Estimating insulin sensitivity and ß-cell function from the oral glucose tolerance test: validation of a new insulin sensitivity and secretion (ISS) model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and ß-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes (T2D). Existing methods range in sensitivity, input data, and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new insulin secretion and sensitivity (ISS) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. This model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. This model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including postchallenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had a strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.NEW & NOTEWORTHY The pathogenesis of type 2 diabetes (T2D) is determined by a balance between insulin sensitivity (SI) and ß-cell function (BCF), which can be determined by gold standard direct measurements or estimated by fitting differential equation models to oral glucose tolerance tests (OGTTs). We propose and validate a new differential equation model that is simpler to use than current models and requires less data while maintaining good correlation and agreement with gold standards. Matlab and Python code is freely available.

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.

BACKGROUND: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD). OBJECTIVE: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG). METHODS: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity. RESULTS: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups. CONCLUSIONS: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease. TRIAL REGISTRATION: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022.

Metabolomic Profiling of an Ultraprocessed Dietary Pattern in a Domiciled Randomized Controlled Crossover Feeding Trial.

BACKGROUND: Objective markers of ultraprocessed foods (UPF) may improve the assessment of UPF intake and provide insight into how UPF influences health. OBJECTIVES: To identify metabolites that differed between dietary patterns (DPs) high in or void of UPF according to Nova classification. METHODS: In a randomized, crossover, controlled-feeding trial (clinicaltrials.govNCT03407053), 20 domiciled healthy participants (mean ± standard deviation: age 31 ± 7 y, body mass index [kg/m2] 22 ± 11.6) consumed ad libitum a UPF-DP (80% UPF) and an unprocessed DP (UN-DP; 0% UPF) for 2 wk each. Metabolites were measured using liquid chromatography with tandem mass spectrometry in ethylenediaminetetraacetic acid plasma, collected at week 2 and 24-h, and spot urine, collected at weeks 1 and 2, of each DP. Linear mixed models, adjusted for energy intake, were used to identify metabolites that differed between DPs. RESULTS: After multiple comparisons correction, 257 out of 993 plasma and 606 out of 1279 24-h urine metabolites differed between UPF-DP and UN-DP. Overall, 21 known and 9 unknown metabolites differed between DPs across all time points and biospecimen types. Six metabolites were higher (4-hydroxy-L-glutamic acid, N-acetylaminooctanoic acid, 2-methoxyhydroquinone sulfate, 4-ethylphenylsulfate, 4-vinylphenol sulfate, and acesulfame) and 14 were lower following the UPF-DP; pimelic acid, was lower in plasma but higher in urine following the UPF-DP. CONCLUSIONS: Consuming a DP high in, compared with 1 void of, UPF has a measurable impact on the short-term human metabolome. Observed differential metabolites could serve as candidate biomarkers of UPF intake or metabolic response in larger samples with varying UPF-DPs. This trial was registered at clinicaltrials.gov as NCT03407053 and NCT03878108.

Childhood Obesity and Cardiovascular Disease Risk.

PURPOSE OF REVIEW: The global epidemic of youth-onset obesity is tightly linked to the rising burden of cardiometabolic disease across the lifespan. While the link between childhood obesity and cardiovascular disease is established, this contemporary review summarizes recent and novel advances in this field that elucidate the mechanisms and impact of this public health issue. RECENT FINDINGS: The review highlights the emerging data supporting the relationship between childhood adverse events, social determinants of health, and systemic and institutional systems as etiological factors. We also provide updates on new screening and treatment approaches including updated nutrition and dietary guidelines and benchmarks for pediatric obesity screening, novel pharmacological agents for pediatric obesity and type 2 diabetes such as glucagon-like 1 peptide receptor agonists, and we discuss the long-term safety and efficacy data on surgical management of pediatric obesity. The global burden of pediatric obesity continues to rise and is associated with accelerated and early vascular aging especially in youth with obesity and type 2 diabetes. Socio-ecological determinants of risk mediate and moderate the relationship of childhood obesity with cardiometabolic disease. Recognizing the importance of neighborhood level influences as etiological factors in the development of cardiovascular disease is critical for designing effective policies and interventions. Novel surgical and pharmacological interventions are effective pediatric weight-loss interventions, but future research is needed to assess whether these agents, within a socio-ecological framework, will be associated with abatement of the pediatric obesity epidemic and related increased cardiovascular disease risk.

