Insulin Secretion-Sensitivity Index-2 Research Articles

A Glycemic Threshold Above Which the Improvement of β-Cell Function and Glycemia in Response to Insulin Therapy Is Amplified in Early Type 2 Diabetes: The Reversal of Glucotoxicity.

Alleviation of unrecognized glucotoxicity, with resultant recovery of β-cell function, could amplify the glucose-lowering effect of pharmacotherapy and contribute to the variable therapeutic response observed among patients with type 2 diabetes (T2D). However, clinical evidence supporting this concept is lacking. Short-term intensive insulin therapy (IIT) can ameliorate glucotoxicity and improve β-cell function in early T2D. Thus, for evidence of recovery of glucotoxicity-associated β-cell dysfunction, we sought to determine whether there exists a baseline fasting glucose threshold above which the post-IIT improvement in both β-cell function and glycemia is amplified. IIT (glargine, lispro) was administered for 3 weeks to 108 adults with T2D (mean duration 1.8 ± 1.4 years). Oral glucose tolerance tests before and after IIT enabled assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-insulin resistance. For each level of baseline fasting glycemia from 6.0 to 10.5 mmol/L, we modeled the difference in IIT-induced percentage change in β-cell function between those at/above the indicated glucose level and those below it. The relationship between baseline fasting glucose and the differential change in β-cell function was nonlinear. Instead, this relationship was best fit by a cubic regression model with inflection (amplification) at fasting glucose at 9.3 mmol/L. Moreover, baseline fasting glucose at 9.3 mmol/L also identified the inflection point at which nonlinear reductions in fasting glucose and 2-h glucose, respectively, were both amplified. The respective improvements in β-cell function and glycemia in response to short-term IIT are amplified in those in whom baseline fasting glucose exceeds a defined threshold, consistent with reversal of glucotoxicity.

The impact of time-restricted eating on beta-cell function in adults with type 2 diabetes: a randomized cross-over trial.

Time-restricted eating (TRE) which consists of restricting the eating window to typically 4-8h (while fasting for the remaining hours of the day) has been proposed as a non-pharmacological strategy with cardio-metabolic benefits but little is known about its metabolic impact in type 2 diabetes (T2DM). We evaluated whether TRE can improve pancreatic beta-cell function and metabolic status in overweight individuals with early T2DM. In a randomized cross-over trial, 39 participants [mean 2.9 years of diabetes duration, baseline glycated hemoglobin (HbA1c) 6.6% ± 0.7% and body mass index (BMI) 32.4 ± 5.7 kg/m2] were randomized to either an initial intervention consisting of 6-weeks of TRE (20h-fasting/4h-eating) or standard lifestyle. The primary outcome of beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2) derived from an oral glucose tolerance test. Trial registration: clinicaltrials.gov NCT05717127. As compared to standard lifestyle, TRE induced a 14% increase in ISSI-2 (+14.0 ± 39.2%, p = 0.03) accompanied by 14% reduction of hepatic insulin resistance as evaluated by HOMA-IR [-11.6% (-49.3-21.9), p = 0.03]. Fasting glucose did not differ between interventions, but TRE yielded a significant reduction in HbA1c (-0.32 ± 0.48%, p <0.001). These metabolic improvements were coupled by a reduction of body weight of 3.86% (-3.86 ± 3.1%, p <0.001) and waist circumference of 3.8 cm (-3.8 ± 7.5 cm, p = 0.003). TRE improved beta-cell function and insulin resistance in overweight patients with early diabetes, accompanied by beneficial effects on adiposity.

Impact of breastfeeding on risk of glucose intolerance in early postpartum after gestational diabetes.

To determine the impact of breastfeeding on the risk of postpartum glucose intolerance in women with gestational diabetes. Sub-analysis of two multi-centric prospective cohort studies (BEDIP-N and MELINDA) in 1008 women with gestational diabetes. Data were collected during pregnancy and at a mean of 12 weeks postpartum. Multivariate logistic regression was used to estimate the effect of breastfeeding on glucose intolerance, with adjustment for ethnicity, education, income, professional activity and BMI. Of all participants, 56.3% (567) breastfed exclusively, 10.1% (102) gave mixed milk feeding and 33.6% (339) did not breastfeed. Mean breastfeeding duration was 3.8 ± 2.4 and 3.7 ± 2.1 months in the breastfeeding and mixed milk feeding groups (p=0.496). The rate of glucose intolerance was lower in both the breastfeeding [22.3% (126)] and mixed milk feeding [25.5% (26)] groups compared to the no breastfeeding group [29.5% (100)], with an adjusted OR of 0.7 (95% CI 0.5-1.0) for glucose intolerance in the breastfeeding group compared to no breastfeeding group and an adjusted OR of 0.7 (95% CI 0.4-1.2) for the mixed milk feeding group compared to the no breastfeeding group. Postpartum, breastfeeding women had a lower BMI, less often postpartum weight retention, lower fasting triglycerides, less insulin resistance and a higher insulin secretion-sensitivity index-2 than the mixed milk feeding and no breastfeeding group. The mixed milk feeding group was more often from an non-White background, had a lower blood pressure and lower fasting triglycerides compared to the no breastfeeding group. Breastfeeding (exclusive and mixed milk feeding) is associated with less glucose intolerance and a better metabolic profile in early postpartum in women with gestational diabetes.

