Oral Disposition Index Research Articles

Vitamin D Deficiency in Cushing's Disease: Before and After Its Supplementation.

Background: The primary objective of the study was to assess serum 25-hydroxyvitamin D [25(OH)D] values in patients with Cushing’s disease (CD), compared to controls. The secondary objective was to assess the response to a load of 150,000 U of cholecalciferol. Methods: In 50 patients with active CD and 48 controls, we evaluated the anthropometric and biochemical parameters, including insulin sensitivity estimation by the homeostatic model of insulin resistance, Matsuda Index and oral disposition index at baseline and in patients with CD also after 6 weeks of cholecalciferol supplementation. Results: At baseline, patients with CD showed a higher frequency of hypovitaminosis deficiency (p = 0.001) and lower serum 25(OH)D (p < 0.001) than the controls. Six weeks after cholecalciferol treatment, patients with CD had increased serum calcium (p = 0.017), 25(OH)D (p < 0.001), ISI-Matsuda (p = 0.035), oral disposition index (p = 0.045) and decreased serum PTH (p = 0.004) and total cholesterol (p = 0.017) values than at baseline. Multivariate analysis showed that mean urinary free cortisol (mUFC) was independently negatively correlated with serum 25(OH)D in CD. Conclusions: Serum 25(OH)D levels are lower in patients with CD compared to the controls. Vitamin D deficiency is correlated with mUFC and values of mUFC > 240 nmol/24 h are associated with hypovitaminosis D. Cholecalciferol supplementation had a positive impact on insulin sensitivity and lipids.

Predictive factors for postpartum glucose intolerance in women with gestational diabetes mellitus.

The aim of this prospective cohort study was to evaluate the risk factors for postpartum glucose intolerance (GI) in women with gestational diabetes mellitus (GDM). A total of 140 women with GDM were enrolled. Of these, 115 underwent a 75-g oral glucose tolerance test (OGTT) at 12 weeks after delivery. Clinical factors and parameters in the antepartum 75-g OGTT associated with postpartum GI were evaluated by logistic regression analyses. Twenty-two (19.1%) of the 115 women with GDM developed postpartum GI. The univariate and multivariable logistic regression analyses revealed that low oral disposition index (DI) was a risk factor for postpartum GI (OR, 0.2; 95% CI, 0.04-0.7; p < 0.05), and that no clinical factors were associated with postpartum GI. Lower oral DI on the antepartum 75-g OGTT may be a useful marker for identifying GDM women who are at high risk for postpartum GI.

Parameters of Glucose Homeostasis in the Recognition of the Metabolic Syndrome in Young Adults with Prader-Willi Syndrome.

To verify the accuracy of different indices of glucose homeostasis in recognizing the metabolic syndrome in a group of adult patients with Prader–Willi syndrome (PWS), 102 PWS patients (53 females/49 males), age ±SD 26.9 ± 7.6 yrs, Body Mass Index (BMI) 35.7 ± 10.7, were studied. The following indices were assessed in each subject during an oral glucose tolerance test (OGTT): 1 h (>155 mg/dL) and 2 h (140–199 mg/dL) glucose levels, the oral disposition index (ODI), the insulinogenic index (IGI), the insulin resistance (HOMA-IR) were evaluated at baseline, 1 h and 2 h. Although minor differences among indices were found, according to the ROC analysis, no index performed better in recognizing MetS. Furthermore, the diagnostic threshold levels changed over the years and therefore the age-related thresholds were calculated. The easily calculated HOMA-IR at baseline may be used to accurately diagnose MetS, thus avoiding more complicated procedures.

Hypoglycemic effects of antioxidant-rich plant extracts on postprandial glycemic responses in participants with prediabetes (GLARE study)