Triglyceride Paradox Is Related to Lipoprotein Size, Visceral Adiposity and Stearoyl-CoA Desaturase Activity in Black Versus White Women.

RATIONALE: In black women, triglycerides are paradoxically normal in the presence of insulin resistance. This relationship may be explained by race-related differences in central adiposity and SCD (stearoyl-CoA desaturase)-1 enzyme activity index. OBJECTIVE: In a cross-sectional study, to compare fasting and postprandial triglyceride-rich lipoprotein particle (TRLP) concentrations and size in black compared with white pre- and postmenopausal women and determine the relationship between TRLP subfractions and whole-body insulin sensitivity, hepatic and visceral fat, and SCD-1 levels. METHODS AND RESULTS: In 122 federally employed women without diabetes mellitus, 73 black (58 African American and 15 African immigrant) and 49 white; age, 44±10 (mean±SD) years; body mass index, 30.0±5.6 kg/m2, we measured lipoprotein subfractions using nuclear magnetic resonance. Hepatic fat was measured by proton magnetic resonance spectroscopy, insulin sensitivity index calculated by minimal modeling from a frequently sampled intravenous glucose test, and red blood cell fatty acid profiles were measured by gas chromatography and were used to estimate SCD-1 indices. Hepatic fat, insulin sensitivity index, and SCD-1 were similar in black women and lower than in whites, regardless of menopausal status. Fasting and postprandial large, medium, and small TRLPs, but not very small TRLPs, were lower in black women. Fasting large, medium, and very small TRLPs negatively correlated with insulin sensitivity index and positively correlated with visceral and hepatic fat and SCD-1 activity in both groups. In multivariate models, visceral fat and SCD-1 were associated with total fasting TRLP concentrations (adjR2, 0.39; P=0.001). Black women had smaller postprandial changes in large (P=0.005) and medium TRLPs (P=0.007). CONCLUSIONS: Lower visceral fat and SCD-1 activity may contribute to the paradoxical association of lower fasting and postprandial TRLP subfractions despite insulin resistance in black compared with white pre- and postmenopausal women. Similar concentrations of very small TRLPs are related to insulin resistance and could be important mediators of cardiometabolic disease risk in women. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01809288.

Energy expenditure due to gluconeogenesis in pathological conditions of insulin resistance.

Gluconeogenesis (GNG), the formation of glucose from noncarbohydrate precursors, requires adenosine triphosphate (ATP). Previous studies have estimated the energetic cost of GNG in humans based on theoretical calculations of rates of GNG, moles of oxygen consumption by GNG, and average oxygen consumption. Few human studies have measured the energy expenditure (EE) due to GNG. We estimated EE attributable to GNG in patients with three insulin resistance conditions and high GNG rates (insulin receptor pathogenic variants, lipodystrophy, and type 2 diabetes) and obesity without diabetes. Fractional GNG was measured by incorporation of deuterium from body water into newly formed glucose, endogenous glucose production (EGP) as glucose appearance following administration of [6,6-2H2]glucose, and total GNG as fractional GNG × EGP. EE was measured by indirect calorimetry and compared with predicted EE from the Mifflin St. Jeor equation. EE attributable to GNG was estimated using linear regression after accounting for age and fat-free mass (FFM). EE in patients with insulin resistance was significantly higher than predicted by the Mifflin St. Jeor equation. GNG correlated with resting EE (REE). EE attributable to GNG in patients with insulin resistance was almost one-third of REE, substantially higher than theorized in healthy subjects. Our findings demonstrate that GNG is a significant contributor to EE in insulin-resistant states. Prediction equations may underestimate caloric needs in patients with insulin resistance. Therefore, targeting caloric needs to account for higher EE due to increased GNG should be considered in energy balance studies in patients with insulin resistance.NEW & NOTEWORTHY Gluconeogenesis is an energy-requiring process that is upregulated in diabetes, contributing to hyperglycemia. Previous studies have estimated that gluconeogenesis accounts for less than 10% of resting energy expenditure. This study estimates the energy expenditure attributable to gluconeogenesis in uncommon and severe forms of insulin resistance and common, milder forms of insulin resistance. In these populations, gluconeogenesis accounts for almost one-third of resting energy expenditure, substantially higher than previously theorized in the literature.

Metformin treatment and gastrointestinal symptoms in youth: Findings from a large tertiary care referral center.