Normalization of impaired glucose tolerance after kidney transplantation is associated with improved β-cell function.

Our previous study revealed that over 50% of recipients with pretransplant impaired glucose tolerance (IGT) improved to normal glucose tolerance after kidney transplantation. However, the mechanism is unclear. We aimed to investigate whether the changes in glucose tolerance are associated with β-cell function and insulin resistance in Japanese kidney transplant recipients with pretransplant IGT. Of the 265 recipients who received kidney transplantation, 54 with pretransplant IGT were included. We divided the recipients into improvement and nonimprovement groups according to the change in the area under the curve for glucose obtained from the oral glucose tolerance test (OGTT). β-Cell function was estimated by the insulin secretion sensitivity index-2 (ISSI-2) and the disposition index (DI). Insulin resistance was estimated by the Matsuda index (MI) and the homeostasis model assessment of insulin resistance (HOMA-IR). ISSI-2 and DI increased significantly after transplantation in the improved group (P < 0.01, P < 0.05, respectively), but not in the nonimproved group. ΔISSI-2 and ΔDI were significantly and positively associated with pretransplant 60-min OGTT plasma glucose levels (both P < 0.01). There were no differences in MI or HOMA-IR between these two groups after transplantation. In recipients not on pretransplant dialysis, a significant negative association was found between Δblood urea nitrogen (BUN) and ΔDI (correlation coefficient = -0.48, P < 0.05). In pretransplant IGT recipients, improvements in glucose tolerance after kidney transplantation were linked to improvements in β-cell function. The higher the 60-min OGTT plasma glucose level, the greater the improvement in posttransplant β-cell function. Improvements in BUN after transplantation were associated with improvements in β-cell function.NEW & NOTEWORTHY In recipients with pretransplant impaired glucose tolerance, improvements in glucose tolerance after kidney transplantation were associated with improvements in β-cell function. The higher the pretransplant 60-min OGTT plasma glucose level, the greater the improvement in posttransplant β-cell function. Although glucose tolerance is known to be impaired after transplantation, the present study focused on the reason for the improvement in glucose tolerance rather than the development of posttransplantation diabetes mellitus.

Prospective associations between breast feeding, metabolic health, inflammation and bone density in women with prior gestational diabetes mellitus

IntroductionThe aim of the study is to investigate prospective associations between breastfeeding and metabolic outcomes, inflammation, and bone density in women with prior gestational diabetes mellitus (GDM).Research design and methodsWe...

Association of point in range with β-cell function and insulin sensitivity of type 2 diabetes mellitus in cold areas

Abstract Background and Objective Self-monitoring of blood glucose (SMBG) is crucial for achieving a glycemic target and upholding blood glucose stability, both of which are the primary purpose of anti-diabetic treatments. However, the association between time in range (TIR), as assessed by SMBG, and β-cell insulin secretion as well as insulin sensitivity remains unexplored. Therefore, this study aims to investigate the connections between TIR, derived from SMBG, and indices representing β-cell functionality and insulin sensitivity. The primary objective of this study was to elucidate the relationship between short-term glycemic control (measured as points in range [PIR]) and both β-cell function and insulin sensitivity. Methods This cross-sectional study enrolled 472 hospitalized patients with type 2 diabetes mellitus (T2DM). To assess β-cell secretion capacity, we employed the insulin secretion-sensitivity index-2 (ISSI-2) and (ΔC-peptide0–120/Δglucose0–120) × Matsuda index, while insulin sensitivity was evaluated using the Matsuda index and HOMA-IR. Since SMBG offers glucose data at specific point-in-time, we substituted TIR with PIR. According to clinical guidelines, values falling within the range of 3.9–10 mmol were considered “in range, ” and the corresponding percentage was calculated as PIR. Results We observed significant associations between higher PIR quartiles and increased ISSI-2, (ΔC-peptide0–120/Δglucose0–120) × Matsuda index, Matsuda index (increased) and HOMA-IR (decreased) (all P &lt; 0.001). PIR exhibited positive correlations with log ISSI-2 (r = 0.361, P &lt; 0.001), log (ΔC-peptide0–120/Δglucose0–120) × Matsuda index (r = 0.482, P &lt; 0.001), and log Matsuda index (r = 0.178, P &lt; 0.001) and negative correlations with log HOMA-IR (r = -0.288, P &lt; 0.001). Furthermore, PIR emerged as an independent risk factor for log ISSI-2, log (ΔC-peptide0–120/Δglucose0–120) × Matsuda index, log Matsuda index, and log HOMA-IR. Conclusion PIR can serve as a valuable tool for assessing β-cell function and insulin sensitivity.

