Insulin Sensitivity Parameters Research Articles

S-12-3: BENEFICIAL EFFECTS OF EMPAGLIFLOZIN ON METABOLIC PARAMETERS AND DIASTOLIC FUNCTION IN SPONTANEOUSLY HYPERTENSIVE RATS FED A HIGH-FAT DIET

Objective: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial pathological syndrome characterized by lipid accumulation in hepatocytes. This can lead to non-alcoholic steatohepatitis (NASH) which can progress to liver fibrosis, cirrhosis and liver cancer. Unfortunately, the pathogenesis of NAFLD is still unknown. However, current studies suggest that gliflozins, primarily antidiabetics, could have beneficial effects on liver metabolism. The aim of this study was therefore to examine whether empagliflozin (10 mg.kg-1.day-1 in drinking fluid) will have beneficial effects. Design and methods: NAFLD was induced by eight weeks of high-fat diet feeding (60% protein) in adult (6-month-old) spontaneously hypertensive rats (SHR). Control SHR were fed a standard diet. Then, the animals were either untreated or treated with empagliflozin for eight weeks. The evaluation of renal function (metabolic cages) and oral glucose tolerance (OGT) test were performed before the start of the treatment and at the end of the study. Cardiac function evaluated by echocardiography as well as metabolic parameters in serum and in liver were determined at the end of the experiment. Results: High-fat diet feeding increased body weight and visceral adiposity. Moreover, it worsened insulin resistance (evaluated as OGT test). In addition, it induced increase in triglycerides and cholesterol levels. Although it had no effect on renal function, it substantially deteriorated not only systolic but also diastolic function of the heart in SHR rats. Empagliflozin had no effect on body weight or visceral fat deposition but improved insulin sensitivity (OGT test) and several metabolic parameters (plasma insulin, non-esterified fatty acids, uric acid and HDL-cholesterol). Moreover, it had beneficial effects on systolic (fractional shortening) and especially diastolic (PWTd, RWT, and E/A ratio) function. Conclusions: Our results demonstrated that the treatment with empagliflozin had beneficial hepatoprotective and cardioprotective actions in hypertensive rats with experimentally induced non-alcoholic liver fatty disease.

Cytokine modulation by etanercept ameliorates metabolic syndrome and its related complications induced in rats administered a high-fat high-fructose diet

The aim of the present study was to investigate the effect of etanercept (ETA)—an anti-tumor necrosis factor α (TNF-α) monoclonal antibody—on metabolic disorders such as obesity, hypertension, dyslipidemia, and insulin resistance associated with the metabolic syndrome (MS). MS was induced in rats via high-fat high-fructose (HFHF) administration for 8 weeks. Rats were divided into three groups: negative control, HFHF model, and ETA-treated groups [HFHF + ETA (0.8 mg/kg/twice weekly, subcutaneously) administered in the last 4 weeks]. ETA effectively diminished the prominent features of MS via a significant reduction in the percent body weight gain along with the modulation of adipokine levels, resulting in a significant elevation of serum adiponectin consistent with TNF-α and serum leptin level normalization. Moreover, ETA enhanced dyslipidemia and the elevated blood pressure. ETA managed the prominent features of MS and its associated complications via the downregulation of the hepatic inflammatory pathway that induces nonalcoholic steatohepatitis (NASH)—from the expression of Toll-like receptor 4, nuclear factor kappa B, and TNF-α until that of transforming growth factor—in addition to significant improvements in glucose utilization, insulin sensitivity, and liver function parameter activity and histopathological examination. ETA was effective for the treatment of all prominent features of MS and its associated complications, such as type II diabetes mellitus and NASH.

Cardiovascular Risk Factors in Children and Adolescents with Type 1 Diabetes Mellitus: The Role of Insulin Resistance and Associated Genetic Variants

