Metabolic-associated fatty liver disease is characterized by a post-oral glucose load hyperinsulinemia in individuals with mild metabolic alterations.

Metabolic-associated fatty liver disease (MAFLD) has been identified as risk factor of incident type 2 diabetes (T2D), but the underlying postprandial mechanisms remain unclear. We compared the glucose metabolism, insulin resistance, insulin secretion, and insulin clearance post-oral glucose tolerance test (OGTT) between individuals with and without MAFLD. We included 50 individuals with a body mass index (BMI) between 25 and 40 kg/m2 and ≥1 metabolic alteration: increased fasting triglycerides or insulin, plasma glucose 5.5-6.9 mmol/L, or glycated hemoglobin 5.7-5.9%. Participants were grouped according to MAFLD status, defined as hepatic fat fraction (HFF) ≥5% on MRI. We used oral minimal model on a frequently sampled 3 h 75 g-OGTT to estimate insulin sensitivity, insulin secretion, and pancreatic ß-cell function. Fifty percent of participants had MAFLD. Median age (IQR) [57 (45-65) vs. 57 (44-63) yr] and sex (60% vs. 56% female) were comparable between groups. Post-OGTT glucose concentrations did not differ between groups, whereas post-OGTT insulin concentrations were higher in the MAFLD group (P < 0.03). Individuals with MAFLD exhibited lower insulin clearance, insulin sensitivity, and first-phase pancreatic ß-cell function. In all individuals, increased insulin incremental area under the curve and decreased insulin clearance were associated with HFF after adjusting for age, sex, and BMI (P < 0.02). Among individuals with metabolic alterations, the presence of MAFLD was characterized mainly by post-OGTT hyperinsulinemia and reduced insulin clearance while exhibiting lower first phase ß-cell function and insulin sensitivity. This suggests that MAFLD is linked with impaired insulin metabolism that may precede T2D.NEW & NOTEWORTHY Using an oral glucose tolerance test, we found hyperinsulinemia, lower insulin sensitivity, lower insulin clearance, and lower first-phase pancreatic ß-cell function in individuals with MAFLD. This may explain part of the increased risk of incident type 2 diabetes in this population. These data also highlight implications of hyperinsulinemia and impaired insulin clearance in the progression of MAFLD to type 2 diabetes.

Glycated Hemoglobin Is Suboptimal for the Screening of Prediabetes and Type 2 Diabetes in Adults With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but T2D screening tests are not well validated in this population. In this study, we assessed performance of glycated hemoglobin (A1C) and fasting plasma glucose (FPG) in glucose dysmetabolism screening and aimed to optimize detection thresholds for individuals with NAFLD. METHODS: We retrospectively included oral glucose tolerance tests (OGTTs) from consecutive patients undergoing a specialized clinic for NAFLD, if A1C and/or fasting glucose was available within 3 months of OGTT. We compared performances of A1C and fasting glucose with the "gold standard" of OGTT using thresholds from the 2018 Diabetes Canada guidelines. A1C and FPG thresholds were optimized for detection of glucose dysmetabolism using receiver operating characteristic curves. RESULTS: We included 63 OGTTs from individuals with NAFLD (52% female, age 48 [interquartile range 35 to 63] years, body mass index 34 [interquartile range 29 to 40] kg/m2). A1C had 16% (95% confidence interval [CI] 6% to 38%) sensitivity (Se) and 97% (95% CI 85% to 100%) specificity (Sp) for T2D detection, and 45% (95% CI 30% to 62%) Se and 100% (95% CI 83% to 100%) Sp for abnormal blood glucose detection. FPG had 67% (95% CI 45% to 83%) Se and 100% (95% CI 92% to 100%) Sp for T2D detection, and 74% (95% CI 59% to 85%) Se and 92% (95% CI 74% to 99%) Sp for abnormal blood glucose detection. Optimal A1C and FPG thresholds were 5.6% and 6.3 mmol/L for T2D detection, which are lower than current recommendations. CONCLUSIONS: A1C is less sensitive than FPG and is suboptimal for T2D detection, suggesting that OGTT may be obtained if A1C is ≥5.6% or FPG is ≥6.3 mmol/L in individuals with NAFLD, to avoid underdiagnosis and treatment inertia.