FRI417 An Interdisciplinary Program Promoting The Adoption Of A Healthy Lifestyle Increases Insulin Sensitivity In Women With Obesity And Infertility

Abstract Disclosure: A. Forget-Renaud: None. M. Belan: None. F. Jean-Denis: None. M. Pesant: None. J. Baillargeon: Grant Recipient; Self; Ferring Pharmaceuticals, JPB received an unrestricted investigator-initiated grant from Ferring Canada, which was not for the reported study. Introduction Obesity increases the risk of ovulatory and anovulatory infertility in women, mainly through the development of polycystic ovary syndrome (PCOS). Insulin resistance contributes to the pathogenesis of PCOS and may play a role in the infertility of PCOS and non-PCOS women with overweight or obesity. Lifestyle modifications are recommended as a first-line therapy in women with PCOS or those with obesity and infertility, as it was associated with improvement in menstrual pattern and fertility outcomes. We therefore hypothesized that a lifestyle intervention may increase insulin sensitivity in women with obesity and infertility. Methods Women with obesity and infertility were randomly allocated to usual fertility care (control group, CG) or to an interdisciplinary intervention promoting the adoption of a healthy lifestyle (LSG) alone for 6 months and then combined with usual care. Insulin resistance was estimated during fasting (HOMA-IR) and a 75-g oral glucose test (Matsuda Insulin Sensitivity Index, ISI(M)), and β-cell function was estimated using the Insulin Secretion-Sensitivity Index (ISSI-2) in women not taking medication affecting insulin sensitivity (except metformin). Data were collected at baseline, 6, 12 and 18 months, and as soon as possible when the participant knew she was pregnant. We estimated the integrated change in insulin sensitivity during follow-up using the incremental area-under-the-curve of ISI(M) divided by time (iAUC-ISI(M)/time). Results Among 130 randomized participants, 105 had available data (LSG=51, CG=54). PCOS was diagnosed using the Rotterdam criteria in 63.2% of participants, equally distributed between the groups. As compared to CG, women in the LSG improved significantly more their ISI(M) after 6 months (+0.24 [IQR: -0.48 - +0.94] vs 0.16 [-1.32 - +0.53], p=0.039, n=90), as well as their iAUC-ISI(M)/time during follow-up (+0.18±0.84 vs -0.21±0,93, p=0.035, n=104). All these results remained statistically significant after correction for baseline BMI, age and use of folic acid. Increases in iAUC-ISI(M)/time in the intervention vs control groups were significantly more important (p for interaction=0.045) in participants with baseline ISI(M) above the median (LSG: +0.10±1.13, n=24, vs CG: -0.62±1.13, n=27, p=0.028) than in those below the median (LSG: +0.26±0.48, n=27, vs CG: +0.21±0.35, n=26, p=0.71). Interactions with PCOS status and other subgroups were not statistically significant. There was no impact on HOMA-IR or ISSI-2. Conclusion An interdisciplinary program promoting the adoption of a healthy lifestyle significantly increases whole-body insulin sensitivity in women with infertility and obesity, mainly in those with higher baseline insulin sensitivity. It may be explained in part by the weight loss associated with the intervention and may have a role in improving fertility in this population. Presentation: Friday, June 16, 2023

Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following pregnancy.

Excess adiposity, insulin resistance and beta cell dysfunction each contribute to the development of prediabetes (impaired glucose tolerance and/or impaired fasting glucose)/diabetes but their comparative impact in relation to one another remains uncertain. We thus ranked their contributions to incident dysglycaemia over the first 5 years postpartum in women reflecting the full spectrum of gestational glucose tolerance (spanning normoglycaemia to gestational diabetes) and hence a range of future diabetic risk. In this study, 302 women with normal glucose tolerance (NGT) on OGTT at 3 months postpartum underwent repeat OGTT at 1 year, 3 years and 5 years, enabling serial assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, HOMA-IR) and beta cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index [IGI]/HOMA-IR). Determinants of prediabetes/diabetes were ranked by change in concordance index (CCI) of Cox proportional hazard regression models. Over 5 years of follow-up, 89 women progressed from NGT to prediabetes/diabetes (progressors). At 3 months postpartum, though all women were normoglycaemic, future progressors had higher fasting glucose (p=0.03) and 2 h glucose (p<0.0001) than non-progressors, coupled with higher BMI (p=0.001), greater insulin resistance (both Matsuda index and HOMA-IR, p≤0.02) and poorer beta cell function (both ISSI-2 and IGI/HOMA-IR, p≤0.006). Unlike their peers, progressors exhibited deteriorating beta cell function from 1 year to 5 years (both p<0.0001). On regression analyses, the dominant determinants of progression to prediabetes/diabetes were time-varying ISSI-2 (change in CCI 25.2%) and IGI/HOMA-IR (13.0%), in contrast to time-varying Matsuda index (2.9%) and HOMA-IR (0.5%). Neither time-varying BMI nor waist were significant predictors after adjustment for beta cell function and insulin sensitivity/resistance. Declining beta cell function is the dominant determinant of incident prediabetes/diabetes in young women following pregnancy.