Introduction: Type 1 diabetes (T1D) is associated with an increased risk of cardiovascular disease. Insulin resistance is an important cardiovascular risk factor (CVRF), also in subjects with T1D, but the influence of the genetic predisposition of insulin resistance on cardiovascular risk is still unknown in T1D. We aimed to determine whether a genetic score composed of six variants, previously associated with insulin resistance and type 2 diabetes (T2D) risk, associates with insulin sensitivity and known CVRFs in children and adolescents with T1D. Materials and Methods: 330 children and adolescents (174 males; mean age 15.7 ± 3.5 years) with T1D were genotyped for the following genetic variants: rs1801278 (IRS1), rs1044498 (ENPP1), rs2295490 (TRIB3), rs1801282 (PPARG), rs780094 (GCKR), and rs35767 (IGF1). An additive genetic risk score (GRS) and cardiovascular risk score (CVRS) were calculated. Anthropometric, glycemic control, insulin sensitivity, blood pressure, and biochemical parameters were assessed. Multivariate regression between evaluated phenotypes and GRS was performed. Results: We found a significant association between the GRS and estimated insulin sensitivity (β = −0.027 [−0.040 to −0.013], R² = 0.86, p≤ 0.001), diastolic blood pressure (β = 0.68 [0.08–1.27], R² = 0.20, p = 0.026), triglycerides (β = 4.26 [1.74–6.77], R² = 0.13, p = 0.001), waist to height ratio (β = 0.003 [0.001–0.006], R² = 0.75, p = 0.010), non-HDL-cholesterol (β = 3.63 [1.39–5.87], R² = 0.12, p = 0.002), and CVRS (β = 0.063 [0.008–0.118], R² = 0.19, p = 0.025), independent of age, sex, BMI, pubertal stage, diabetes duration, glycated hemoglobin, type of treatment, and total insulin requirement. The addition of the GRS to established clinical risk factors significantly improved the discriminatory capability of the regression model for predicting subjects with more CVRFs (C-statistic 0.89 [95% CI: 0.84–0.95] versus 0.83 (0.73–0.93); p = 0.037). Conclusions: Insulin resistance and T2D risk-associated genetic variants influence insulin sensitivity and known CVRFs in children and adolescents with T1D.

PSUN299 GLP-1 Contribution to Insulin Secretory Response to Protein Ingestion and Insulin Kinetics Following Gastric Bypass and Sleeve Gastrectomy

Abstract Rapid passage of ingested nutrients to the gut after Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG) results in hyperinsulinemia after glucose ingestion, in part due to an enhanced glucagon-like peptide-1 (GLP-1)-induced insulin secretory response (ISR) and reduced metabolic clearance rate of insulin (MCRI). The effect of endogenous GLP-1 on insulin kinetics is unknown, and so is GLP-1 contribution to insulin secretory response to non-glucose nutrient ingestion. In non-surgical subjects, protein ingestion enhances insulin secretion and reduces MCRI. We hypothesized that protein ingestion enhances GLP-1-induced ISR and alters MCRI in proportion to changes in nutrient influx after GB and SG. To test this hypothesis ISR, β-cell sensitivity to glucose (BGS), MCRI, and oral glucose insulin sensitivity (OGIS) were measured on 3 days during 50 g glucose ingestion as well as 50 g protein ingestion with and without GLP-1R antagonist, exendin (9-39) [Ex-9] infusion. Ten GB-treated subjects, 9 SG-treated, and 7 non-operated controls (CN) were enrolled. The 3 non-diabetic groups were matched for age, BMI, fat-free mass, HbA1c; surgical groups were matched for weight loss and time post-surgery. Fasting glucose, insulin, and ISR were similar among the 3 groups and among the 3 studies but fasting MCRI was greater in surgical groups than CN (p<0.05). Compared to glucose, protein ingestion led to larger BGS in 3 groups despite smaller overall ISR response (AUCISR3h) (p<0.05). Blocking GLP-1R during protein ingestion decreased AUCISR3h only in surgical subjects (p<0.05 for interaction), whereas BGS was reduced similarly in 3 groups during Ex-9 infusion (p<0.05). OGIS was smaller during protein than glucose ingestion in 3 groups (p<0.05). GLP-1R blockade did not affect insulin sensitivity. Following nutrient ingestion in parallel with increase in insulin secretion MCRI was reduced to nadir values at 40 minutes, but then gradually increased approaching premeal values at different pace among surgical and non-surgical subjects (p<0.05). The slope of MCRI: Insulin (0-40 min) was smaller after protein ingestion than glucose, and after protein with Ex-9 infusion than without in 3 groups (p<0.05). Blocking GLP-1R had no effect on MCRI values in the latter phase of protein ingestion when insulin secretion reduced approaching premeal values. There was no association between parameters of insulin sensitivity and insulin clearance during glucose or protein ingestion. Our findings indicate that the regulation of insulin secretion and clearance during protein ingestion is altered after GB and SG. Further, endogenous GLP-1 contribution to insulin secretory response to protein ingestion after GB and SG is enhanced, but GLP-1 effect on insulin kinetics is trivial. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

OR03-5 Identification of Four New Glucotypes during the First Year after Type 1 Diabetes Onset Using Continuous Glucose Monitoring Metrics