Background: Plant extracts may help to improve glycemic control in individuals with poor glycemic control. However, few studies have been investigated in the prediabetes cohort, which is a high-risk condition for T2DM. Thus, this study aimed to investigate the acute effect of grape seed, rooibos tea, and olive leaf extracts on postprandial blood glucose and insulin in participants with prediabetes. Methods: An acute, single-blind, placebo-controlled, non-randomized, crossover study (ACTRN12617000837325) where placebo and extracts of grape seed, rooibos tea and olive leaf standardized for total antioxidant capacity were given separately during an oral glucose tolerance test to participants (n=19, five men and fourteen women, aged 65.0 ± 1.6 years, Body Mass Index (BMI) 27.3 ± 1.1 kg/m2) with prediabetes (Glycated hemoglobin A1c (HbA1c) 42 ± 1 mmol/mol). The primary outcome incremental area under the curve of glucose (iAUCglucose) was examined with other glycemic measures. Data was analyzed using linear mixed model for repeated measures. Secondary analysis was conducted by stratifying participants into either a healthier or less healthy subgroup based on the postprandial time to glucose and insulin peaks, with the less healthy subgroup experiencing delayed glucose and/or insulin peaks.Results: There were no overall significant changes to glucose and insulin measures between all plant extracts and placebo (p&gt;0.05). Upon secondary analysis, all extracts affected glycemic responses in the less healthy subgroup. Compared to placebo, grape seed reduced plasma iAUCglucose(p=0.016, 21.9% reduction), 2 h postprandial glucose (2hPG) (p=0.034, 14.7% reduction) and metabolic clearance rate of glucose (MCRglucose) (p=0.016, 16.7% increase). It also improved insulin indices such as 2 h postprandial insulin (2hPI) (p=0.029, 22.4% reduction) and Stumvoll overall insulin sensitivity index (ISIoverall) (p=0.028, 15.0% increase). Rooibos tea extract significantly improved β-cell function as demonstrated by the increased oral disposition index (DI) (p=0.031, 32.4% increase) compared to placebo. Olive leaf extract significantly increased incremental area under the curve of insulin (iAUCinsulin) (p=0.040, 16.7% increase). Conclusion: Grape seed, rooibos tea and olive leaf extracts demonstrated acute hypoglycemic benefits in adults with prediabetes and having less healthy metabolic profiles. A chronic study on the plant extracts is warranted to determine their longer-term impact on prediabetes.Trial Registration ID: ACTRN12617000837325Keywords: grape seed extract; rooibos tea extract; olive leaf extract; impaired glycemic control; hyperglycemia; hypoglycemic effects; insulin sensitivity; beta-cell function

Abstract 14047: Extended Follow-Up Results From a Prospective RCT for Transcatheter Bariatric Embolotherapy for Weight Loss in Obese Subjects

Introduction: Obesity is an important risk factor associated with poor cardiovascular outcomes. Lifestyle modification, pharmaceutical, and intragastric balloons weight loss therapy are often unsuccessful, unsustainable, or accompanied by risks. Transcatheter bariatric embolotherapy (TBE) is a promising therapy in which the left gastric artery is embolized to reduce the expression of “hunger” hormones from the gastric fundus. Despite several early clinical trials, long-term safety or efficacy has yet to be studied. We originally studied TBE in a double-blind, sham procedure, first in human RCT of 40 obese patients (pts) (NCT03185949). Complete details regarding the initial RCT were previously published, briefly the study demonstrated up to 9.3% TBWL at 1-year post-TBE. Following completion of the initial study at 1 year follow-up, we asked subjects to return for long-term evaluation. Methods: Subjects who previously completed the RCT with no major protocol deviations were asked to return for SOC follow-up visits at 2-, 2.5-, and 3-years post-embolization for further evaluation on weight loss, blood pressure, pre-diabetic clinical status, satiety, and Quality of Life (QoL). Given the evolving situation of the COVID-19 pandemic, the study site was unable to complete all planned study visits. Results: Between 2-3 years post-TBE subjects (n=11) demonstrated a mean 9% TBWL and 25% EBWL. This cohort of patients demonstrated a long-term weight loss maintenance, with previously reported weight loss of 8% TBWL at 1-year post-embolization. Overall QoL at 2 years post-TBE increased by approximately 22%. The volume to achieve satiety was reduced by 33% in long-term follow-up. Oral Disposition Index increased from 1.89 mM -1 at 6 months post-TBE to 4.41 mM -1 2 years post-TBE. 1-hr Oral Glucose Tolerance Test (OGTT) C-Peptide levels decreased from 3.22 nmol/L at 6 months to 2.53 nmol/L at 2 years post-TBE. 2-hr OGTT C-Peptide levels also showed a decrease from 2.95 nmol/L at 6 months to 1.78 nmol/L at 2 years post-TBE, possibly indicating an improvement in pre-diabetic status. Conclusions: Bariatric embolization is safe and when used along with lifestyle therapy, results in clinically significant and sustained weight loss up to 2-3 years post-TBE.

Changes in OGTT-derived biomarkers in response to lifestyle intervention among Latino adolescents with obesity.