Factors associated with nocturnal and diurnal glycemic variability in patients with type 2 diabetes: a cross-sectional study.

There is little information on factors that influence the glycemic variability (GV) during the nocturnal and diurnal periods. We aimed to examine the relationship between clinical factors and GV during these two periods. This cross-sectional study included 134 patients with type 2 diabetes. 24-h changes in blood glucose were recorded by a continuous glucose monitoring system. Nocturnal and diurnal GV were assessed by standard deviation of blood glucose (SDBG), coefficient of variation (CV), and mean amplitude of glycemic excursions (MAGE), respectively. Robust regression analyses were performed to identify the factors associated with GV. Restricted cubic splines were used to determine dose-response relationship. During the nocturnal period, age and glycemic level at 12:00 A.M. were positively associated with GV, whereas alanine aminotransferase was negatively associated with GV. During the diurnal period, homeostatic model assessment 2-insulin sensitivity (HOMA2-S) was positively associated with GV, whereas insulin secretion-sensitivity index-2 (ISSI2) was negatively associated with GV. Additionally, we found a J-shape association between the glycemic level at 12:00 A.M. and MAGE, with 9.0mmol/L blood glucose level as a cutoff point. Similar nonlinear associations were found between ISSI2 and SDBG, and between ISSI2 and MAGE, with ISSI2 value of 175 as a cutoff point. Factors associated with GV were different between nocturnal and diurnal periods. The cutoff points we found in this study may provide the therapeutic targets for beta-cell function and pre-sleep glycemic level in clinical practice.

180-OR: Baseline Predictors of Remission of Type 2 Diabetes in Response to Short-Term Insulin-Based Therapy—The Pivotal Role of Beta-Cell Function

Short-term treatment with insulin can induce remission of type 2 diabetes (T2DM) in some patients but not others. We thus sought to identify baseline predictors of diabetes remission in response to short-term insulin-based therapy. In this study, adult patients with T2DM of &amp;lt;7 years duration were randomized to 8-weeks treatment with (i) insulin glargine, (ii) glargine + thrice-daily lispro, or (iii) glargine + twice-daily exenatide, followed by 12-weeks washout that enabled assessment of remission (defined as A1c&amp;lt;6.5% after ≥3 months without glucose-lowering therapy). At baseline, 8-weeks, and washout, beta-cell function was assessed with 4 measures: Insulin Secretion-Sensitivity Index-2 (ISSI-2), insulinogenic index/HOMA-IR, ΔCpeptide0-120/Δglucose0-120×Matsuda, and ΔISR0-120/Δgluc0-120×Matsuda. Diabetes remission was achieved in 31 of 90 participants (34.4%). Compared to their peers, those who went on to remission had lower A1c (p&amp;lt;0.001) and better beta-cell function at baseline (all 4 measures p≤0.01). The non-remission and remission groups did not otherwise differ in baseline insulin sensitivity/resistance (Matsuda, HOMA-IR), BMI, duration of diabetes, pre-trial diabetes medications, or allocated insulin-based therapy during the trial. On logistic regression analyses, each baseline measure of beta-cell function emerged as a significant predictor of remission (log ISSI-2: adjusted OR 4.41 (95%CI: 1.71-11.34); log insulinogenic index/HOMA-IR: 2.21 (1.26-3.89); log ΔCpeptide0-120/Δglucose0-120×Matsuda: 1.62 (1.00-2.64); log ΔISR0-120/Δgluc0-120×Matsuda: 1.87 (1.09-3.23). Similarly, higher baseline ISSI-2 tertile predicted longer time to glycemic relapse after cessation of the insulin-based therapy (log-rank P=0.029). In conclusion, beta-cell function is the dominant baseline determinant of the likelihood of achieving remission of diabetes in response to short-term insulin-based therapy. Disclosure R.Retnakaran: Other Relationship; Sanofi, Eli Lilly and Company, Research Support; Boehringer Ingelheim/Mount Sinai Hospital, Novo Nordisk. J.Pu: None. A.Emery: None. C.K.Kramer: Research Support; Boehringer Ingelheim Inc. B.Zinman: Consultant; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk A/S, Novo Nordisk Canada Inc., Boehringer Ingelheim Inc., Merck &amp; Co., Inc. Funding Canadian Institutes of Health Research (MOP136938)

Association of circulating branched chain fatty acids with insulin sensitivity and beta cell function in the PROMISE cohort.

