both lower than those of controls, whereas glucose levels at 120 and 180 min after glucose load were significantly higher in IUGR group. Between 3 and 15 weeks of age, both the fasting glucose and insulin levels were elevated and the glucose tolerance was impaired with time in IUGR rats. At age 15 weeks, the area under curve of insulin(AUCi) after glucose load in IUGR rats elevated markedly. Meanwhile, the stimulating index of islets in IUGR group during GSIS test at age 15 weeks was significantly lower than that of controls. ITT showed no significant difference in two groups before 7 weeks of age. However, in 15-week-old IUGR rats, there was a markedly blunted glycemic response to insulin load compared with normal group. These findings demonstrate that IUGR rats had both impaired pancreatic development and deteriorated glucose tolerance and insulin sensitivity, which would be the internal causes why they were prone to develop type 2 diabetes.

SFR-116 Long term follow-up after laparoscopic sleeve gastrectomy as a final step for the treatment of morbid obesity

Methods: Between January 2004 and October 2010, 4 patients with GGF underwent metabolic testing during an oral glucose tolerance test pre-and postrepair. Data was collected on glucose, insulin, ghrelin, GIP, GLP-1, and PYY. Results: There was no significant difference between preoperative and postoperative levels of fasting glucose, glucose area under curve (AUC), fasting insulin, peak insulin, insulin AUC, ghrelin nadir, GIP peak, GIP AUC, GLP-1 peak, GLP-1 AUC, PYY peak, PYY AUC. There was a significant decrease in fasting ghrelin (459.5 vs 267.0 pg/ml, p 0.029) and percent maximum suppressed ghrelin (383.7 vs 187.9, p 0.027). Conclusion: GGF repair re-establishes duodenal bypass without altering the rest of the gastrointestinal tract. Ghrelin levels decrease significantly after GGF repair, likely due to partial gastrectomy associated with the repair. Notably, though, GGF fistula repair does not increase GLP-1, GIP, or insulin levels significantly, suggesting that duodenal bypass is not the mechanism by which RYGB elevates incretin levels.

Differences in maintenance of mean blood glucose (BG) and their association with response to "recognizing hunger".

Background:Meals begin and end subjectively. We trained healthy subjects to recognize initial hunger as a preprandial target for meal consumption, and to create a “recognizing hunger” or initial hunger meal pattern.Objective:Training subjects to “recognize hunger” lowers blood glucose (BG) and improves energy balance, and lowers metabolic risks and bodyweight. A minority may have low BG and low metabolic risks at recruitment, but the others may recover this favorable condition by training.Methods:In a 7-day food diary, subjects reported their preprandial BG measurements; BG and energy availability by blood were assessed at the lowest BG during the day, and diary-mean BG thus characterized the individual meal pattern (daily energy intake). We analyzed the same diaries of a recent paper on a global, randomized comparison of subjects trained in “recognizing hunger” with control subjects. This time, we checked whether subjects who had maintained low BG (LBG subgroup) at recruitment were able to decrease mean BG and metabolic risk factors during “hunger recognition” like those who presented high BG (HBG subgroup).Results:At recruitment, the BG means of 120 investigated subjects were within mean confidence limits of ± 3.84 mg/dL, and we could stratify subjects in ten small strata of which each significantly differed by mean BG. Mean BG was stable in each control subject over five months; the mean absolute change being 6.0 ± 4.6 mg/dL. Only three out of 34 trained subjects who had lower mean BG than 81.8 mg/dL significantly decreased mean BG, whereas 41 out of 55 subjects whose mean BG was greater than 81.8 mg/dL significantly decreased mean BG after training (P < 0.0001). At recruitment, the LBG subgroup showed significantly lower insulin, lower BG area under curve (AUC) in the oral glucose tolerance test (GTT), and lower HbA1c than the HBG group. After training, only HBG subjects, compared with HBG controls, significantly decreased preprandial BG from 91.6 ± 7.7 mg/dL to 81.0 ± 7.7 mg/dL, in association with a decrease of HbA1c from 4.81% ± 0.44% to 4.56% ± 0.47%, of GTT insulin AUC from 244 ± 138 mU/L to 164 ± 92 mU/L, and of energy intake from 1872 ± 655 kcal to 1251 ± 470 kcal (P < 0.001), with an increase of indices of insulin sensitivity from 5.9 ± 3.3 to 9.8 ± 5.6 and of beta cell function from 1.0 ± 0.7 to 1.4 ± 1.1 (P < 0.05). LBG subjects only decreased weekly-diary BG standard deviation in comparison with controls.Conclusion:At recruitment, the 120 subjects maintained mean BG at one personal level of ten possibilities, and 34 subjects were below 81.8 mg/dL (LBG) and 55 were over (HBG). The 55 HBG subjects showed higher mean insulin resistance, HbA1c, other cardiovascular risk factors, and increased bodyweight compared with the 34 LBG subjects. A total of 41 out of the 55 HBG subjects regressed to LBG with training.