Glucose concentrations during an oral glucose tolerance test (OGTT) have been used as biomarkers to differentiate type 2 diabetes risk phenotypes. No studies have examined changes in OGTT-glucose phenotypes following lifestyle intervention among high-risk youth. To examine changes in OGTT-glucose phenotypes following lifestyle intervention and to explore differences in insulin sensitivity and β-cell function among post-intervention phenotypes. Latino adolescents with obesity (n=48, age 15.4 ± 1.0, BMI% 98.2 ± 1.4, female 56.3%) completed a 12-week lifestyle intervention that included weekly nutrition education and physical activity. At baseline and 12 weeks, youth completed a 2-h OGTT with glucose and insulin concentrations assessed at 0', 30', 60', 90' and 120'. Glucose concentrations during the OGTT were used to identify biomarkers, 1-h glucose, glucose response curve and time to glucose peak. Using these respective biomarkers, high-risk (1-h glucose ≥ 155 mg/dl, Monophasic, Late Peak) and lower-risk phenotypes (1-h glucose < 155 mg/dl, Biphasic, Early Peak) were categorized. Insulin sensitivity was estimated by whole-body insulin sensitivity index (WBISI) and β-cell function by oral disposition index (oDI). Following intervention, the prevalence of Monophasic phenotypes decreased from 81% to 67% (p=0.048) and 1-h glucose ≥ 155 mg/dl from 38% to 10% (p=0.054). Although Late Peak phenotypes did not significantly change (from 58% to 29%, p=0.200), Early Peak phenotypes at post-intervention demonstrated significantly higher WBISI compared to Late Peak (2.3 ± 0.1 vs 1.7 ± 0.2, p=0.023). OGTT-glucose phenotypes improve following lifestyle intervention among high-risk youth. These findings further support their potential utility as clinical biomarkers to identify diabetes risk and risk reduction in youth.

Impact of SARS-CoV-2 on Progression of Glycemic and Cardiometabolic Variables and Changes in Insulin Indices: A Longitudinal Study.

IntroductionWe aimed to evaluate whether SARS-CoV-2 infection is associated with beta cell dysfunction and progression of glycemic and cardiometabolic variables in an established cohort.MethodsStudy participants (n = 352, 46.9% men) underwent a detailed evaluation at two time points: (a) pre-COVID (2016–19) and (b) peri-COVID (2020–21). At the second visit, SARS-CoV-2 infection was determined on the basis of a quantitative S1/S2 IgG antibody test (DiaSorin Liaison) and/or a documented history of infection.ResultsA total of 159 (45.2%) participants were seropositive for SARS-CoV-2, of whom 122 (76.7%) had mild/asymptomatic infection. Progression in body mass index (BMI) category [34 (21.4%) vs. 22 (11.4%), p = 0.011] was seen in a significantly higher proportion of the participants in the infected group compared to the non-infected group. Progression in glycemic and insulin indices [homeostasis model assessment of insulin resistance (HOMA-IR), Matsuda index, and oral disposition index (oDI)] categories was also evident in a larger proportion of participants in the infected group; however, the difference was not statistically significant. On logistic regression analysis, the association between SARS-CoV-2 infection and BMI category progression was statistically significant [fully adjusted OR 2.14 (95% CI, 1.18–3.90; p = 0.013)].ConclusionIn this longitudinal study, predominant mild/asymptomatic SARS-CoV-2 infection was associated with increase in BMI, but not with worsening of beta cell function and insulin resistance, nor glycemic progression.

The Relationship Between Continuous Glucose Monitoring and OGTT in Youth and Young Adults With Cystic Fibrosis.