Branched chain fatty acids (BCFAs) are mainly saturated fatty acids with a methyl branch on the penultimate or antepenultimate carbon atom. While BCFAs are endogenously produced via the catabolism of branched chain amino acids, the primary exogenous source of BCFAs in the human body is via the diet, including dairy products. Recently, BCFAs have been identified as having a potentially protective role in the etiology of cardiometabolic disorders although current literature is limited. We aimed to investigate the longitudinal associations of circulating BCFAs across four serum pools with insulin sensitivity, beta cell function, and glucose concentrations in the PROMISE Cohort. Estimates of insulin sensitivity were assessed using Matsuda's insulin sensitivity index (ISI) and the homeostasis model assessment of insulin sensitivity (HOMA2). Estimates of beta cell function were determined using the insulinogenic index divided by HOMA insulin resistance and the insulin secretion-sensitivity index-2 (ISSI-2). Baseline serum samples were analyzed for BCFAs using gas-chromatography flame ionization detection. Longitudinal associations were determined using generalized estimating equations. In the free fatty acid (FFA) pool, iso15:0 and anteiso15:0 were positively associated with logHOMA2 (iso15:0 logHOMA2-%S: β = 6.86, 95% CI: [1.64, 12.36], p < 0.05, anteiso15:0 logHOMA2-%S: β = 6.36, 95% CI: [0.63, 12.42], p < 0.05) while anteiso14:0 was inversely associated with measures of insulin sensitivity (iso14:0 logHOMA2-%S: β = -2.35, 95% CI: [-4.26, -0.40], p < 0.05, logISI: β = -2.30, 95% CI: [-4.32, -0.23], p < 0.05, anteiso14:0 logHOMA2-%S: β = -4.72, 95% CI: [-7.81, -1.52], p < 0.05, logISI: β = -6.13, 95% CI: [-9.49, -2.66], p < 0.01). Associations in other pools were less consistent. We identified the potential importance of specific BCFAs, specifically iso14:0, anteiso14:0, iso15:0, anteiso15:0, in cardiometabolic phenotypes underlying type 2 diabetes.

Association between residual islet beta-cell function and achieving the target of time in range in inpatients with type 2 diabetes undergoing antidiabetic treatment: An observation study.

To assess whether the beta-cell function of inpatients undergoing antidiabetic treatment influences achieving time in range (TIR) and time above range (TAR) targets. This cross-sectional study included 180 inpatients with type 2 diabetes. TIR and TAR were assessed by a continuous glucose monitoring system, with target achievement defined as TIR more than 70% and TAR less than 25%. Beta-cell function was assessed by the insulin secretion-sensitivity index-2 (ISSI2). Following antidiabetic treatment, logistic regression analysis showed that lower ISSI2 was associated with a decreased number of inpatients achieving TIR (OR=3.10, 95% CI: 1.19-8.06) and TAR (OR=3.40, 95% CI: 1.35-8.55) targets after adjusting for potential confounders. Similar associations still existed in those participants treated with insulin secretagogues (TIR: OR=2.91, 95% CI: 0.90-9.36, P=.07; TAR, OR=3.14, 95% CI: 1.01-9.80) or adequate insulin therapy (TIR: OR=2.84, 95% CI: 0.91-8.81, P=.07; TAR, OR=3.24, 95% CI: 1.08-9.67). Furthermore, receiver operating characteristic curves showed that the diagnostic value of the ISSI2 for achieving TIR and TAR targets was 0.73 (95% CI: 0.66-0.80) and 0.71 (95% CI: 0.63-0.79), respectively. Beta-cell function was associated with achieving TIR and TAR targets. Stimulating insulin secretion or exogenous insulin treatment could not overcome the disadvantage of lower beta-cell function on glycaemic control.