OBJECTIVES: Metformin is the only oral therapy for youth with type 2 diabetes, but up to 50% require additional agents within 2 years of diagnosis. Extended-release (XR) metformin formulations may improve adherence and tolerability-important mediators of treatment response-but data in youth is lacking. To evaluate rates of gastrointestinal (GI) symptoms in patients treated with metformin (SR and XR) and the change in GI symptoms after changes in metformin therapy. RESEARCH DESIGN AND METHODS: Retrospective chart review of youth with Type 2 or prediabetes seen in a multidisciplinary clinic during 2016-2019. RESULTS: Of 488 eligible patients, 41.4% and 21.1% were taking metformin SR and XR respectively, with most (58%, n = 178/305) taking a total daily dose of ≥1500 mg/day. Those not on metformin tended to be younger, leaner, and had lower HbA1cs than those taking metformin, p < 0.05. Thirty percentage of patients described GI symptoms, most commonly, abdominal pain and diarrhea. There was no difference in GI symptoms in those on SR versus XR (18.3% vs. 14.6%, p = 0.41). Among patients who initiated metformin, rates of GI symptoms increased (13%-33%, p = 0.001, n = 99), while rates tended to decrease when metformin was discontinued (28%-12%, p = 0.076, n = 50). Rates of GI symptoms were unchanged among those that switched from SR to XR metformin (17% vs. 14%, p = 0.6, n = 58). CONCLUSIONS: GI symptoms are common in youth with type 2 diabetes taking metformin XR and SR. Adjuncts to mitigate GI symptoms in youth on metformin therapy are needed to improve quality of life and medication adherence.

Metformin improves blood glucose by increasing incretins independent of changes in gluconeogenesis in youth with type 2 diabetes.

AIMS/HYPOTHESIS: Metformin is the only approved oral agent for youth with type 2 diabetes but its mechanism of action remains controversial. Recent data in adults suggest a primary role for the enteroinsular pathway, but there are no data in youth, in whom metformin efficacy is only ~50%. Our objectives were to compare incretin concentrations and rates of glucose production and gluconeogenesis in youth with type 2 diabetes before and after short-term metformin therapy compared with peers with normal glucose tolerance (NGT). METHODS: This is a case-control observational study in youth with type 2 diabetes who were not on metformin (n = 18) compared with youth with NGT (n = 10) who were evaluated with a 2 day protocol. A 75 g OGTT was administered to measure intact glucagon-like 1 peptide (iGLP-1), gastric inhibitory polypeptide (GIP) and peptide YY (PYY). Insulinogenic index (IGI) and whole-body insulin sensitivity were calculated using glucose and insulin levels from the OGTT. Basal rates of gluconeogenesis (2H2O), glucose production ([6,6-2H2]glucose) and whole-body lipolysis ([2H5]glycerol) were measured after an overnight fast on study day 2. Youth with type 2 diabetes (n = 9) were subsequently evaluated with an identical 2 day protocol after 3 months on the metformin study. RESULTS: Compared with individuals with NGT, those with type 2 diabetes had higher fasting (7.8 ± 2.5 vs 5.1 ± 0.3 mmol/l, mean ± SD p = 0.002) and 2 h glucose concentrations (13.8 ± 4.5 vs 5.9 ± 0.9 mmol/l, p = 0.001), higher rates of absolute gluconeogenesis (10.0 ± 1.7 vs 7.2 ± 1.1 µmol [kg fat-free mass (FFM)]-1 min-1, p < 0.001) and whole-body lipolysis (5.2 ± 0.9 vs 4.0 ± 1.4 µmol kgFFM-1 min-1, p < 0.01), but lower fasting iGLP-1 concentrations (0.5 ± 0.5 vs 1.3 ± 0.7 pmol/l, p < 0.01). Metformin decreased 2 h glucose (pre metformin 11.4 ± 2.8 vs post metformin 9.9 ± 1.9 mmol/l, p = 0.04) and was associated with ~20-50% increase in IGI (median [25th-75th percentile] pre 1.39 [0.89-1.47] vs post 1.43 [0.88-2.70], p = 0.04), fasting iGLP-1 (pre 0.3 ± 0.2 vs post 1.0 ± 0.7 pmol/l, p = 0.02), 2 h iGLP (pre 0.4 ± 0.2 vs post 1.2 ± 0.9 pmol/l, p = 0.06), fasting PYY (pre 6.3 ± 2.2 vs post 10.5 ± 4.3 pmol/l, p < 0.01) and 2 h PYY (pre 6.6 ± 2.9 vs post 9.0 ± 4.0 pmol/l, p < 0.01). There was no change in BMI, insulin sensitivity or GIP concentrations pre vs post metformin. There were no differences pre vs post metformin in rates of glucose production (15.0 ± 3.9 vs 14.9 ± 2.2 µmol kgFFM-1 min-1, p = 0.84), absolute gluconeogenesis (9.9 ± 1.8 vs 9.7 ± 1.7 µmol kgFFM-1 min-1, p = 0.76) or whole-body lipolysis (5.0 ± 0.7 vs 5.3 ± 1.3 µmol kgFFM-1 min-1, p = 0.20). Post metformin iGLP-1 and PYY concentrations in youth with type 2 diabetes were comparable to levels in youth with NGT. CONCLUSIONS/INTERPRETATION: Overall, the improved postprandial blood glucose levels and increase in incretins observed in the absence of changes in insulin sensitivity and gluconeogenesis, support an enteroinsular mechanistic pathway in youth with type 2 diabetes treated with short-term metformin.