Early glucose abnormalities in people with cystic fibrosis (PwCF) are commonly detected by continuous glucose monitoring (CGM). Relationships between these CGM abnormalities and oral glucose tolerance testing (OGTT) in PwCF have not been fully characterized. This work aimed to determine the relationship between CGM and common OGTT-derived estimates of β-cell function, including C-peptide index and oral disposition index (oDI) and to explore whether CGM can be used to screen for OGTT-defined prediabetes and cystic fibrosis-related diabetes (CFRD). PwCF not on insulin and healthy controls aged 6 to 25 years were enrolled in a prospective study collecting OGTT and CGM. A subset underwent frequently sampled OGTTs (fsOGTT) with 7-point glucose, insulin, and C-peptide measurements. Pearson correlation coefficient was used to test the association between select CGM and fsOGTT measures. Receiver operating curve (ROC) analysis was applied to CGM variables to determine the cutoff optimizing sensitivity and specificity for detecting prediabetes and CFRD. A total of 120 participants (controls = 35, CF = 85), including 69 with fsOGTTs, were included. CGM coefficient of variation correlated inversely with C-peptide index (Cpeptide30-Cpeptide0/Glucose30-Glucose0) (r = -0.45, P < .001) and oDIcpeptide (C-peptide index)(1/cpep0) (r = -0.48, P < .0001). In PwCF, CGM variables had ROC - areas under the curve ranging from 0.43 to 0.57 for prediabetes and 0.47 to 0.6 for CFRD. Greater glycemic variability on CGM correlated with reduced β-cell function. However, CGM performed poorly at discriminating individuals with and without OGTT-defined CFRD and prediabetes. Prospective studies are now needed to determine how well the different tests predict clinically relevant nonglycemic outcomes in PwCF.

Effects of Metabolic Factors, Race-Ethnicity, and Sex on the Development of Nephropathy in Adolescents and Young Adults With Type 2 Diabetes: Results From the TODAY Study.

To describe the longitudinal effects of sex, race-ethnicity, and metabolic factors on the risk of developing diabetic kidney disease (DKD) in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort. Urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) by serum creatinine and cystatin C were assessed annually for up to 15 years after study entry. Markers of DKD included micro- and macroalbuminuria (UACR ≥30 mg/g and ≥300 mg/g, respectively), hyperfiltration (eGFR ≥135 mL/min/1.73 m2), and rapid eGFR annual decline (>3 mL/min/1.73 m2 and/or ≥3.3%). The relationships between risk factors and DKD were evaluated longitudinally using time-to-event models. Data were available on 677 participants, average age at baseline 14 years, with a mean ± SD follow-up of 10.2 ± 4.5 years. Each 1% increment in HbA1c conferred higher risk of microalbuminuria (hazard ratio 1.24 [95% CI 1.18, 1.30]), macroalbuminuria (1.22, [1.11, 1.34]), hyperfiltration (1.11, [1.05, 1.17]), and rapid eGFR decline (1.12, [1.04, 1.20]). Higher systolic blood pressure and baseline serum uric acid, and lower indices of β-cell function (C-peptide index and oral disposition index [oDI]), increased the risk of microalbuminuria, while higher triglycerides increased risk of micro- and macroalbuminuria. Lower oDI levels, female sex, and Hispanic ethnicity were associated with higher risk of hyperfiltration. Elevated HbA1c was a shared risk factor among all phenotypes of DKD in this longitudinal cohort of adolescents and young adults with youth-onset type 2 diabetes. Other risk factors included elevated blood pressure, triglycerides, serum uric acid, and β-cell dysfunction.

Glucose Metabolism and Insulin Response to Oral Glucose Tolerance Test (OGTT) in Prepubertal Patients with Transfusion-Dependent β-thalassemia (TDT): A Long-Term Retrospective Analysis.

BackgroundGlucose dysregulation (GD), including prediabetes and diabetes mellitus (DM), is a common complication of transfusion-dependent β-thalassemia (TDT) patients. The prevalence increases with age and magnitude of iron overload, affecting a significant proportion of patients. According to the international guidelines, the development of GD is frequently asymptomatic. Therefore, an early diagnosis requires an annual oral glucose tolerance test (OGTT) in all TDT patients aged ten years or older.PurposeThis retrospective study aims to evaluate the prevalence of GD in a homogenous population of prepubertal TDT patients and to enhance understanding of the pathogenesis and progression of glucose homeostasis in this group of patients.MethodsA selected group of 28 TDT patients was followed for at least 10.3 years (range: 10.3 – 28.10 years) from prepubertal age (mean 11.0 ± standard deviation 1.1 years) to adulthood (28.7 ± 3.7 years). Glucose tolerance and insulin response to OGTT were assessed, and indices of β-cell function, insulin sensitivity, and insulin secretion were calculated.ResultsAt baseline, 18 TDT patients had normal glucose tolerance (NGT) and 10 had isolated impaired fasting glycemia (IFG), according to the American Diabetes Association (ADA) criteria. Compared to 18 healthy prepubertal controls (mean ± SD age: 10.9 ± 1.1 years), the fasting plasma glucose (FPG), basal insulin level, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index were significantly higher in the group of TDT patients (p= 0.001, 0.01 and 0.012, respectively). At the last observation, 7/18 patients (38.8%) with NGT and 9/10 (90%) with IFG at baseline deteriorated; 3 female patients developed type 2 DM (1 from the NGT group and 2 from the IFG group). Compared to adult controls, TDT patients with NGT had a reduced oral disposition index (DI) (p= 0.006) but no significant difference in HOMA-IR and Matsuda index. Conversely, all insulin indices (HOMA-IR, MI, and DI) but one [insulinogenic index (IGI)] were statistically different in TDT patients with GD compared to controls.ConclusionThis study underlines the concept that the spectrum of glucose tolerance in TDT patients represents a continuum of glucose homeostasis disturbances and that prepubertal patients with IFG are at higher risk of developing a further deterioration of glucose metabolism with time. Moreover, it appears that one-third of adult TDT patients with normal fasting glucose may develop GD in the second-third decade of life. Thus, early intervention could help to prevent an expected further decline of glucose tolerance.