The Interaction of Obesity and Reproductive Function in Adolescents.

Obesity is increasing worldwide, including in pediatrics. Adequate nutrition is required for initiation of menses, and there is a clear secular trend toward earlier pubertal onset and menarche in females in countries around the globe. Similar findings of earlier pubertal start are suggested in males. However, as individuals and populations have crossed into over-nutritional states including overweight and obesity, the effect of excess weight on disrupting reproductive function has become apparent. Hypothalamic hypogonadism and polycystic ovary syndrome are two conditions where reproductive function appears to directly relate to excess weight. Clinical findings in individuals with certain polygenic and monogenic obesity syndromes, which also have reproductive disruptions, have helped elucidate neurologic pathways that are common to both. Clinical endocrinopathies such as hypothyroidism or panhypopituitarism also aide in the understanding of the role of the endocrine system in weight gain. Understanding the intersection of obesity and reproductive function may lead to future therapies which can treat both conditions.

Trimester-specific gestational weight gain in women with and without previous bariatric surgeries.

OBJECTIVES: The study aimed 1) to compare trimester-specific and total gestational weight gain (GWG) between mothers who had undergone biliopancreatic diversion with duodenal switch (BPD) and two control groups of unoperated women and 2) to examine the associations between GWG, intrauterine fetal growth and neonatal birthweight. METHODS: This retrospective study included data collected in medical records of newborns and mothers from 3 groups: the first control group (PP) included mothers (n = 158) with a pre-pregnancy BMI similar to that of the surgical group (n = 63) and the second one (PS) included mothers (n = 85) with a pre-pregnancy BMI corresponding to that of the surgical group prior to BPD or a BMI > 40 kg/m2. Trimester-specific GWG was obtained using linear interpolation and compared to the recommendations. RESULTS: Women exposed to BPD have an increased prevalence of insufficient weight gain in the second and third trimesters as well as for the whole pregnancy in comparison with women in the PP group. The weekly GWG rate in the third trimester was significantly lower in women exposed to BPD, compared to both control groups. Although the newborns of women with previous BPD were significantly smaller during pregnancy and at birth, no association was found with GWG. CONCLUSION: Women exposed to BPD are at substantial risk of insufficient GWG, however, mechanisms and long-term impacts require further investigation.

Dietary intakes in pregnant women with previous bariatric surgery.

PURPOSE: To (1) assess dietary intakes of pregnant women with previous bariatric surgery in comparison with Dietary Reference Intakes (DRIs); (2) compare their dietary intakes as well as their diet quality with a control group of pregnant women with no history of bariatric surgery. METHODS: Twenty-eight (28) pregnant women with previous surgery (sleeve gastrectomy, n = 7 and biliopancreatic diversion with duodenal switch, n = 21) were matched for pre-pregnancy body mass index with 28 pregnant women with no history of bariatric surgery. In at least one trimester, participants completed a minimum of 2 Web-based 24-h dietary recalls from which energy, macro- and micronutrient intakes as well as the Canadian Healthy Eating Index (C-HEI) were derived. RESULTS: No differences were observed for energy intake between groups. All women had protein intakes within the recommended range, but most women with previous surgery had carbohydrate (67%) and dietary fiber intakes (98%) below recommendations. In both groups, mean total fat, saturated fatty acids, free sugars and sodium intakes were above recommendations, as opposed to mean vitamin D, folic acid and iron dietary intakes below recommendations for most women. Compared with the control group, pregnant women with previous bariatric surgery had lower overall C-HEI scores. CONCLUSION: These results suggest that pregnant women with previous bariatric surgery would benefit from a nutritional follow-up throughout their pregnancy. LEVEL OF EVIDENCE: III: Evidence obtained from well-designed cohort or case-control analytic studies.

Pancreatic fat relates to fasting insulin and postprandial lipids but not polycystic ovary syndrome in adolescents with obesity.