Abstract Current markers of β-cell function poorly reflect glucose homeostasis after diabetes onset, mainly because of the lack of integration of parameters of insulin sensitivity and β-cell responsiveness to glucose. Recently, the widespread use of continuous glucose monitoring (CGM) helped stratify glucose control in patients with long-term diabetes in new clinically relevant glucotypes. In our DIATAG study, we investigated how CGM metrics may help to segregate patients with new-onset type 1 diabetes (T1D) entering or not in partial remission (PR). We collected data from 66 pediatric patients with T1D (10.4±4.7 yo) during the first year after diabetes onset (Δ). Clinical parameters (i.e. A1C, insulin daily dose, insulin-dose adjusted A1c [IDAA1C]) and CGM data were collected at Δ+3, +6, +9, +12 months (n=168, 57% remitters [IDAA1C <9]). A panel of 46 CGM metrics was calculated on an hourly and daily basis using iglu package (1). Using unsupervised hierarchical clustering based on daily CGM metrics and clinical parameters, we identified four clusters of glucose metrics that differed from each other (p<0.05). Cluster 1 was characterized by an increased glucose stability (coefficient of variation [CV] 32±5%) within time in target (TIT [63-140 mg/dL], 83±6%) with 9% of sensor values in 63-70 mg/dL range in the early morning period. Cluster 2 exhibited a progressive decrease of TIT (60±14%) and an increase of target above range (TAR [>180 mg/dL], 20±9%) especially during the day while target in range (TIR [70-180 mg/dL]) was nearly equivalent to Cluster 1 (80±8%). Notably, CV remained low (32±5%) with little time spent below range (TBR [<70 mg/dL], 5±2%). Cluster 3 demonstrated a net increase of CV during all the nycthemere (46±7%) concomitantly to an increase of TBR (14±7%). Interestingly, TIT and TAR remained close to values from Cluster 2 (55±11%; 23±10%). Finally, Cluster 4 demonstrated major hyperglycemias (TAR, 55±13%) with increased CV (47±9%) and decreased TBR (8±6%). Interestingly, clustering allowed clinically relevant segregation of intermediate values of IDAA1C (i.e. 7.5-10) between Cluster 2 and Cluster 3, independently of the remission status. Moreover, participants at Δ+3 months distributed across all clusters (with respectively 38% in Cluster 1, 26% in Cluster 2, 29% in Cluster 3 and 7% in Cluster 4) highlighting the usefulness of CGM in characterizing disease heterogeneity from diabetes onset. In our study, a combination of CGM metrics and clinical parameters unraveled key clinical milestones of glucose homeostasis and remission status during the first year of T1D. 1. Broll et al, 2021;16(4): e0248560. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.

An Insight Into the Association of Sclerostin With Insulin Sensitivity and Glycemic Parameters in Male Indian Prediabetic and Diabetic Population.

BackgroundType 2 diabetes (T2D) is increasing day by day and creating a huge financial and social burden on the Indian population. Insulin resistance results in hyperglycemia, a condition that eventually causes prediabetes and Type 2 diabetes. The etiopathogenesis of T2D is still not clearly defined. Wnt signaling pathway is involved in pancreas development, islet function, insulin production, and secretion. Recent studies show that sclerostin, a Wnt signaling inhibitor, is associated with diabetes. The sclerostin level is altered as a function of race and ethnicity. However, no study has been conducted to observe the sclerostin level in prediabetic and diabetic individuals in the Indian population.ObjectivesThe main objectives of the study are: to determine whether sclerostin is associated with glycemic parameters, serum insulin levels, insulin resistance/ sensitivity, beta-cell function, and adipose tissue insulin resistance (Adipo-IR).MethodsThis observational study was carried out at a tertiary care hospital, in Rishikesh, Uttarakhand, India. Individuals with T2D and prediabetes and healthy references were included in this study. Sclerostin and free fatty acids (FFA) were measured with the enzyme-linked immunosorbent assay (ELISA), and blood sugar, insulin, and glycated haemoglobin (HbA1c) were measured by the hexokinase, chemiluminescent, and chromatography methods, respectively. Messenger RNA (mRNA) was quantified by real-time polymerase chain reaction (PCR) using the SYBR Green protocol. Adipo-IR, homeostasis model assessment-estimated insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-B), quantitative insulin sensitivity check index (QUICKI), and single point insulin sensitivity estimator (SPISE) indices were calculated.ResultsA total of 171 study participants were enrolled in type 2 diabetes, prediabetes, and controls groups, having 57 each in the group. There was a gradual increase in sclerostin levels from healthy [242.12(158.44)] to prediabetes [256.06(299.65)] and diabetes [465.76 (735.71)] with a significant (<0.001) difference from healthy reference. Sclerostin showed a significant positive correlation with fasting blood sugar (r=0.200; p=0.009), HbA1c (r=0.394; p<0.001) and free fatty acids (r=0.205; p=0.007) in total study participants. The SPISE index showed a significant positive correlation (r=0.269, p=0.043) in the prediabetic group. SOST, GLUT4, and insulin receptor (IR) mRNA expression all corroborate with the glycemic status.ConclusionSignificantly higher expression of sclerostin (both protein and gene) in newly diagnosed T2D and prediabetes male patients, as well as significant association with SPISE index, suggest that sclerostin might be an indicator of pathophysiology related to insulin resistance, which is a characteristic feature of diabetes mellitus. However, the identification of causal relationships would warrant a large-scale prospective cohort study.