TCF7L2 Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes.

We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant. None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/IF]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar. In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity.

Genetic Risk Score for Type 2 Diabetes and Traits Related to Glucose-Insulin Homeostasis in Youth: The Exploring Perinatal Outcomes Among Children (EPOCH) Study.

The metabolic phenotype of youth-onset type 2 diabetes (T2D) differs from that of adult-onset T2D, but little is known about genetic contributions. We aimed to evaluate the association between a T2D genetic risk score (GRS) and traits related to glucose-insulin homeostasis among healthy youth. We used data from 356 youth (mean age 16.7 years; 50% female) in the Exploring Perinatal Outcomes Among Children (EPOCH) cohort to calculate a standardized weighted GRS based on 271 single nucleotide polymorphisms associated with T2D in adults. We used linear regression to assess associations of the GRS with log-transformed fasting glucose, 2-h glucose, HOMA of insulin resistance (HOMA-IR), oral disposition index, and insulinogenic index adjusted for age, sex, BMI z score, in utero exposure to maternal diabetes, and genetic principal components. We also evaluated effect modification by BMI z score, in utero exposure to maternal diabetes, and ethnicity. Higher weighted GRS was associated with lower oral disposition index (β = -0.11; 95% CI -0.19, -0.02) and insulinogenic index (β = -0.08; 95% CI -0.17, -0.001), but not with fasting glucose (β = 0.01; 95% CI -0.01, 0.02), 2-h glucose (β = 0.03; 95% CI -0.0004, 0.06), or HOMA-IR (β = 0.02; 95% CI -0.04, 0.07). BMI z score and in utero exposure to maternal diabetes increased the effect of the GRS on glucose levels. Our results suggest that T2D genetic risk factors established in adults are relevant to glucose-insulin homeostasis in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk of T2D.

Time to the Peak, Shape of the Curve and Combination of These Glucose Response Characteristics During Oral Glucose Tolerance Test as Indicators of Early Beta-cell Dysfunction in Obese Adolescents

Objective:Characteristics of the glucose response during oral glucose tolerance test (OGTT) may reflect differences in insulin secretion and action. The aim was to examine whether timing of the glucose peak, shape of the glucose curve and their combination could be indicators of beta-cell dysfunction in obese/severely obese adolescents with normal glucose tolerance (NGT).Methods:Data from 246 obese/severely obese adolescents who completed OGTT were reviewed. Out of 184 adolescents with NGT, 174 could be further classified into groups based on timing of the glucose peak (early/30 minutes vs late/≥60 minutes) and shape of the glucose curve (monophasic vs biphasic). Groups were compared with respect to insulin sensitivity (whole body insulin sensitivity index - WBISI), early-phase insulin secretion (insulinogenic index - IGI) and beta-cell function relative to insulin sensitivity (oral disposition index - oDI).Results:Late glucose peak (p=0.004) and monophasic glucose curve (p=0.001) were both associated with lower oDI after adjustment for age, sex, puberty stage and body mass index z-score. Among obese/severely obese adolescents with NGT, those with coexistent late glucose peak and monophasic glucose curve had lower oDI than those with early glucose peak and biphasic glucose curve (p=0.002). Moreover, a combination of late glucose peak and monophasic glucose curve was the most powerful predictor of the lowest oDI quartile [odds ratio (OR): 11.68, 95% confidence interval: 3.048-44.755, p<0.001].Conclusion:Late timing of the glucose peak, monophasic shape of the glucose curve and, in particular, a combination of those characteristics during OGTT may indicate early beta-cell dysfunction in obese/severely obese adolescents with NGT.