OBJECTIVE: Adolescents with polycystic ovary syndrome (PCOS) and obesity can have insulin resistance, dysglycemia, and hepatic steatosis. Excess pancreatic fat may disturb insulin secretion and relate to hepatic fat. Associations between pancreatic fat fraction (PFF) and metabolic measures in PCOS were unknown. METHODS: This secondary analysis included 113 sedentary, nondiabetic adolescent girls (age = 15.4 [1.9] years), with or without PCOS and BMI ≥ 90th percentile. Participants underwent fasting labs, oral glucose tolerance tests, and magnetic resonance imaging for hepatic fat fraction (HFF) and PFF. Groups were categorized by PFF (above or below the median of 2.18%) and compared. RESULTS: Visceral fat and HFF were elevated in individuals with PCOS versus control individuals, but PFF was similar. PFF did not correlate with serum androgens. Higher and lower PFF groups had similar HFF, with no correlation between PFF and HFF, although hepatic steatosis was more common in those with higher PFF (≥5.0% HFF; 60% vs. 36%; p = 0.014). The higher PFF group had higher fasting insulin (p = 0.026), fasting insulin resistance (homeostatic model assessment of insulin resistance, p = 0.032; 1/fasting insulin, p = 0.028), free fatty acids (p = 0.034), and triglycerides (p = 0.004) compared with those with lower PFF. ß-Cell function and insulin sensitivity were similar between groups. CONCLUSIONS: Neither PCOS status nor androgens related to PFF. However, fasting insulin and postprandial lipids were worse with higher PFF.

IGFBP-2 partly mediates the early metabolic improvements caused by bariatric surgery.

Insulin-like growth factor-binding protein (IGFBP)-2 is a circulating biomarker of cardiometabolic health. Here, we report that circulating IGFBP-2 concentrations robustly increase after different bariatric procedures in humans, reaching higher levels after biliopancreatic diversion with duodenal switch (BPD-DS) than after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). This increase is closely associated with insulin sensitization. In mice and rats, BPD-DS and RYGB operations also increase circulating IGFBP-2 levels, which are not affected by SG or caloric restriction. In mice, Igfbp2 deficiency significantly impairs surgery-induced loss in adiposity and early improvement in insulin sensitivity but does not affect long-term enhancement in glucose homeostasis. This study demonstrates that the modulation of circulating IGFBP-2 may play a role in the early improvement of insulin sensitivity and loss of adiposity brought about by bariatric surgery.

Fasting plasma metabolomic profiles are altered by three days of standardized diet and restricted physical activity.

OBJECTIVE: Few studies have examined the effects of participants' diet and activity prior to sample collection on metabolomics profiles, and results have been conflicting. We compared the effects of overnight fasting with or without 3 days of standardized diet and restricted physical activity on the human blood metabolome, and examined the effects of these protocols on our ability to detect differences in metabolomics profiles in adolescent girls with obesity and polycystic ovary syndrome (PCOS) vs. sex and BMI-matched controls. METHODS: This was a cross-sectional study of 16 adolescent girls with obesity and PCOS and 5 sex and BMI-matched controls. Fasting plasma metabolomic profiles were measured twice in each participant: once without preceding restriction of physical activity or control of macronutrient content ("typical fasting visit"), and again after 12 h of monitored inpatient fasting with 3 days of standardized diet and avoidance of vigorous exercise ("controlled fasting visit"). Moderated paired t-tests with FDR correction for multiple testing and multilevel sparse partial least-squares discriminant analysis (sPLS-DA) were used to examine differences between the 2 visits and to compare the PCOS and control groups with the 2 visits combined and again after stratifying by visit. RESULTS: Twenty-three known metabolites were significantly different between the controlled fasting and typical fasting visits. Hypoxanthine and glycochenodeoxycholic acid had the largest increases in relative abundance at the controlled fasting visit compared to the typical fasting visit, while oleoyl-glycerol and oleamide had the largest increases in relative abundance at the typical fasting visit compared to the controlled fasting visit. sPLS-DA showed excellent discrimination between the 2 visits; however, when the samples from the 2 visits were combined, differences between the PCOS and control groups could not be detected. After stratifying by visit, discrimination of PCOS status was improved. CONCLUSIONS: There were differences in fasting metabolomic profiles following typical fasting vs monitored fasting with preceding restriction of physical activity and control of macronutrient content, and combining samples from the two visits obscured differences by PCOS status. In studies performing metabolomics analysis, careful attention should be paid to acute diet and activity history. Depending on the sample size of the study and the expected effect size of the outcomes of interest, control of diet and physical activity beyond typical outpatient fasting may not be required.