From the Outside In: Biological Mechanisms Linking Social and Environmental Exposures to Chronic Disease and to Health Disparities.

The ongoing epidemic of chronic diseases involves a spectrum of clinical entities now understood to represent late manifestations of progressive metabolic dysfunction initiated in early life. These diseases disproportionately affect disadvantaged populations, exacerbating health disparities that persist despite public health efforts. Excessive exposure to stressful psychosocial and environmental forces is 1 factor known to contribute to population-level disparities in at-risk settings. Yet increasing evidence reveals that even a single adverse environmental exposure-especially during very early developmental years-can become literally biologically embedded, inducing long-lasting disease-promoting pathways that amplify responses (e.g., cortisol, immune, inflammatory) to all future adverse stressors, thus enhancing their disease-promoting impacts. The same pathways may also interact with ancestrally linked genetic variants to modify chronic disease risk. We address how, in at-risk populations, environmentally activated disease-promoting pathways can contribute to a biologically based disease-susceptible phenotype; this is likely to be uniquely damaging in populations with multiple adverse exposures and is capable of cross-generational transmission. Intended to complement existing models, this biological perspective highlights key research opportunities and life-stage priorities with potential to enhance the reduction of health disparities.

Two- vs one-hour glucose tolerance testing: Predicting prediabetes in adolescent girls with obesity.

BACKGROUND: During an oral glucose tolerance test (OGTT), morphological features of the glucose curve (monophasic curve, glucose peak >30 minutes and 1-hour glucose ≥ 155 mg/dL) maybe associated with higher prediabetes risk, but their reproducibility and predictive ability in adolescents with obesity are unknown. METHODS: Nondiabetic adolescent girls with obesity underwent a multiple-sample OGTT at baseline (n = 93), 6 weeks (n = 83), and 1 year (n = 72). Short-term reproducibility (baseline to 6 weeks) and the predictive ability for prediabetes (baseline to 1 year) for each feature were compared with standard fasting and 2-hour OGTT diagnostic criteria. RESULTS: There was fair/moderate short-term reproducibility (κ < 0.5) for all morphological features. At 1 year, compared with standard OGTT criteria, the areas under the receiver operating curve (ROC-AUCs) for glucose peak > 30 minutes, 1 hour ≥155 mg/dL or a combination of the two criteria were comparable (all P > 0.05), but the monophasic curve had the lowest ROC-AUC (P < 0.001). CONCLUSIONS: In adolescent girls with obesity, glucose peak > 30 minutes and/or glucose ≥155 mg/dL had similar reproducibility and 1-year predictive ability for prediabetes compared with standard OGTT criteria. The shortened 1-hour OGTT may provide diagnostic equivalence for prediabetes risk with the additional advantage of a less time-consuming risk assessment.

TGF-ß1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis.

Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-ß1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-ß1/Smad3 signals suppressed endogenous glucose production. TGF-ß1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-ß1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-ß1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance.

Low-carbohydrate diets for the treatment of obesity and type 2 diabetes.