Plasma Branched-Chain Amino Acid Concentrations and Glucose Homeostasis in Kidney Transplant Recipients and Candidates

Post-transplant diabetes mellitus (PTDM) encompasses new-onset and previously unrecognized type 2 diabetes. Kidney failure masks type 2 diabetes. Branched-chain amino acids (BCAA) are closely associated with glucose metabolism. Therefore, understanding BCAA metabolism both in kidney failure and after kidney transplantation may inform PTDM mechanisms. To understand the impact of present or absent kidney function on plasma BCAA concentrations. Cross-sectional study of kidney transplant recipients and kidney transplant candidates. Large kidney transplant center in Toronto, Canada. We measured plasma BCAA and aromatic amino acid (AAA) concentrations in 45 pre-kidney transplant candidates (15 with type 2 diabetes, 30 without type 2 diabetes) and 45 post-kidney transplant recipients (15 PTDM, 30 non-PTDM), along with insulin resistance and sensitivity by 75 g oral glucose loading for those in each group without type 2 diabetes. Plasma AA concentrations were analyzed using MassChrom AA Analysis and compared between groups. The insulin sensitivity for oral glucose tolerance tests or Matsuda index (a measure of whole-body insulin resistance), Homeostatic Model Assessment for Insulin Resistance (a measure of hepatic insulin resistance), and Insulin Secretion-Sensitivity Index-2 (ISSI-2, a measure of pancreatic β-cell response) was calculated from fasting insulin and glucose concentrations, and compared with BCAA concentrations. Each BCAA concentration was higher in post-transplant subjects than pre-transplant subjects (P < .001 for leucine, isoleucine, valine). In post-transplant subjects, each BCAA concentration was higher in PTDM versus non-PTDM (odds ratio for PTDM 3-4 per 1 SD increase in BCAA concentration, P < .001 for each). Tyrosine concentrations were also higher in post-transplant subjects than pre-transplant subjects, but tyrosine did not differ by PTDM status. By contrast, neither BCAA nor AAA concentrations were different in pre-transplant subjects with or without type 2 diabetes. Whole-body insulin resistance, hepatic insulin resistance, and pancreatic β-cell response did not differ between nondiabetic post-transplant and pre-transplant subjects. Branched-chain amino acid concentrations correlated with the Matsuda index and Homeostatic Model Assessment for Insulin Resistance (P < .05 for each) only in nondiabetic post-transplant subjects-not in nondiabetic pre-transplant subjects. Branched-chain amino acid concentrations did not correlate with ISSI-2 in either pre-transplant or post-transplant subjects. The sample size was small, and subjects were not studied prospectively for the development of type 2 diabetes. Plasma BCAA concentrations are higher post-transplant in type 2 diabetic states, but do not differ by diabetes status in the presence of kidney failure. The association of BCAA with measures of hepatic insulin resistance among nondiabetic post-transplant patients is consistent with impaired BCAA metabolism as a characteristic of kidney transplantation.

Higher systolic blood pressure is specifically associated with better islet beta-cell function in T2DM patients with high glycemic level

BackgroundPatients with type 2 diabetes mellitus (T2DM) usually have higher blood viscosity attributed to high blood glucose that can decrease blood supply to the pancreas. A mild increase in blood pressure (BP) has been reported as a potential compensatory response that can maintain blood perfusion in the islet. However, how BP influences beta-cell function in T2DM subjects remains inconsistent. This study aimed to examine the relationship between BP and beta-cell function in patients with T2DM under different HbA1c levels.MethodsThis is a cross-sectional study of 615 T2DM patients, whose clinical data were extracted from hospital medical records. Beta-cell function was assessed by insulin secretion-sensitivity index-2 (ISSI2). Multivariable linear regression analysis and restricted cubic splines (RCS) analysis were performed to identify the association between systolic BP (SBP) and ISSI2. Mediation analysis was performed to determine whether higher SBP could reduce blood glucose by enhancing beta-cell function.ResultsAfter adjustment of potential confounders, in participants with HbA1c ≥ 10%, the SBP between 140 to150 mmHg had the highest log ISSI2 (b = 0.227, 95% CI 0.053–0.402), an association specific to participants with < 1 year duration of diabetes. RCS analyses demonstrated an inverted U-shaped association between SBP and ISSI2 with the SBP at 144 mmHg corresponding to the best beta-cell function. This higher SBP was “paradoxically” associated with lower 2 h postprandial blood glucose (PBG) when SBP < 150 mmHg that was almost exclusively mediated by ISSI2 (mediating effect = − 0.043, 95%CI − 0.067 to − 0.018; mediating effect percentage = 94.7%, P < 0.01). SBP was however not associated with improvement in ISSI2 or 2 h PBG in participants with HbA1c < 10%.ConclusionsIn early stage of diabetes, a slightly elevated SBP (140–150 mmHg) was transiently associated with better beta-cell function in T2DM patients with HbA1c ≥ 10% but not in those with HbA1c < 10%.