Long Term Metabolic Effects of Sacubitril/Valsartan in Non-Diabetic and Diabetic Patients With Heart Failure Reduced Ejection Fraction: A Real Life Study.

Sacubitril/Valsartan (sac/val) has improved clinical prognosis in patients affected by heart failure (HF) with reduced ejection fraction (HFrEF). HF and type 2 diabetes mellitus (T2DM) frequently coexist, with a prevalence of T2DM of 35%–40% in patients with HF. T2DM is the third co-morbidities in patients with HF and a strong independent risk factor for the progression of HF. In a post hoc analysis of PARADIGM-HF, improved glycemic control was shown in patients with T2DM and HFrEF receiving sac/val compared to enalapril at 12 months of follow-up. The aim of the present study was to evaluate, in a series of repeated observations in 90 HFrEF patients, the long term effect of sac/val treatment on renal function, glycometabolic state and insulin sensitivity parameters, according to diabetic status. We studied 90 patients (74 men and 16 women, mean age 68 ± 10 years, 60 diabetics and 30 non-diabetics) suffering from HFrEF and still symptomatic despite optimal pharmacological therapy. Patients with left ventricular ejection fraction (LVEF) <35% and II-III NYHA functional class were enrolled. All patients underwent clinical-instrumental and laboratory determinations and Minnesota Living with HF Questionnaire (MLHFQ) every 6 months until 30 months to evaluate benefits and adverse events. After 30 months follow-up, we observed a significant improvement in glycometabolic parameters including HbA1c, fasting glucose and insulin, insulin-like growth factor-1 (IGF-1), HOMA index, and LDL cholesterol. Moreover, renal function, NTpro-BNP levels and echocardiographic parameters significantly improved. In diabetic patients a significant reduction in use of oral antidiabetic drugs and insulin was observed after 30 months of sac/val treatment. In the whole population, multivariate analysis shows that the evolution of cardiac index (CI) was significantly associated to simultaneous changes in HOMA, IGF-1 and visit; per each visit and for 1 ng/ml increase in IGF-1 there was an increase in CI of 64.77 ml/min/m2 (p < 0.0001) and 0.98 ml/min/m2 (p = 0.003), respectively, whereas 1 point increase in HOMA was associated with a −7.33 ml/min/m2 (p = 0.003) reduction in CI. The present data confirm persistent metabolic improvement in patients with HFrEF after treatment with sac/val and highlights its potential therapeutical role in patients with metabolic comorbidities.

Insulin secretion and action affect glucose variability in the early stages of glucose intolerance

Since it is unknown whether glucose variability (GV) is increased and whether this is related to worsening of insulin secretion and action in prediabetes, we have assessed insulin secretion and sensitivity, and daily GV in early stages of dysglycemia. Twenty subjects with normal glucose tolerance (NGT; age 45.0±9.5years; BMI 31.1±6.4kg/m2), 25 with NGT and 1hrOGTT>8.6mmol/L (1hrOGTT; 45.7±8.5years; 32.4±7.0kg/m2), and 59 with isolated impaired glucose tolerance (iIGT; 47.7±11.2years; 31.3±6.1kg/m2) underwent OGTT and MMTT. CGM was performed with blinded FreeStyle Libre Pro for 24h under standard conditions. Parameters of beta-cell function, insulin sensitivity and GV were calculated. Overall insulin secretion and action as well as GV progressively worsened across glucose tolerance categories. On a matrix analysis, GV parameters were inversely related to ISSI-2; r=-0.37 to -0.52; p<0.0001; and IGI; r=-0.28 to -0.48; p<0.0001 for CV, SD, J-index, LI, HBGI and MAGE. Insulin secretion (IGI) and b-cell function (ISSI-2) emerged as independent contributors to GV in early stage of dysglycemia accounting for about 16%-38% of its variability. Our results show that daily GV worsens already with mild impairment of glucose tolerance. The increase in GV is inversely related to insulin secretion and action.

Prepuberal insulin secretory indices are long-term predictors of short adult stature in cystic fibrosis.