Efficacy of 2-hour post glucose insulin levels in predicting insulin resistance in polycystic ovarian syndrome with infertility

BACKGROUND:Insulin resistance (IR) is central to the pathogenesis of polycystic ovarian syndrome (PCOS), but tests for determining IR are elaborate, tedious and expensive.AIMS:To evaluate if “2-hour post-glucose insulin level” is an effective indicator of IR and can aid in diagnosing IR in infertile PCOS women.SETTINGS AND DESIGN:Observational study at infertility clinic of a tertiary care center.MATERIALS AND METHODS:50 infertile women with PCOS and 20 females with tubal/male factor infertility were evaluated for the presence of IR, as defined by the fasting/2-hour post-glucose insulin levels cutoffs of >25/>41 μU/mL, respectively. The clinical, metabolic and endocrinologic profile was determined in both the groups.STATISTICAL ANALYSIS:Statistical analysis was performed using SPSS (Chicago, IL, USA).RESULTS:Body mass index, post load glucose, insulin, glucose/insulin ratio, area under curve (AUC) of glucose and insulin and insulinogenic index were significantly lower in the controls as compared to the PCOS group. “2-hour post-glucose insulin levels” were elevated in 88% of PCOS individuals but were normal in all females not suffering from PCOS. These levels significantly correlated with AUC of glucose and insulin, and insulinogenic index and inversely correlated with 2-hour glucose to insulin ratio (r=0.827, 0.749 and –0.732, respectively).CONCLUSIONS:“2-hour post-glucose insulin levels” appears to be a good indicator of IR. It can be a useful tool, especially in low resource setting where a single sample can confirm the diagnosis, thus reducing cost and repeat visits.

Potential role of TCF7L2 gene variants on cardiac sympathetic/parasympathetic activity

Variants in transcription factor 7-like 2 (266096218TCF7L2266096218USuser266096218Gene names have been italicized per house style. Please check and confirm whether there are other instances that need to be italicized or instances where italics have been inappropriately applied.) gene have been found strongly associated with an increased risk of type 2 diabetes, as well as with an impairment of glucagon-like peptide-1 (GLP-1) signalling chain. In rats, stimulation of central GLP-1 receptors increases heart rate and activates autonomic regulatory neurons. We aimed to evaluate the potential role of TCF7L2 gene polymorphisms on sympathovagal response in relation to changes in plasma insulin and/or GLP-1 concentration after glucose ingestion. Genotyping was performed for rs12255372 and rs7903146 TCF7L2 gene variants in 250 non-related healthy volunteers (mean age 27±3 years). Consistent with previous reports, both single-nucleotide polymorphisms were in strong linkage disequilibrium (D'=0.87, r(2)=0.76). A subset of 167 patients underwent an oral glucose tolerance test while a continuous recording of heart rate variability was performed. At baseline, no differences in fasting plasma insulin, in GLP-1 levels and in LF/HF (low frequency/high frequency) ratio between the three genotypes were found. Along with glucose ingestion TT subjects had lower INS(AUC) (insulin area under curve), as well as higher LF/HF(AUC) (LF/HF area under curve) values. No difference in GLP-1(AUC) (GLP-1 area under curve) between TCF7L2 gene variants was found. A multivariate analysis including multiple covariates showed that only INS(AUC,) GLP-1(AUC) and TCF7L2 gene variants were independently associated with LF/HF(AUC). In conclusion, TT genotype of rs12255372 and rs7903146 TCF7L2 gene variants is associated with lower insulin secretion and higher cardiosympathetic activity. Moreover, such effect is independent of GLP-1 and insulin plasma concentrations suggesting a potential role of such gene variants in increasing cardiovascular risk through enhanced sympathetic nervous system activity.

Effect of Resistance Exercise Training with Dehydroepiandrosterone Supplementation on Glucose Absorption Ability

Previous studies have demonstrated that chronic dehydroepiandrosterone (DHEA) supplementation could improve glucose disposal and metabolic status. However, glucose absorption ability with response to acute and chronic exercise training along with DHEA supplementation is currently unclear. In this study, we investigated the effect of resistance training along with DHEA supplementation on glucose tolerance and hormone response. Nineteen healthy females (age: 39.4±1.54) were recruited in this study and all the subjects were performed the maximal repetition test (RM) to determine the basal maximal strength before the treatment. Subjects were divided into three groups; DHEA supplementation (n=5; 50 mg, daily), resistance training (n=6; 70% of RM) and resistance training plus DHEA supplementation (n=8). Blood samples were collected at study beginning, after 3 days and 8 weeks to determine the hormone response, glucose area under curve (GAUC) and insulin area under curve (IAUC). Body composition and muscular strength were also measured. In the results we observed subjects' sit-up ability was increased in resistance training group. The concentration of cortisol in trained group was significantly increased only after 3 days. However, the concentration of testosterone were significantly increased in resistance training plus DHEA supplementation group compared to resistance training group, but GAUC and IAUC were trendily decreased. After 8-week treatment, the level of cortisol was significantly lower than baseline. The major findings of this study were that DHEA supplementation in the early phase of resistance training could improve glucose tolerance and insulin sensitivity. However, this beneficial effect was not reflected in the chronic treatment.