The metabolic effects of adding exenatide to basal insulin therapy when targeting remission in early type 2 diabetes in a randomized clinical trial

Combining a glucagon-like peptide-1 receptor agonist (GLP1-RA) with basal insulin is an emerging option when initiating injectable therapy in longstanding type 2 diabetes (T2DM). Recognizing that short-term insulin therapy can improve beta-cell function and induce glycemic remission in early T2DM, we hypothesized that adding the short-acting GLP1-RA exenatide to basal insulin in early T2DM may enhance the achievability of these outcomes. In this completed, 20-week, open-label, parallel-arm trial at an academic hospital, 103 individuals aged 30–80 years with <7 years duration of T2DM were randomized (by computer-generated sequence) to 8-weeks treatment with (i) insulin glargine (Glar; n = 33), (ii) glargine + thrice-daily lispro (Glar/Lispro; n = 35), or (iii) glargine + twice-daily exenatide (Glar/Exenatide; n = 35), followed by 12-weeks washout. The analyzed population of 102 participants (median 3.5 years of T2DM, A1c 6.6% ±0.7%) consisted of 33 on Glar, 35 on Glar/Lispro and 34 on Glar/Exenatide. Oral glucose tolerance tests at baseline, 4-weeks, 8-weeks and 20-weeks enabled assessment of beta-cell function (Insulin Secretion-Sensitivity Index-2 (ISSI-2)) and glycemic control. Mean ISSI-2 over the 8-week intervention (primary outcome) did not differ across the groups (Glar/Exenatide 237 ± 11; Glar/Lispro 208 ± 11; Glar 223 ± 11; p = 0.19). Baseline-adjusted A1c at 8-weeks (secondary outcome) was lowest in Glar/Exenatide followed by Glar/Lispro and Glar (mean 5.9% vs 6.0% vs 6.2%; p = 0.0007). After 12-weeks washout, however, neither baseline-adjusted A1c nor baseline-adjusted ISSI-2 (secondary outcomes) differed between the groups, nor did (additional outcome) rates of remission (Glar/Exenatide 26.7%, Glar/Lispro 43.8%, Glar 32.1%; p = 0.35). There were no severe hypoglycemia episodes. In conclusion, adding exenatide to basal insulin in early T2DM does not further enhance underlying beta-cell function or the capacity to achieve diabetes remission, despite yielding on-treatment glycemic benefit.

New Entity-Thalassemic Endocrine Disease: Major Beta-Thalassemia and Endocrine Involvement.

New Entity-Thalassemic Endocrine Disease: Major Beta-Thalassemia and Endocrine Involvement.

120-OR: Hepatic Steatosis Is Inversely Associated with Improvement of Pancreatic Beta-Cell Function after Vertical Sleeve Gastrectomy in Patients with Type 2 Diabetes

Background: Improvement of beta-cell function is reportedly involved in the improvement of glucose tolerance and remission of diabetes after bariatric and metabolic surgery. However, the impact of this surgery on beta-cell function in Japanese patients is not clear. The objective of this study was to investigate the effect of this surgery on beta-cell function and the characteristics and factors related to changes in beta-cell function. Methods: We conducted a prospective study of patients with type 2 diabetes who underwent vertical sleeve gastrectomy. A 75-g OGTT was performed before and 1 year after this surgery. Glucose tolerance was evaluated using the area under the blood glucose curve (AUCglu) during the OGTT. Insulin secretion was evaluated by the insulin secretion-sensitivity index-2 (ISSI-2) and disposition index (DI) , and insulin sensitivity was estimated using the Matsuda index (MI) and HOMA-IR. Visceral fat and subcutaneous fat area were quantified by abdominal CT examination, and hepatic fat content was quantified using the MRI proton density fat fraction. Results: The mean age of 15 patients (6 females) was 41.9 ± 8.8 years. After 1 year of the surgery, BMI (Before 42.0±8.2 kg/m2, After 32.7±7.2 kg/m2; P &amp;lt; 0.01) , HbA1c, and AUCglu were significantly reduced. ISSI-2 and DI were significantly increased, with no significant changes in the MI or HOMA-IR. Changes in ISSI-2 and DI were inversely associated with hepatic fat content before the surgery (ISSI-2: r = -0.63, P &amp;lt; 0.05; DI: r = -0.59, P &amp;lt; 0.05) , but not with age, BMI, visceral fat area, AUCglu, ISSI-2, DI, MI or HOMA-IR before the surgery. Conclusion: Our results showed that beta-cell function was improved by vertical sleeve gastrectomy even in Japanese obese patients with type 2 diabetes. The degree of improvement in beta-cell function was associated with the degree of preoperative hepatic steatosis, suggesting that a hepatic-pancreatic association may exist. Disclosure A. Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. Y. Oe: None. M. Kusumi: None. H. Nomoto: None. H. Kameda: None. K. Cho: None. K. Ogawa: None. Y. Ebihara: None. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL &amp; BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd.