PURPOSE OF REVIEW: Summarize the physiological effects of low-carbohydrate diets as they relate to weight loss, glycemic control, and metabolic health. RECENT FINDINGS: Low-carbohydrate diets are at least as effective for weight loss as other diets, but claims about increased energy expenditure and preferential loss of body fat are unsubstantiated. Glycemic control and hyperinsulinemia are improved by low-carbohydrate diets, but insulin sensitivity and glucose-stimulated insulin secretion may be impaired, especially in the absence of weight loss. Fasting lipid parameters are generally improved, but such improvements may depend on the quality of dietary fat and the carbohydrates they replaced. Postprandial hyperlipemia is a potential concern given the high fat content typical of low-carbohydrate diets. SUMMARY: Low-carbohydrate diets have several potential benefits for treatment of obesity and type 2 diabetes, but more research is required to better understand their long-term consequences as well as the variable effects on the endocrine control of glucose, lipids, and metabolism.

Time to glucose peak during an oral glucose tolerance test identifies prediabetes risk.

CONTEXT: Morphological characteristics of the glucose curve during an oral glucose tolerance test (OGTT) (time to peak and shape) may reflect different phenotypes of insulin secretion and action, but their ability to predict diabetes risk is uncertain. OBJECTIVE: To compare the ability of time to glucose peak and curve shape to detect prediabetes and ß-cell function. DESIGN AND PARTICIPANTS: In a cross-sectional evaluation using an OGTT, 145 adults without diabetes (age 42±9 years (mean±SD), range 24-62 years, BMI 29.2±5.3 kg/m2 , range 19.9-45.2 kg/m2 ) were characterized by peak (30 minutes vs >30 minutes) and shape (biphasic vs monophasic). MAIN OUTCOME MEASURES: Prediabetes and disposition index (DI)-a marker of ß-cell function. RESULTS: Prediabetes was diagnosed in 36% (52/145) of participants. Peak>30 minutes, not monophasic curve, was associated with increased odds of prediabetes (OR: 4.0 vs 1.1; P<.001). Both monophasic curve and peak>30 minutes were associated with lower DI (P≤.01). Time to glucose peak and glucose area under the curves (AUC) were independent predictors of DI (adjR2 =0.45, P<.001). CONCLUSION: Glucose peak >30 minutes was a stronger independent indicator of prediabetes and ß-cell function than the monophasic curve. Time to glucose peak may be an important tool that could enhance prediabetes risk stratification.

Glycated Albumin Identifies Prediabetes Not Detected by Hemoglobin A1c: The Africans in America Study.

BACKGROUND: Following immigration to the US, many Africans transition from a low-normal to a high-normal or overweight body mass index (BMI). This weight change is associated with a high rate of prediabetes in the nonobese. Studies in East Asians reveal that glycated albumin is effective in identifying prediabetes in nonobese Asians. Whether this is true in African immigrants is unknown. Therefore, we evaluated the ability of hemoglobin A1c (Hb A1c) and glycated albumin to detect prediabetes in nonobese (BMI <30 kg/m2) and obese (BMI ≥30 kg/m2) African immigrants. METHODS: Oral glucose tolerance tests (OGTTs) were performed in 236 self-identified healthy African immigrants [mean (SD) BMI 27.6 (4.4) kg/m2]. Prediabetes diagnosis was based on glucose criteria for the OGTT. Diagnostic sensitivity of Hb A1c and glycated albumin was determined by thresholds at the upper quartile for each [Hb A1c ≥5.7% (39 mmol/mol), glycated albumin ≥13.77%]. RESULTS: Based on glucose criteria for the OGTT, prediabetes was detected in 36% (85/236). BMI and Hb A1c were positively correlated (r = 0.22, P < 0.001), whereas BMI and glycated albumin were negatively correlated (r = -0.24, P < 0.001). Although the sensitivities of Hb A1c and glycated albumin were similar in nonobese immigrants (37% vs 42%, P = 0.75), prediabetes was detected in 21 nonobese Africans by glycated albumin alone, in 18 by Hb A1c alone, and in 4 by both tests. Therefore, sensitivity of the combined tests was better than for Hb A1c alone(72% vs 37%, P < 0.01). In the obese, Hb A1c was a much better diagnostic test than glycated albumin (64% vs 16%, P < 0.01) and combining the tests did not improve sensitivity (72% vs 64%, P = 0.50). CONCLUSIONS: Glycated albumin contributes by identifying prediabetes not detected by Hb A1c in nonobese African immigrants. ClinicalTrials.gov Identifier: NCT00001853.