Bile acids during pregnancy: Trimester variations and associations with glucose homeostasis.

BACKGROUND AND AIMS: Bile acids are known to contribute to hepatic glucose and lipid metabolism regulation. Although glucose homeostasis sustains well-characterized modifications during uncomplicated pregnancies, changes in bile acids concentrations and relative proportions throughout pregnancy remain unknown. Furthermore, literature shows strong associations between bile acids profiles and glucose homeostasis under normal metabolic conditions. We seek, first, to characterize bile acids' metabolic changes across trimesters and, second, to evaluate associations between changes in bile acids and glucose homeostasis indexes in the first and second trimesters. METHODS: A total of 78 women were recruited and followed at each trimester of pregnancy. Fasting serum samples were collected once per trimester in which quantitative measurement of 30 different bile acids' molecules were performed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Glucose homeostasis indexes were measured in the first and second trimesters, after a 12-hour fast and following a 75 g oral glucose tolerance test. RESULTS: Total bile acids increased from the first trimester to late pregnancy, along with the cholic acid: chenodeoxycholic acid and conjugated: unconjugated bile acids ratios. Changes in bile acids were positively associated with elevated peripheral and hepatic insulin resistance indexes, as well as with trimestral changes in these indexes. CONCLUSION: Our findings suggest that modifications occurring in bile acids' profiles during normal pregnancy are associated with changes in glucose homeostasis. Further research is needed to examine the nature of those associations and the possible outcome of bile acids changes on pathological glucose homeostasis alterations during pregnancy.

Oral minimal model-based estimates of insulin sensitivity in obese youth depend on oral glucose tolerance test protocol duration.

INTRODUCTION: The Oral Minimal Model (OMM), a differential-equations based mathematical model of glucose-insulin dynamics, utilizes data from a frequently sampled oral glucose tolerance test (OGTT) to quantify insulin sensitivity ( S I ). OMM-based estimates of S I can detect differences in insulin resistance (IR) across population groups and quantify effects of clinical or behavioral interventions. These estimates of S I have been validated in healthy adults using data from OGTTs with durations from 2 to 7 h. However, data demonstrating how protocol duration affects S I estimates in highly IR populations such as adolescents with obesity are limited. METHODS: A 6-h frequently sampled OGTT was performed in adolescent females with obesity. Two, 3-, and 4- hour implementations of OMM assuming an exponentially-decaying rate of glucose appearance beyond measured glucose concentrations were compared to the 6-h implementation. A 4- hour OMM implementation with truncated data (4h Tr) was also considered. RESULTS: Data from 68 participants were included (age 15.8 ± 1.2 years, BMI 35.4 ± 5.6 kg/m2). Although S I values were highly correlated for all implementations, they varied with protocol duration (2h: 2.86 ± 3.31, 3h: 2.55 ± 2.62, 4h: 2.81 ± 2.59, 4h tr: 3.13 ± 3.14, 6h: 3.06 ± 2.85 x 10-4 dl/kg/min per U/ml). S I estimates based on 2 or 3 h of data underestimated S I values, whereas 4-h S I estimates more closely approximated 6-h S I values. DISCUSSION: These results suggest that OGTT protocol duration should be considered when implementing OMM to estimate S I in adolescents with obesity and other IR populations.

Peer mentoring for professional and personal growth in academic medicine.