1128-P: Genetic Risk Score for Type 2 Diabetes (T2D) and Glycemic Traits: The Exploring Perinatal Outcomes among Children (EPOCH) Study

T2D prevalence has been increasing worldwide in both adults and youth. Youth-onset T2D is strongly associated with obesity and has been linked to increased morbidity and mortality. We aimed to evaluate the association between a T2D genetic risk score (GRS) and glycemic traits during childhood using data from N=356 nondiabetic participants (mean age 16.7 years, 50% female) in the EPOCH Study, a cohort of youth in Colorado. We calculated a weighted GRS based on 271 genetic variants associated with T2D in adults. We used linear regression models adjusted for age, sex and 5 genetic principal components to assess associations of the GRS with fasting glucose, HOMA-IR, oral disposition index, and insulinogenic index, and for effect modification by body mass index z-score (BMIz). Higher GRS was associated with lower oral disposition index and insulinogenic index (see Table). Additionally, higher GRS was associated with increased fasting glucose, but only with higher BMIz (interaction p-value=0.01). Our results suggest that T2D genetic risk factors established in adults are relevant to glycemic traits in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk for T2D. Disclosure M. Stanislawski: None. E. M. Litkowski: None. S. Raghavan: None. K. K. Harrall: None. D. H. Glueck: None. E. M. Lange: None. D. Dabelea: None. L. Lange: None. Funding National Institute of Diabetes and Digestive and Kidney Disease (R01DK068001)

Predictive factors of polycystic ovary syndrome in girls with precocious pubarche.

ObjectiveThe aim of this study is to clarify, in girls with premature pubarche (PP), the influence of premature androgenization on the prevalence of polycystic ovary syndrome (PCOS).Design and patientsNinety-nine PP girls, 63 who developed PCOS and 36 who did not develop PCOS, were retrospectively included. Clinical, anthropometric, and metabolic parameters were evaluated at the time of diagnosis of PP and after 10 years from menarche to find predictive factors of PCOS.ResultsYoung females with PP showed a PCOS prevalence of 64% and showed a higher prevalence of familial history of diabetes (P = 0.004) and a lower prevalence of underweight (P = 0.025) than PP-NO-PCOS. In addition, girls with PP-PCOS showed higher BMI (P < 0.001), waist circumference (P < 0.001), total testosterone (P = 0.026), visceral adiposity index (VAI) (P = 0.013), total cholesterol (P < 0.001), LDL-cholesterol (P < 0.001), non-HDL cholesterol (P < 0.001) and lower age of menarche (P = 0.015), ISI-Matsuda (P < 0.001), DIo (P = 0.002), HDL cholesterol (P = 0.026) than PP-NO-PCOS. Multivariate analysis showed that WC (P = 0.049), ISI-Matsuda (P < 0.001), oral disposition index (DIo) (P < 0.001), VAI (P < 0.001), total testosterone (P < 0.001) and LDL-cholesterol (P < 0.001) are independent predictive factors for PCOS in girls with PP.ConclusionsOur study established a strong association between multiple risk factors and development of PCOS in PP girls. These risk factors are predominantly related to the regulation of glucose, lipid, and androgen metabolism. Among these factors, WC, ISI-Matsuda, DIo, VAI, total testosterone, and LDL-cholesterol predict PCOS.

Reduced glycodeoxycholic acid levels are associated with negative clinical outcomes of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is characterized by glycemia and insulin disorders. Bile acids (BAs) have emerged as vital signaling molecules in glucose metabolic regulation. BA change in GDM is still unclear, which exerts great significance to illustrate the change of BAs in GDM. GDM patients and normal pregnant women were enrolled during the oral glucose tolerance test (OGTT) screening period. Fasting serums were sampled for the measurement of BAs. BA metabolism profiles were analyzed in both pregnant women with GDM and those with normal glucose tolerance (NGT). Delivery characteristics, delivery gestational age, and infant birthweight were extracted from medical records. GDM patients presented distinctive features compared with NGT patients, including higher body mass index (BMI), elevated serum glucose concentration, raised insulin (both fasting and OGTT), and increased hemoglobin A1c (HbA1c) levels. Higher homeostasis model assessment of insulin resistance (HOMA-IR) and decreased β-cell compensation (i.e., oral disposition index (DIo)) were also prevalent in this group. Total BAs (TBAs) remained stable, but glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA) levels declined significantly in GDM. GDCA was inversely correlated with HOMA-IR and positively correlated with DIo. No obvious differences in clinical outcome between the GDM and NGT groups were observed. However, GDM patients with high HOMA-IR and low DIo tended to have a higher cesarean delivery rate and younger delivery gestational age. In conclusion, GDCA provides a valuable biomarker to evaluate HOMA-IR and DIo, and decreased GDCA levels predict poorer clinical outcomes for GDM.