116-OR: Changes in Glucose Tolerance and Related Factors after Renal Transplantation in Recipients with Impaired Glucose Tolerance

Background and Aims: Our previous study revealed that more than half of patients with impaired glucose tolerance (IGT) before renal transplantation improved to normal glucose tolerance after transplantation. However, the mechanism was not clear. This study aimed to investigate whether changes in glucose tolerance were associated with insulin secretion and resistance in Japanese renal transplant recipients diagnosed with IGT before transplantation. Materials and Methods: We analyzed data for 179 patients ≥20 years of age who received their first renal transplantation in our hospital from April 2005-October 20 and had no history of diabetes before transplantation. A total of 54 recipients who received the oral glucose tolerance test (OGTT) before and 1 year after transplantation and were diagnosed with IGT before transplantation. Patients were divided into two groups according to negative or positive changes in area under the blood glucose curves from 0-120 min after ingestion: improved group and non-improved group, respectively. Insulin secretion was estimated by the insulin secretion sensitivity index-2 (ISSI-2) and insulin sensitivity was estimated by the Matsuda index (MI) and homeostasis model assessment of insulin resistance (HOMA-IR) . Results: Thirty and 24 patients were in the improved and non-improved groups, respectively. ISSI-2 significantly increased from 1.67±0.44 to 2.00±0.60 (P&amp;lt;0.01) after transplantation in the improved group, but not in the non-improved group. ΔISSI-2 was significantly associated with the 60-min blood glucose level of the OGTT and ISSI-2 level before transplantation (β=0.01, P&amp;lt;0. and β=−0.59, P&amp;lt;0.01, respectively) . There were no differences in MI or HOMA-IR before and after transplantation between these two groups. Conclusion: Improvement of glucose tolerance after renal transplantation in patients diagnosed with IGT before transplantation is related to improvement of insulin secretion. Disclosure M. Kusumi: None. A. Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H. Nomoto: None. H. Kameda: None. K. Cho: None. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL &amp; BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.

Screening for glucose dysregulation in β-thalassemia major (β-TM): An update of current evidences and personal experience.

Glucose dysregulation (GD) in patients with β-thalassemia major (β-TM) usually develops gradually. Prediabetes consists of two abnormalities, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), the latter detected by a standardized oral glucose tolerance test (OGTT). Diagnosis of prediabetes is essential for an early identification of high-risk individuals who will benefit from intensive iron chelation therapy and lifestyle modification. Therefore, patients with β-TM should undergo annual screening for glucose abnormalities, according to international recommendations, starting from the age of 10 years. OGTT remains the preferred screening method as it is more sensitive for GD than fasting plasma glucose (FPG), although it is poorly reproducible. The use of HbA1c measurement has limited use as it is generally considered unreliable in patients with thalassemia. Continuous glucose monitoring system (CGMS) is an accurate method to detect the variability of glucose fluctuations and offers the opportunity for better assessment of glucose homeostasis in a selected group of β-TM patients. Pancreatic Magnetic Resonance Imaging (MRI) associated with insulin secretion-sensitivity index-2 (ISSI-2) could be a complementary test, minimizing the necessity for OGTT and identifying high-risk patients before irreversible pancreatic damage occurs. The aims of this short report are to give practical guidance for an early identification of GD in β-TM patients, to summarise our experience, and to offer an impetus for further research in the field. (www.actabiomedica.it)

Profile of Daughters and Sisters of Women With Polycystic Ovary Syndrome: The Role of Proband's Glucose Tolerance.

First-degree relatives of women with polycystic ovary syndrome (PCOS) present hormonal and metabolic alterations compared to girls unrelated to PCOS. It is unknown whether glucose intolerance in the PCOS proband confers a more severe metabolic predisposition on their first-degree relatives. To determine whether glucose tolerance status in women with PCOS is associated with worsened glucose metabolism and sex hormone levels in their peripubertal daughters or sisters. Cross-sectional study. Seven academic centers in North America, South America, and Europe. Sixty-four pairs of women with PCOS and their daughters or younger sisters aged between 8 and 14 years were recruited. Twenty-five mothers or older sisters with PCOS were glucose intolerant (GI) and 39 were normal glucose tolerant (NGT). Beta-cell function estimated by the insulin secretion-sensitivity index-2 (ISSI-2) during an oral glucose tolerance test and by the disposition index during a frequently sampled IV glucose tolerance test. Free testosterone and 17-hydroxyprogesterone (17-OHP) levels. Being related to a GI PCOS proband was associated with a lower ISSI-2 (P-value = 0.032) after adjusting for ethnicity, body mass index z-score, and pubertal stage. They also had higher free testosterone (P-value = 0.011) and 17-OHP levels compared to girls with an NGT proband, the latter becoming significant after adjusting for confounders (P-value = 0.040). Compared to first-degree female relatives of women with PCOS and NGT, first-degree relatives of women with PCOS and GI display lower beta-cell function and hyperandrogenemia, putting them at higher risk of GI and PCOS development.