Mentorship is a critical component of career development, particularly in academic medicine. Peer mentorship, which does not adhere to traditional hierarchies, is perhaps more accessible for underrepresented groups, including women and minorities. In this article, we review various models of peer mentorship, highlighting their respective advantages and disadvantages. Structured peer mentorship groups exist in different settings, such as those created under the auspices of formal career development programs, part of training grant programs, or through professional societies. Social media has further enabled the establishment of informal peer mentorship through participatory online groups, blogs, and forums that provide platforms for peer-to-peer advice and support. Such groups can evolve rapidly to address changing conditions, as demonstrated by physician listserv and Facebook groups related to the COVID-19 pandemic. Peer mentorship can also be found among colleagues brought together through a common location, interest, or goal, and typically these relationships are informal and fluid. Finally, we highlight here our experience with intentional formation of a small peer mentoring group that provides structure and a safe space for professional and social-emotional growth and support. In order to maximize impact and functionality, this model of peer mentorship requires commitment among peers and a more formalized process than many other peer mentoring models, accounting for group dynamics and the unique needs of members. When done successfully, the depth of these mentoring relationships can produce myriad benefits for individuals with careers in academic medicine including, but not limited to, those from underrepresented backgrounds.

Good agreement between hyperinsulinemic-euglycemic clamp and 2 hours oral minimal model assessed insulin sensitivity in adolescents.

BACKGROUND/OBJECTIVE: Rates of dysglycemia are increasing in youth, secondary to obesity and decreased insulin sensitivity (IS) in puberty. The oral minimal model (OMM) has been developed in order to measure IS using an easy oral glucose load, such as an oral glucose tolerance test (OGTT), instead of an hyperinsulinemic-euglycemic clamp (HE-clamp), a more invasive and time-consuming procedure. However, this model, following a standard 2 hour- OGTT has never been validated in youth, a population known for a different physiologic response to OGTT than adults. Thus, we compared IS measurements obtained from OMM following a 2-hour OGTT to HE-clamp and isotope tracer-assessed tissue IS in adolescents. We also compared the liver/muscle-specific IS from HE-clamp with other liver/muscle-specific IS surrogates following an OGTT previously validated in adults. METHODS: Secondary analysis of a cross-sectional study. Adolescent girls with (n = 26) and without (n = 7) polycystic ovary syndrome (PCOS) (14.6 ± 1.7 years; BMI percentile 23.3%-98.2%) underwent a 2-hour 75 g OGTT and a 4-phase HE-clamp. OMM IS (Si), dynamic Si (Sid ) and other OGTT-derived muscle and liver IS indices were correlated with HE-clamp tissue-specific IS. RESULTS: OMM Si and Sid correlated with HE-clamp-measured peripheral IS (r = 0.64, P <.0001 and r = 0.73; P <.0001, respectively) and the correlation coefficient trended higher than the Matsuda index (r = 0.59; P =.003). The other tissue-specific indices were poorly correlated with their HE-clamp measurements. CONCLUSION: In adolescent girls, the 2-hour OMM provided the best estimate of peripheral IS. Additional surrogates for hepatic IS are needed for youth.

Association between changes in bioactive osteocalcin and glucose homeostasis after biliopancreatic diversion.

PURPOSE: Bone may regulate glucose homeostasis via uncarboxylated bioactive osteocalcin (ucOCN). This study explored whether changes in ucOCN and bone remodeling are associated with change in glucose homeostasis after biliopancreatic diversion (BPD). METHODS: In this secondary exploratory analysis of a 1-year prospective observational study, 16 participants (11 men/5 women; 69% with type 2 diabetes; mean BMI 49.4 kg/m2) were assessed before, 3 days, 3 months and 12 months after BPD. Changes in plasma ucOCN and bone markers (C-terminal telopeptide (CTX), total osteocalcin (OCN)) were correlated with changes in insulin resistance or sensitivity indices (HOMA-IR; adipose tissue insulin resistance index (ADIPO-IR) and insulin sensitivity index (SI) from the hyperinsulinemic-euglycemic clamp), insulin secretion rate (ISR) from the hyperglycemic clamp, and disposition index (DI: SI × ISR) using Spearman correlations before and after adjustment for weight loss. RESULTS: ucOCN was unchanged at 3 days but increased dramatically at 3 months (+257%) and 12 months (+498%). Change in ucOCN correlated significantly with change in CTX at 3 months (r = 0.62, p = 0.015) and 12 months (r = 0.64, p = 0.025) before adjustment for weight loss. It also correlated significantly with change in fasting insulin (r = -0.53, p = 0.035), HOMA-IR (r = -0.54, p = 0.033) and SI (r = 0.52, p = 0.041) at 3 days, and ADIPO-IR (r = -0.69, p = 0.003) and HbA1c (r = -0.69, p = 0.005) at 3 months. Change in OCN did not correlate with any glucose homeostasis indices. Results were similar after adjustment for weight loss. CONCLUSION: The increase in ucOCN may be associated with the improvement in insulin resistance after BPD, independently of weight loss. These findings need to be confirmed in larger, less heterogeneous populations.