Efficacy of metformin and fermentable fiber combination therapy in adolescents with severe obesity and insulin resistance: study protocol for a double-blind randomized controlled trial

BackgroundAccumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Pre-clinical animal models have established that the addition of fiber to metformin monotherapy improves glucose tolerance. However, possible synergistic effects of combination therapy (metformin plus fiber) have not been investigated in humans. Moreover, the underlying mechanisms of synergy have yet to be elucidated. The aim of this study is to compare in adolescents with obesity the metabolic effects of metformin and fermentable fibers in combination with those of metformin or fiber alone. We will also determine if therapeutic responses correlate with compositional and functional features of the gut microbiome.MethodsThis is a parallel three-armed, double-blinded, randomized controlled trial. Adolescents (aged 12–18 years) with obesity, insulin resistance (IR), and a family history of type 2 diabetes mellitus (T2DM) will receive either metformin (850 mg p.o. twice/day), fermentable fibers (35 g/day), or a combination of metformin plus fiber for 12 months. Participants will be seen at baseline, 3, 6, and 12 months, with a phone follow-up at 1 and 9 months. Primary and secondary outcomes will be assessed at baseline, 6, and 12 months. The primary outcome is change in IR estimated by homeostatic model assessment of IR; key secondary outcomes include changes in the Matsuda index, oral disposition index, body mass index z-score, and fat mass to fat-free mass ratio. To gain mechanistic insight, endpoints that reflect host-microbiota interactions will also be assessed: obesity-related immune, metabolic, and satiety markers; humoral metabolites; and fecal microbiota composition, short-chain fatty acids, and bile acids.DiscussionThis study will compare the potential metabolic benefits of fiber with those of metformin in adolescents with obesity, determine if metformin and fiber act synergistically to improve IR, and elucidate whether the metabolic benefits of metformin and fiber associate with changes in fecal microbiota composition and the output of health-related metabolites. This study will provide insight into the potential role of the gut microbiome as a target for enhancing the therapeutic efficacy of emerging treatments for T2DM prevention.Trial registrationClinicalTrials.gov NCT04578652. Registered on 8 October 2020.

Effects of a 12-Week Lifestyle Intervention on Novel Biomarkers for Type 2 Diabetes (T2D) in Obese Latino Youth

In obese non-diabetic youth, glucose response curve (GRC) and 1-hr glucose concentration during an oral glucose tolerance test (OGTT) represent novel biomarkers for T2D risk. Obese youth with monophasic- vs. biphasic-GRC and 1-hr glucose concentration of ≥155 (Above155) vs. &lt;155 mg/dL (Below155) are at increased risk for T2D. However, to date, it is unknown whether these OGTT-derived phenotypes can be improved in response to any interventions, thereby hindering their practical use as indicators of intervention effectiveness. The purpose of this was to investigate the effects of lifestyle intervention on OGTT-GRC and 1-hr glucose concentration in obese Latino youth at increased risk for T2D. Sixteen obese Latino youth (age 15.6±0.9 years; 7M/9F; body mass index %tile=98.3±1.2) completed a 12-week lifestyle intervention that included weekly nutrition education and 180 minutes of moderate-vigorous exercise per week. All participants completed a 2-hr OGTT before and after the lifestyle intervention to assess changes in OGTT-GRC &amp; 1-hr glucose as well as other pathophysiological risk factors including insulin sensitivity index, insulinogenic index, and oral disposition index (oDI). Chi-square and paired t test were used to compare changes in response to the intervention. At baseline, the prevalence of biphasic-GRC and Below155 was 12.5% and 43.8%, respectively. After the 12-week intervention, OGTT-derived phenotypes were improved, exhibiting significant increases in the prevalence of biphasic-GRC (37.5%, P=0.05) and Below155 (75%, P=0.042). Together with improvement on GRC and 1-hr glucose, oDI was enhanced (Pre: 7.36 ± 6.20 vs. Post: 8.16 ± 5.13, P&lt;0.05), despite no improvement in insulin sensitivity index and insulinogenic index. A 12-week lifestyle intervention is efficacious in improving glucose response curve and 1-hr glucose concentration during an OGTT in conjunction with ß-cell improvement in obese Latino youth. Our data further suggest that these emerging T2D risk biomarkers have prospective utility in terms of assessing change following interventions/therapeutic trials.