ObjectiveDiabetes is a frequent comorbidity in cystic fibrosis (CF), related to multiple unfavorable outcomes. During the progression of β-cell dysfunction to diabetes, insulin deficiency could possibly reduce the anabolic support to grow even in the absence of significant glycemic derangements. To test this hypothesis, we evaluated whether prepuberal insulin secretory indices are independent predictors of adult height.DesignObservational cohort study.Research design and methodsA longitudinal analysis of 66 CF patients (33 females) from an ongoing cohort received at prepuberal age (median age of 12 years) modified 3-h oral glucose tolerance tests with 30-min insulin and C-peptide sampling, modeling of insulin secretory and sensitivity parameters, anthropometric evaluation. The latter was repeated when adults after a median follow-up of 9 years.ResultsIn alternative models, we found a positive association with either basal insulin secretion (mean 0.22, 95% CI 0.01, 0.44 z-scores) or prepuberal β-cell glucose sensitivity (mean 0.23, 95% CI 0.00, 0.46 z-scores) and adult height, while total insulin secretion was negatively related to adult height (mean −0.36, 95% CI −0.57, −0.15 z-scores or mean −0.42, 95% CI −0.69, −0.16 z-scores, respectively). The high total insulin secretion of low adult height patients was mainly due to late (>60 min) secretion and was associated with a worse glucose response during OGTT.ConclusionsAbnormal insulin secretion associated with high glucose response during OGTT predicts a decrease in adult height z-score. Our results suggest that insulin secretory defects in CF affect growth prior to the development of fasting hyperglycemia.

Durable metabolic improvements 2 years after duodenal mucosal resurfacing (DMR) in patients with type 2 diabetes (REVITA-1 Study)

AimsDuodenal mucosal resurfacing (DMR) is an endoscopic procedure developed to improve metabolic parameters and restore insulin sensitivity in patients with diabetes. Here we report long-term DMR safety and efficacy from the REVITA-1 study. Materials and MethodsREVITA-1 was a prospective, single-arm, open-label, multicenter study of DMR feasibility, safety, and efficacy in patients with type 2 diabetes (hemoglobin A1c [HbA1c] of 7.5–10.0% (58–86 mmol/mol)) on oral medication. Safety and glycemic (HbA1c), hepatic (alanine aminotransferase [ALT]), and cardiovascular (HDL, triglyceride [TG]/HDL ratio) efficacy parameters were assessed (P values presented for LS mean change). ResultsMean ± SD HbA1c levels reduced from 8.5 ± 0.7% (69.1 ± 7.1 mmol/mol) at baseline (N = 34) to 7.5 ± 0.8% (58.9 ± 8.8 mmol/mol) at 6 months (P < 0.001); and this reduction was sustained through 24 months post-DMR (7.5 ± 1.1% [59.0 ± 12.3 mmol/mol], P < 0.001) while in greater than 50% of patients, glucose-lowering therapy was reduced or unchanged. ALT decreased from 38.1 ± 21.1 U/L at baseline to 32.5 ± 22.1 U/L at 24 months (P = 0.048). HDL and TG/HDL improved during 24-months of follow-up. No device- or procedure-related serious adverse events, unanticipated device effects, or hypoglycemic events were noted between 12 and 24 months post-DMR. ConclusionsDMR is associated with durable improvements in insulin sensitivity and multiple downstream metabolic parameters through 24 months post-treatment in type 2 diabetes.Clinical trial reg. no. NCT02413567, clinicaltrials.gov.

Oral Magnesium Supplementation for Treating Glucose Metabolism Parameters in People with or at Risk of Diabetes: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials.

There is a large and growing body of literature focusing on the use of oral magnesium (Mg) supplementation for improving glucose metabolism in people with or at risk of diabetes. We therefore aimed to investigate the effect of oral Mg supplementation on glucose and insulin-sensitivity parameters in participants with diabetes or at high risk of diabetes, compared with a placebo. Several databases were searched investigating the effect of oral Mg supplementation vs placebo in patients with diabetes or conditions at high risk of diabetes. Data were reported as standardized mean differences (SMDs) with their 95% confidence intervals (CIs) using follow-up data of glucose and insulin-sensitivity parameters. Compared with placebo, Mg supplementation reduced fasting plasma glucose in people with diabetes. In people at high risk of diabetes, Mg supplementation significantly improved plasma glucose per se, and after a 2 h oral glucose tolerance test. Furthermore, Mg supplementation demonstrated an improvement in insulin sensitivity markers. In conclusion, Mg supplementation appears to have a beneficial role and improves glucose parameters in people with diabetes. Moreover, our work indicates that Mg supplementation may improve insulin-sensitivity parameters in those at high risk of diabetes.

Robust dynamic output feedback control of blood glucose level in diabetic rat with robust descriptor Kalman filter

This paper deals with the robust control problem for a model of blood glucose system in Type-1 diabetic rats with disturbances (food, physical activity, and insulin sensitivity parameter) and model uncertainties. The considered model has a special structure, which can be written as a descriptor model. The robust control law is designed such that the output of the system tracks the desired reference signal despite the parameter uncertainties. By utilizing the μ-synthesis-based and H∞ controller design methods, the desired input signals (insulin for injection) are designed for both approaches and compared with each other. Moreover, the control structure is considered in a way that the states are not essential to be directly measured, and instead, the states estimation is utilized which operates in the closed-loop system together with a control law. Due to the existence of the model uncertainties, external disturbances, and also the characteristics of the descriptor system, the robust descriptor Kalman filter is designed for this system. Finally, to demonstrate the efficiency of the proposed methods, they are applied to the model, and simulations are provided. The results show the closed-loop system including the descriptor model, robust controller, and robust descriptor Kalman filter can force the blood glucose level to maintain in the normal range successfully with an acceptable state estimation error.