Poor Sleep Is Related to Metabolic Syndrome Severity in Adolescents With PCOS and Obesity.

CONTEXT: Polycystic ovary syndrome (PCOS) is a common endocrine disorder and is associated with metabolic syndrome (MS). Development of MS in PCOS is likely multifactorial and may relate to poor sleep. OBJECTIVE: The objective of this research is to investigate differences in objective markers of sleep in adolescents with obesity and PCOS with and without MS. We also aimed to examine the relationships between markers of sleep with MS markers. DESIGN: A cross-sectional study was conducted. PARTICIPANTS: Participants included adolescents with PCOS and obesity with MS (N = 30) or without MS (N = 36). OUTCOME MEASURES: Hormone and metabolic measurements, abdominal magnetic resonance imaging for hepatic fat fraction, actigraphy to estimate sleep, and overnight polysomnography (PSG). RESULTS: Adolescents with obesity and PCOS who also had MS had significantly worse sleep-disordered breathing including higher apnea-hypopnea index (AHI, P = .02) and arousal index (P = .01) compared to those without MS. Actigraphy showed no differences in habitual patterns of sleep behaviors including duration, timing, or efficiency between groups. However, a greater number of poor sleep health behaviors was associated with greater number of MS components (P = .04). Higher AHI correlated with higher triglycerides (TG) (r = 0.49, P = .02), and poorer sleep efficiency correlated with higher percentage of liver fat (r = -0.40, P = .01), waist circumference (r = -0.46, P < .01) and higher TG (r = -0.34, P = .04). CONCLUSIONS: Among girls with PCOS and obesity, sleep-disordered breathing was more prevalent in those with MS, and poor sleep behaviors were associated with metabolic dysfunction and more MS symptoms. Sleep health should be included in the assessment of adolescents with PCOS and obesity.

Bariatric Surgery Rapidly Decreases Cardiac Dietary Fatty Acid Partitioning and Hepatic Insulin Resistance Through Increased Intra-abdominal Adipose Tissue Storage and Reduced Spillover in Type 2 Diabetes.

Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8-12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value [SUV]) 1.75 (interquartile range 1.39-2.57) before to 1.09 (1.04-1.53) after surgery (P = 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (P = 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04-0.31] before to 0.49 (0.20-0.59) SUV after surgery (P = 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (r = -0.79, P = 0.05) and reduced DFA spillover (r = 0.76, P = 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.

Clinical prediction score of nonalcoholic fatty liver disease in adolescent girls with polycystic ovary syndrome (PCOS-HS index).

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is common in obese adolescents with polycystic ovary syndrome (PCOS), but there are no inexpensive ways to accurately identify NAFLD in PCOS. The objective was to develop a simple clinical score to screen for NAFLD risk in obese adolescents with PCOS. DESIGN: This is a secondary analysis of 3 cross-sectional studies on metabolic characterization of obese adolescents with PCOS. 108 overweight and obese adolescents with PCOS (BMI > 90th percentile, age 12-19 years) were enrolled from 2012 to 2018. METHODS: Magnetic resonance imaging was used to quantify hepatic fat fraction (HFF). A development cohort of 87 girls were divided by presence of NAFLD (HFF > 5.5%). A logistic regression model with the outcome of NAFLD and candidate predictor variables was fit. A simplified model (PCOS-HS index) was created using backwards stepdown elimination. Validation was performed using 200 bootstrapped sample and in a second cohort of 21 PCOS participants. RESULTS: 52% of the development cohort had NAFLD. The PCOS-HS index that included BMI percentile, waist circumference, ALT and SHBG had an AUCROC of 0.81, sensitivity 82%, specificity 69%, negative predictive value (NPV) 78% and positive predictive value 74%, using a threshold of 0.44 to predict HS. A threshold of 0.15 ruled out NAFLD with a NPV 90%. In the validation cohort, the model showed an accuracy of 81%, sensitivity of 91% and specificity of 70%. CONCLUSIONS: We developed a clinical index to identify NAFLD in girls with PCOS who would need further evaluation and treatment.