High Overweight and Obesity in Fontan Patients: A 20-Year History.

The prevalence of obesity in long-term survivors with complex congenital heart disease may be increasing, and little is known about the timing and onset of weight gain and growth patterns in these high-risk patients. Prevalence rates of overweight/obesity and longitudinal changes in body mass index (BMI) with age were determined in 606 patients with Fontan circulation seen at a tertiary care cardiology center from 1992 to 2012. The number of clinic encounters (n) was stratified by age group (n = 401, 2-5 years; n = 333, 6-11 years; n = 217, 12-19 years; and n = 129, >20 years). Among adults, 39% were overweight/obese at last clinic visit; 22% overweight, and 17% obese. Childhood anthropometric data were available for 82 adults, of which 15% (n = 12/82) were overweight/obese in childhood. The likelihood of being overweight/obese as an adult was three times higher if there was a BMI ≥ 85th percentile in childhood (CI 2.1-4.5, P < 0.01). Overweight/obesity in adulthood was associated with lower heart failure rates (4 vs. 19%, P = 0.03). Pediatric rates of overweight/obesity were comparable to national data (NHANES 2011-2012) in every age group: at 2-5 years, (25 vs. 23%), 6-11 years (26 vs. 34%), and 12-19 years (15 vs. 35%). Systolic blood pressure was higher in overweight/obese children as young as 2-5 years of age. Childhood and adult survivors with Fontan circulation have high rates of overweight/obesity. Childhood obesity is a strong predictor of future adiposity and is linked to changes in systolic blood pressure at a very young age.

Increased gluconeogenesis in youth with newly diagnosed type 2 diabetes.

AIMS/HYPOTHESIS: The role of increased gluconeogenesis as an important contributor to fasting hyperglycaemia at diabetes onset is not known. We evaluated the contribution of gluconeogenesis and glycogenolysis to fasting hyperglycaemia in newly diagnosed youths with type 2 diabetes following an overnight fast. METHODS: Basal rates (µmol kg(FFM) (-1) min(-1)) of gluconeogenesis ((2)H2O), glycogenolysis and glycerol production ([(2)H5] glycerol) were measured in 18 adolescents (nine treatment naive diabetic and nine normal-glucose-tolerant obese adolescents). RESULTS: Type 2 diabetes was associated with higher gluconeogenesis (9.2 ± 0.6 vs 7.0 ± 0.3 µmol kg(FFM) (-1) min(-1), p < 0.01), plasma fasting glucose (7.0 ± 0.6 vs 5.0 ± 0.2 mmol/l, p = 0.004) and insulin (300 ± 30 vs 126 ± 31 pmol/l, p = 0.001). Glucose production and glycogenolysis were similar between the groups (15.4 ± 0.3 vs 12.4 ± 1.4 µmol kg(FFM) (-1) min(-1), p = 0.06; and 6.2 ± 0.8 vs 5.3 ± 0.7 µmol kg(FFM) (-1) min(-1), p = 0.5, respectively). After controlling for differences in adiposity, gluconeogenesis, glycogenolysis and glucose production were higher in diabetic youth (p ≤ 0.02). Glycerol concentration (84 ± 6 vs 57 ± 6 µmol/l, p = 0.01) and glycerol production (5.0 ± 0.3 vs 3.6 ± 0.5 µmol kg(FFM) (-1) min(-1), p = 0.03) were 40% higher in youth with diabetes. The increased glycerol production could account for only ~1/3 of substrate needed for the increased gluconeogenesis in diabetic youth. CONCLUSION/INTERPRETATIONS: Increased gluconeogenesis was a major contributor to fasting hyperglycaemia and hepatic insulin resistance in newly diagnosed untreated adolescents and was an early pathological feature of type 2 diabetes. Increased glycerol availability may represent a significant source of new carbon substrates for increased gluconeogenesis but would not account for all the carbons required to sustain the increased rates.

Biochemical and clinical deficiency is uncommon in African immigrants despite a high prevalence of low vitamin D: the Africans in America study.