Can offsetting the energetic cost of hibernation restore an active season phenotype in grizzly bears (Ursus arctos horribilis)?

Hibernation is characterized by depression of many physiological processes. To determine if this state is reversible in a non-food caching species, we fed hibernating grizzly bears (Ursus arctos horribilis) dextrose for 10 days to replace 53% or 100% of the estimated minimum daily energetic cost of hibernation. Feeding caused serum concentrations of glycerol and ketones (β-hydroxybutyrate) to return to active season levels irrespective of the amount of glucose fed. By contrast, free fatty acids (FFAs) and indices of metabolic rate, such as general activity, heart rate, strength of heart rate circadian rhythm, and insulin sensitivity were restored to approximately 50% of active season levels. Body temperature was unaffected by feeding. To determine the contribution of adipose to the metabolic effects observed after glucose feeding, we cultured bear adipocytes collected at the beginning and end of the feeding and performed metabolic flux analysis. We found a ∼33% increase in energy metabolism after feeding. Moreover, basal metabolism before feeding was 40% lower in hibernation cells compared with fed cells or active cells cultured at 37°C, thereby confirming the temperature independence of metabolic rate. The partial depression of circulating FFAs with feeding likely explains the incomplete restoration of insulin sensitivity and other metabolic parameters in hibernating bears. Further depression of metabolic function is likely to be an active process. Together, the results provide a highly controlled model to examine the relationship between nutrient availability and metabolism on the hibernation phenotype in bears.

Protective effects of rice bran hydrolysates on heart rate variability, cardiac oxidative stress, and cardiac remodeling in high fat and high fructose diet-fed rats

Objective: To examine the ameliorative effect of rice bran hydrolysates (RBH) on metabolic disorders, cardiac oxidative stress, heart rate variability (HRV), and cardiac structural changes in high fat and high fructose (HFHF)-fed rats. Methods: Male Sprague-Dawley rats were daily fed either standard chow diet with tap water or an HFHF diet with 10% fructose in drinking water over 16 weeks. RBH (500 and 1 000 mg/kg/day) was orally administered to the HFHF-diet-fed rats during the last 6 weeks of the study period. At the end of the treatment, metabolic parameters, oxidative stress, HRV, and cardiac structural changes were examined. Results: RBH administration significantly ameliorated metabolic disorders by improving lipid profiles, insulin sensitivity, and hemodynamic parameters. Moreover, RBH restored HRV, as evidenced by decreasing the ratio of low-frequency to high-frequency power of HRV, a marker of autonomic imbalance. Cardiac oxidative stress was also mitigated after RBH supplementation by decreasing cardiac malondialdehyde and protein carbonyl, upregulating eNOS expression, and increasing catalase activity in the heart. Furthermore, RBH mitigated cardiac structural changes by reducing cardiac hypertrophy and myocardial fibrosis in HFHF-diet-fed rats. Conclusions: The present findings suggest that consumption of RBH may exert cardioprotective effects against autonomic imbalances, cardiac oxidative stress, and structural changes in metabolic syndrome.

Antidiabetic potential of Moringa oleifera Lam. leaf extract in type 2 diabetic rats, and its mechanism of action

Purpose: To explore the antidiabetic potential of Moringa oleifera leaf extract in type 2 diabetic rats, and the underlying mechanisms.Methods: Streptozotocin (STZ) at a dose of 40 mg/kg was given to high fat diet (HFD)- fed rats to induce type 2 diabetes. M. oleifera leaf extract at doses 100, 200 and 400 mg/kg were given to 3 groups of type 2 diabetic rats. The area under curve (AUC) of glucose and homeostasis model assessment of insulin resistance (HOMA-R) were calculated using appropriate formulas, whereas levels of glucose,insulin, peroxisome proliferator activated receptor-γ (PPARγ, dipeptidyl peptidase-IV (DPP-IV) and inflammatory cytokines (IL-6, IL-1β and TNFα) were assayed using ELISA kits.Results: The leaf extract of M. oleifera significantly reduced the levels of glucose, insulin and cytokines in treated type 2 diabetic groups (p &lt; 0.05). DC group had significantly increased AUC for glucose, whereas the extract-treated groups showed significant decrease in glucose AUC. There was significant decrease in insulin sensitivity parameters, as indicated by increase in HOMA-R and decrease in PPARγ levels in the DC group (p &lt; 0.05). However, treatment with the M. oleifera extract reversed this trend via marked decrease in HOMA-R level and significant rise in PPARγ level. In contrast, the extract had no effect on DPP-IV concentration in diabetic treated groups (p &lt; 0.05).Conclusion: These results indicate that M. oleifera leaf extract mitigates hyperglycemia in type 2 DM by modulating hyperinsulinemia, PPARγ and inflammatory cytokines. Thus, the extract is a potential source of drug for the management of type 2 DM.&#x0D; Keywords: Moringa oleifera, Diabetes mellitus, Streptozotocin, Peroxisome proliferator activated receptor-γ, Dipeptidyl peptidase IV