Effects of 6-month vitamin D supplementation on insulin sensitivity and secretion: a randomised, placebo-controlled trial.

OBJECTIVE: To determine whether vitamin D3 supplementation improves insulin sensitivity, using the hyperinsulinemic-euglycemic clamp. DESIGN: This single-centre, double-blind, placebo-controlled trial randomised 96 participants at high risk of diabetes or with newly diagnosed type 2 diabetes to vitamin D3 5000 IU daily or placebo for 6 months. METHODS: We assessed at baseline and 6 months: (1) primary aim: peripheral insulin sensitivity (M-value using a 2-h hyperinsulinemic-euglycemic clamp); (2) secondary aims: other insulin sensitivity (HOMA2%S, Matsuda) and insulin secretion (insulinogenic index, C-peptide area under the curve, HOMA2-B) indices using a 2-h oral glucose tolerance test (OGTT); ß-cell function (disposition index: M-value × insulinogenic index); fasting and 2-h glucose post OGTT; HbA1c; anthropometry. RESULTS: Baseline characteristics were similar between groups (% or mean ± s.d.): women 38.5%; age 58.7 ± 9.4 years; BMI 32.2 ± 4.1 kg/m2; prediabetes 35.8%; diabetes 20.0%; 25-hydroxyvitamin D (25(OH)D) 51.1 ± 14.2 nmol/L. At 6 months, mean 25(OH)D reached 127.6 ± 26.3 nmol/L and 51.8 ± 16.5 nmol/L in the treatment and placebo groups, respectively (P < 0.001). A beneficial effect of vitamin D3 compared with placebo was observed on M-value (mean change (95% CI): 0.92 (0.24-1.59) vs -0.03 (-0.73 to 0.67); P = 0.009) and disposition index (mean change (95% CI): 267.0 (-343.4 to 877.4) vs -55.5 (-696.3 to 585.3); P = 0.039) after 6 months. No effect was seen on other outcomes. CONCLUSIONS: In individuals at high risk of diabetes or with newly diagnosed type 2 diabetes, vitamin D supplementation for 6 months significantly increased peripheral insulin sensitivity and ß-cell function, suggesting that it may slow metabolic deterioration in this population.

A simple method to monitor hepatic gluconeogenesis and triglyceride synthesis following oral sugar tolerance test in obese adolescents.

Hepatic energy metabolism is a key element in many metabolic diseases. Hepatic anaplerosis provides carbons for gluconeogenesis (GNG) and triglyceride (TG) synthesis. We aimed to optimize a protocol that measures hepatic anaplerotic contribution for GNG, TG synthesis, and hepatic pentose phosphate pathway (PPP) activity using a single dose of oral [U-13C3]glycerol paired with an oral sugar tolerance test (OSTT) in a population with significant insulin resistance. The OSTT (75 g glucose + 25 g fructose) was administered to eight obese adolescents with polycystic ovarian syndrome (PCOS) followed by ingestion of [U-13C3]glycerol at t = 180 or t = 210 min. 13C-labeling patterns of serum glucose and TG-glycerol were determined by nuclear magnetic resonance. 13C enrichment in plasma TG-glycerol was detectable and stable from 240 to 390 min with the [U-13C3]glycerol drink at t = 180 min(3.65 ± 2.3 to 4.47 ± 1.4%; P > 0.4), but the enrichment was undetectable at 240 min with the glycerol drink at t = 210 min. The relative contribution from anaplerosis was determined at the end of the OSTT [18.5 ±3.4% (t = 180 min) vs. 16.0 ± 3.5% (t = 210 min); P = 0.27]. [U-13C3]glycerol was incorporated into GNG 390 min after the OSTT with an enrichment of 7.5-12.5%. Glucose derived from TCA cycle activity was 0.3-1%, and the PPP activity was 2.8-4.7%. In conclusion, it is possible to obtain relative measurements of hepatic anaplerotic contribution to both GNG and TG esterification following an OSTT in a highly insulin-resistant population using a minimally invasive technique. Tracer administration should be timed to allow enough de novo TG esterification and endogenous glucose release after the sugar drink.