Insulin sensitivity and pancreatic β-cell function in patients with primary aldosteronism.

Primary aldosteronism (PA) is associated with an increased risk for dysglycemia. However, the effects of hyperaldosteronism on insulin sensitivity and β-cell function are unclear. Using a cross-sectional study design, we assessed insulin sensitivity and pancreatic β-cell function from an oral glucose tolerance test (OGTT) in patients from two cohorts: subjects with PA (n = 21) and essential hypertension control (EHC) subjects (n = 22). Age, sex, BMI, and mean arterial pressure adjusted measures of insulin sensitivity and β-cell function were compared between the groups. PA individuals were less insulin sensitive compared to EHC subjects (Quantitative insulin sensitivity check index [QUICKI]: 0.340 ± 0.006 vs. 0.374 ± 0.013, p < 0.001; Matsuda index: 4.14 ± 0.49 vs. 7.87 ± 1.42, p < 0.001; SI: 11.45 ± 4.85 vs. 21.23 ± 6.11 dL/kg/min per μU/mL, p = 0.02). The hepatic insulin resistance index (HIRI) was higher in PA subjects (PA: 5.61 ± 1.01 vs. EHC: 4.13 ± 0.61, p = 0.002). The insulinogenic index (IGI), an index of β-cell function was higher in the PA cohort (PA: 1.49 ± 0.27 vs. 1.11 ± 0.21 μU/mL/mg/dL, p = 0.03). However, the oral disposition index (DI) was similar between the groups (PA: 4.77 ± 0.73 vs. EHC: 5.46 ± 0.85, p = 0.42), which likely accounts for the similar glucose tolerance between the two cohorts, despite lower sensitivity. In summary, insulin sensitivity is significantly lower in PA with an appropriately compensated β-cell function. These results suggest that excess aldosterone and/or other steroids in the context of PA may negatively affect insulin action without adversely impacting β-cell function.

The Association of Cortisol Excretion with Weight and Metabolic Parameters in Nondiabetic Patients with Morbid Obesity

Introduction: Cortisol is involved in the regulation of gluconeogenesis and glucose utilization. In morbid obesity (MO), the association of cortisol excretion with metabolic parameters is not well-characterized. In our study, we evaluated cortisol excretion in nondiabetic subjects with MO and its effect on glucose metabolism. Methods: We included 1,249 nondiabetic patients with MO (79.8% females, mean BMI 44.9 ± 6.5 kg/m², mean age 38 ± 11 years). Anthropometric data and cardiovascular risk factors were assessed, and an oral glucose tolerance test for calculation of insulin resistance was performed. Cortisol excretion was assessed on 2 consecutive days (24 h urine specimens). Results: Regarding cortisol excretion, patients were divided into 3 tertiles (urinary cortisol ≤51.6, >51.6 and <117.6, and ≥117.6 μg/24 h, respectively). Patients in the highest tertile were younger (p = 0.003), more obese (BMI: p = 0.040), had lower diastolic blood pressure ([DBP]; p = 0.012), lower total (p = 0.032) and LDL cholesterol (p = 0.021), fasting (p = 0.049) and 2-h glycemia (p = 0.028), 2-h insulinemia (p = 0.020), and HbA1c (p < 0.001), and a higher estimated glomerular filtration rate (eGFR) (p < 0.001). The glucose (p < 0.001) and insulin (p = 0.011) area under the curve (AUC) were also lower. Urinary cortisol excretion adjusted for age, sex, and eGFR was positively correlated with body weight (BW, beta = 0.076, p = 0.004) and overall glucose tolerance (oral disposition index, beta = 0.090, p = 0.011), and negatively with HbA1c (beta = −0.179, p < 0.001), 2-h glycemia (beta = −0.075, p = 0.032), AUC glucose (beta = −0.103, p = 0.002), and DBP (beta = −0.139, p < 0.001). HbA1c, BW, and DBP remained significant after multivariable analysis. Discussion/Conclusion: Despite being more obese, patients with higher cortisol excretion have a more favorable metabolic profile. These results deserve further attention regarding the respective mechanisms.