Insulin Action, Glucose Homeostasis and Free Fatty Acid Metabolism: Insights From a Novel Model.

Glucose and free fatty acids (FFA) are essential nutrients that are both partly regulated by insulin. Impaired insulin secretion and insulin resistance are hallmarks of aberrant glucose disposal, and type 2 diabetes (T2DM). In the current study, a novel model of FFA kinetics is proposed to estimate the role insulin action on FFA lipolysis and oxidation allowing estimation of adipose tissue insulin sensitivity (SIFFA ). Twenty-five normal volunteers were recruited for the current study. To participate, volunteers had to be less than 40 years of age and have a body mass index (BMI) < 30 kg/m2, and be free of medical comorbidity. The proposed model of FFA kinetics was used to analyze the data derived from the insulin-modified FSIGT. Mean fractional standard deviations of the parameter estimates were all less than 20%. Standardized residuals of the fit of the model to the FFA temporal data were randomly distributed, with only one estimated point lying outside the 2-standard deviation range, suggesting an acceptable fit of the model to the FFA data. The current study describes a novel one-compartment non-linear model of FFA kinetics during an FSIGT that provides an FFA metabolism insulin sensitivity parameter (SIFFA ). Furthermore, the models suggest a new role of glucose as the modulator of FFA disposal. Estimates of SIFFA confirmed previous findings that FFA metabolism is more sensitive to changes in insulin than glucose metabolism. Novel derived indices of insulin sensitivity of FFA (SIFFA ) were correlated with minimal model indices. These associations suggest a cooperative rather than competitive interplay between the two primary nutrients (glucose and FFA) and allude to the FFA acting as the buffer, such that glucose homeostasis is maintained.

Comparative Efficacy of Metformin vs. Pioglitazone alone and in Combination with High Dose Oral Cholecalciferol among Women with Polycystic Ovary Syndrome (PCOS): A Six-month Randomized, Open Label Study

Purpose: We aimed to evaluate the comparative efficacy of metformin and pioglitazone coadministered with high dose VD on clinical, biochemical, hormonal and insulin sensitivity parameters in women with PCOS. Material and Methods: In this open label randomised study, a total of 136 women, aged 18-40 years, diagnosed with PCOS as per the AE PCOS 2009 criteria, were randomly assigned into four groups (n=34 per group). The four groups received Metformin-1gm/day alone, metformin-1gm/day+cholecalciferol4000IU/ d,pioglitazone-30mg/day alone and pioglitazone- 30mg/day+cholecalciferol-4000IU/d.The clinical, biochemical, hormonal and insulin sensitivity parameters were evaluated at 0, 3 months and 6 months after the intervention. Results: The mean age of subjects was 21.89±4.99 years with mean BMI of 22.19±3.24kg/m2. The mean serum 25OHD level at the baseline in the metformin+VD and pioglitazone+VD group was 13.28±8.44ng/ml and 11.17±7.46ng/ml and it improved to 63.33±19.76ng/ml and 57.69±14.43ng/ ml respectively after six months of intervention. The mean no. of cycles/year and Ferriman-Gallwey (FG) score improved in all four arms. Significant decrease in the total serum testosterone level was observed in the groups that received VD in addition to metformin and pioglitazone, the effect being more significant in the metformin+VD group (64.60±23.59ng/dl at 0 months to 41.24±12.83ng/dl after 6 months). Plasma glucose and insulin levels from a two-hour OGTT showed a significant improvement in subjects receiving VD in addition to pioglitazone. Conclusion: Metformin and pioglitazone are equally efficacious for treatment of women with PCOS. High dose oral cholecalciferol co-administration significantly improved the metabolic outcomes among these women. Key words: Metformin; Pioglitazone; PCOS; Insulin resistance; Vitamin D deficiency.

Maternal Overweight vs. Polycystic Ovary Syndrome: Disentangling Their Impact on Insulin Action in Pregnancy-A Prospective Study.