UNLABELLED: African ancestry is associated with low vitamin D levels but high bone density. Fifty percent of African immigrants had low vitamin D levels, but <10 % had evidence of deficiency. The value of providing vitamin D supplementation to African immigrants without evidence of deficiency needs to be determined. INTRODUCTION: The Endocrine Society and Institute of Medicine (IOM) have concluded from studies in largely white populations that 25(OH)D is necessary for bone health. However, their definition of vitamin D insufficiency differs. The Endocrine Society recommends a 25(OH)D threshold of <30 ng/mL. The IOM uses a lower threshold of 25(OH)D of <20 ng/mL. As African ancestry is associated with decreased 25(OH)D but increased bone mineral density (BMD), the applicability of these thresholds to Africans is unknown. Therefore, we examined in African immigrants the relationship of 25(OH)D to parathyroid hormone (PTH) and BMD. METHODS: One hundred eighty-six African immigrants(69 % male, age 38 ± 10 (mean ± SD), range 20-64 years) living in metropolitan Washington, DC, were enrolled. BMD was determined from whole-body dual-energy X-ray absorptiometry (DXA) scans. Decreased BMD required T-scores ≤-1.0. The threshold for low 25(OH)D was the concentration of 25(OH)D at which PTH became suppressed. This is known as the inflection point. Biochemical deficiency required low 25(OH)D and PTH of >65 pg/mL. Clinical deficiency required low 25(OH)D and T-scores ≤-1.0. RESULTS: 25(OH)D <30 and <20 ng/mL occurred in 83 and 46 % of African immigrants, respectively. PTH inversely correlated with 25(OH)D (r = -0.31, P = 0.002). The inflection point occurred at a 25(OH)D concentration of 20 ng/mL. Biochemical and clinical deficiency occurred in only 8 and 3 % of immigrants, respectively. CONCLUSION: As PTH became suppressed at 25(OH)D of 20 ng/mL, the 25(OH)D <20 ng/mL threshold for insufficiency may apply to African immigrants. However, ~50 % of African immigrants have 25(OH)D <20 ng/mL, but only <10 % had evidence of deficiency. The value of providing vitamin D supplementation to the large number of African immigrants with 25(OH)D <20 ng/mL and no detectable evidence of deficiency needs to be determined.

Reevaluating First-line Therapies in Youth-Onset Type 2 Diabetes.

The prevalence of youth-onset type 2 diabetes is growing worldwide and current first-line treatment with metformin and intensive behavior and lifestyle changes are suboptimal in over 50% of youth within 2 years of diagnosis. This perspective article is a call to action for reevaluation of existing strategies and critical appraisal of metformin as first-line therapy in youth-onset type 2 diabetes. Increased attention should be given to novel therapeutics approved in youth, including glucagon-like 1 receptor agonists, sodium glucose cotransporter-2, and sociocultural interventions that will promote diabetes self-management.

Prediction of resting energy expenditure for adolescents with severe obesity: A multi-centre analysis.

BACKGROUND AND OBJECTIVES: Resting energy expenditure (REE) assessments can help inform clinical treatment decisions in adolescents with elevated body mass index (BMI), but current equations are suboptimal for severe obesity. We developed a predictive REE equation for youth with severe obesity and obesity-related comorbidities and compared results to previously published predictive equations. METHODS: Data from indirect calorimetry, clinical measures, and body composition per Dual x-ray absorptiometry (DXA) were collected from five sites. Data were randomly divided into development (N = 438) and validation (N = 118) cohorts. A predictive equation was developed using Elastic Net regression, using sex, race, ethnicity, weight, height, BMI percent of the 95th%ile (BMIp95), waist circumference, hip circumference, waist/hip ratio, age, Tanner stage, fat and fat-free mass. This equation was verified in the validation cohort and compared with 11 prior equations. RESULTS: Data from the total cohort (n = 556, age 15 ± 1.7 years, 77% female, BMIp95 3.3 ± 0.94) were utilized. The best fit equation was REE = -2048 + 18.17 × (Height in cm) - 2.57 × (Weight in kg) + 7.88 × (BMIp95) + 189 × (1 = male, 0 = female), R2 = 0.466, and mean bias of 23 kcal/day. CONCLUSION: This new equation provides an updated REE prediction that accounts for severe obesity and metabolic complications frequently observed in contemporary youth.

Glycemia and Gluconeogenesis With Metformin and Liraglutide: A Randomized Trial in Youth-onset Type 2 Diabetes.

OBJECTIVE: Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and ß-cell function after therapy in AA Y-T2D. METHODS: In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. ß-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test. RESULTS: At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P = .003) but not gluconeogenesis or mSI. CONCLUSION: Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance ß-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.