Morning Circadian Misalignment Is Associated With Insulin Resistance in Girls With Obesity and Polycystic Ovarian Syndrome.

CONTEXT: To our knowledge, circadian rhythms have not been examined in girls with polycystic ovarian syndrome (PCOS), despite the typical delayed circadian timing of adolescence, which is an emerging link between circadian health and insulin sensitivity (SI), and decreased SI in PCOS. OBJECTIVE: To examine differences in the circadian melatonin rhythm between obese adolescent girls with PCOS and control subjects, and evaluate relationships between circadian variables and SI. DESIGN: Cross-sectional study. PARTICIPANTS: Obese adolescent girls with PCOS (n = 59) or without PCOS (n = 33). OUTCOME MEASURES: Estimated sleep duration and timing from home actigraphy monitoring, in-laboratory hourly sampled dim-light, salivary-melatonin and fasting hormone analysis. RESULTS: All participants obtained insufficient sleep. Girls with PCOS had later clock-hour of melatonin offset, later melatonin offset relative to sleep timing, and longer duration of melatonin secretion than control subjects. A later melatonin offset after wake time (i.e., morning wakefulness occurring during the biological night) was associated with higher serum free testosterone levels and worse SI regardless of group. Analyses remained significant after controlling for daytime sleepiness and sleep-disordered breathing. CONCLUSION: Circadian misalignment in girls with PCOS is characterized by later melatonin offset relative to clock time and sleep timing. Morning circadian misalignment was associated with metabolic dysregulation in girls with PCOS and obesity. Clinical care of girls with PCOS and obesity would benefit from assessment of sleep and circadian health. Additional research is needed to understand mechanisms underlying the relationship between morning circadian misalignment and SI in this population.

Amino acid and fatty acid metabolomic profile during fasting and hyperinsulinemia in girls with polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is associated with insulin resistance (IR) and altered muscle mitochondrial oxidative phosphorylation. IR in adults with obesity and diabetes is associated with changes in amino acid, free fatty acid (FFA), and mitochondrial acylcarnitine (AC) metabolism. We sought to determine whether these metabolites are associated with IR and/or androgens in youth-onset PCOS. We enrolled obese girls with PCOS [ n = 15, 14.5 yr (SD 1.6), %BMI 98.5 (SD 1.0)] and without PCOS [ n = 6, 13.2 yr (SD 1.2), %BMI 98.0 (SD 1.1)]. Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp. Untargeted metabolomics of plasma was performed while fasting and during hyperinsulinemia. Fasting arginine, glutamine, histidine, lysine, phenylalanine, and tyrosine were higher ( P < 0.04 for all but P < 0.001 for valine), as were glutamine and histidine during hyperinsulinemia ( P < 0.03). Higher valine during hyperinsulinemia was associated with IR ( r = 0.59, P = 0.006). Surprisingly, end-clamp AC C4 was lower in PCOS, and lower C4 was associated with IR ( r = -0.44, P = 0.04). End-clamp FFAs of C14:0, C16:1, and C18:1 were higher in PCOS girls, and C16:1 and C18:1 strongly associated with IR ( r = 0.73 and 0.53, P < 0.01). Free androgen index related negatively to short-, medium-, and long-chain AC ( r = -0.41 to -0.71, P < 0.01) but not FFA or amino acids. Obese girls with PCOS have a distinct metabolic signature during fasting and hyperinsulinemia. As in diabetes, IR related to valine and FFAs, with an unexpected relationship with AC C4, suggesting unique metabolism in obese girls with PCOS.