Background: To investigate insulin sensitivity and glucose metabolism in pregnant lean and overweight polycystic ovary syndrome (PCOS) patients vs. lean and overweight controls without PCOS. Methods: Prospective cohort study on 67 pregnant women (31 with PCOS and 36 controls, subdivided into overweight or obese and normal weight). All women underwent a 2h-OGTT including glucose, insulin, and C-peptide in early- and mid-gestation and were followed-up until delivery. Results: Insulin sensitivity and glucometabolic parameters were comparable between PCOS patients and controls, whereas marked differences were observed between overweight/obese and lean mothers. Impaired whole-body insulin sensitivity at early pregnancy is mainly a consequence of higher BMI (body mass index; p < 0.001) compared to PCOS (p = 0.216), whereby no interaction between overweight/obesity and PCOS was observed (p = 0.194). Moreover, overweight was significantly associated with gestational diabetes (p = 0.0003), whereas there were no differences between women with and without PCOS (p = 0.51). Birth weight was inversely related to whole-body insulin sensitivity (rho = −0.33, p = 0.014) and positively associated with higher pregestational BMI (rho = 0.33, p = 0.012), whereas there was no association with PCOS. Conclusions: Impaired insulin action was mainly a consequence of overweight rather than PCOS. Our data suggest that overweight is more relevant than PCOS for the effects on insulin sensitivity and impaired glucose metabolism.

Replay Simulations with Personalized Metabolic Model for Treatment Design and Evaluation in Type 1 Diabetes.

The capacity to replay data collected in real life by people with type 1 diabetes mellitus (T1DM) would lead to individualized (vs population) assessment of treatment strategies to control blood glucose and possibly true personalization. Patek et al introduced such a technique, relying on regularized deconvolution of a population glucose homeostasis model to estimate a residual additive signal and reproduce the experimental data; therefore, allowing the subject-specific replay of what-if scenarios by altering the model inputs (eg, insulin). This early method was shown to have a limited domain of validity. We propose and test in silico a similar approach and extend the method applicability. A subject-specific model personalization of insulin sensitivity and meal-absorption parameters is performed. The University of Virginia (UVa)/Padova T1DM simulator is used to generate experimental scenarios and test the ability of the methodology to accurately reproduce changes in glucose concentration to alteration in meal and insulin inputs. Method performance is assessed by comparing true (UVa/Padova simulator) and replayed glucose traces, using the mean absolute relative difference (MARD) and the Clarke error grid analysis (CEGA). Model personalization led to a 9.08 and 6.07 decrease in MARD over a prior published method of replaying altered insulin scenarios for basal and bolus changes, respectively. Replay simulations achieved high accuracy, with MARD <10% and more than 95% of readings falling in the CEGA A-B zones for a wide range of interventions. In silico studies demonstrate that the proposed method for replay simulation is numerically and clinically valid over broad changes in scenario inputs, indicating possible use in treatment optimization.

The Metabolic Effects of Cynara Supplementation in Overweight and Obese Class I Subjects with Newly Detected Impaired Fasting Glycemia: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

Impaired fasting glucose (IFG) is a condition that precedes diabetes and increases the risk of developing it. Studies support the hypoglycemic effect of Cynara scolymus (Cs) extracts due to the content of chlorogenic acid, which is a potent inhibitor of glucose 6-phosphate translocase and of dicaffeoylquinic acid derivatives that modulate the activity of alpha-glucosidase. Given this background, we investigated whether a new highly standardized Cs extract could improve glycemic control, insulin sensitivity and other metabolic parameters (total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) Triglycerides, Apolipo protein B (ApoB), Apolipo protein A (ApoA), waist circumference, visceral adipose tissue (VAT) by dual-energy X-ray absorptiometry (DXA) in overweight subjects with newly diagnosed IFG. Fifty-four subjects (females/males 26/28, mean ± SD age 51.5 ± 6.2) were randomly assigned to the supplemented group (n = 27) and placebo (n = 27). After multiple testing correction, statistically significant interactions between time and group were observed for the primary endpoint glycemia (β = 0.36, p < 0.0001) and for the secondary endpoints HDL (β = −0.10, p < 0.0001), total cholesterol/HDL (β = 0.27, p < 0.0001), LDL (β = 0.15, p = 0.005), LDL/HDL (β = 0.23, p = 0.001), insulin (β = 1.28, p = 0.04), glycated hemoglobin (β = 0.21, p = 0.0002), A1c-derived average glucose (β = 0.34, p = 0.0002), ApoB (β = 6.00, p = 0.01), ApoA (β = −4.50, p = 0.04), ApoB/ApoA (β = 0.08, p = 0.003), waist circumference (β = 1.89, p = 0.05), VATβ = 222.37, p = 0.005). In conclusion, these results confirm that Cs supplementation has a significant effect on metabolic parameters in IFG patients.