Malnutrition, fat malabsorption/vitamin D deficiency, and pulmonary decline traditionally characterize cystic fibrosis (CF). Fortunately, >90% of patients with CF ≥ 6 yrs old are now eligible for ...exacaftor/tezacaftor/ivacaftor (ETI) therapy which vastly improves lung function and nutrition by partially correcting the CF mutation. However, overweight/obesity is a rising concern. Although previously rare conditions of high blood pressure (BP) and dyslipidemia are also emerging in adults, pediatric CF data is limited. Moreover, data is lacking in minoritized groups such as Hispanics, who in the non-CF population are more prone to obesity when compared to non-Hispanic whites (NHW). To evaluate the impact of ethnicity on changes in body mass index (BMI) and obesity-related conditions, we performed a retrospective chart review of patients ≤18yrs old treated with ETI for at least 12 mo at our CF Center. Demographics including self-reported ethnicity (Hispanic vs NHW) and BMI, BP, A1c, liver profile, Vitamin D, lipids, and lung function (FEV1) at baseline and 12 mo post-ETI initiation were extracted from the medical record. Thirty-five children with CF 54% Hispanic, 57% male, age 13±3 yrs were assessed. At baseline, Hispanics were more likely to have Medicaid, higher FEV1, and lower Vitamin D (all p<0.05). Nine (26%) children 7 Hispanic, 2 NHW were overweight/obese. Post-ETI, BMI and FEV1 (both p<0.001) increased similarly in Hispanics and NHW, and Vitamin D improved in Hispanics (interaction, p<0.05). Lipid data was limited to 3 patients, therefore excluded from analyses. Post-ETI, 13 (37%) children were overweight/obese 8 Hispanic, 5 NHW. Overweight/obesity is a rising complication in our ethnically diverse CF center. Both Hispanic and NHW children experienced increases in BMI after 12 mo of ETI therapy. Obesity research is imperative to inform CF nutrition guidelines and obesity-related screening (i.e., lipids) for children receiving ETI therapy.
Disclosure
K.Vavrina: Speaker's Bureau; AbbVie Inc., Chiesi USA, Inc., Alcresta Therapeutics. R.Pillai: None. M.S.Rayas: None.
Funding
National Institutes of Health (KL2TR002646)
Roux-en-Y gastric bypass (GB) surgery and sleeve gastrectomy (SG) improve glucose tolerance, in part, by enhancing prandial insulin levels. Post-meal hyperinsulinemia after GB is caused by larger ...insulin secretion and lower metabolic clearance rate of insulin (MCRI) . Reduced prandial MCRI after GB is exaggerated in those with post-GB complication of hypoglycemia, suggesting that altered MCRI is a pathogenic factor. We investigated the role of GB or SG on insulin kinetics in fasting and fed states.
The MCRI were measured during a mixed meal text (MMT) in 9 GB and 7 SG subjects: and during MMT combined with hyperinsulinemic hypoglycemic clamp in 9 GB, 7 SG, and 5 CN. Three groups were matched for age and BMI and surgical groups for time and weight loss since surgery; none had diabetes or liver disease.
Fasting MCRI was greater in GB and SC than CN (p<0.05) . Meal ingestion diminished MCRI to a larger extent in GB subjects compared to SG reaching nadir values in 20-50 min (relative reduction in GB vs. SG: 82±3% vs. 74±3%, p<0.05) . The relative postprandial reduction in MCRI was inversely associated with the glycemic excursion and insulin response. During the clamp hepatic insulin clearance was larger in GB and SG compared to CN (p<0.05) . There was no association between hepatic insulin clearance and peripheral insulin sensitivity (M/I) . Induced hyperinsulinemia approximating 300 µU/ml reduced MCRI in 3 groups despite a larger M/I in surgical subjects. Meal ingestion during hyperinsulinemic hypoglycemia clamp raised MCRI in 3 groups (p<0.05) returning to pre-meal values in an hour. These findings demonstrate that the differences in basal MCRI among GB, SG and CN are mainly attributed to variations in insulin clearance in the liver and independent on peripheral insulin sensitivity. Further, prandial reduction in MCRI is greater after GB than SG in proportion to the rates of nutrient influx.; the effect of nutrient ingestion on insulin kinetics is altered during hyperinsulinemic hypoglycemia.
Disclosure
M.S.Rayas: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. A.Gastaldelli: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Boehringer Ingelheim International GmbH, Inventiva Pharma, Other Relationship; Eli Lilly and Company, Gilead Sciences, Inc., Pfizer Inc., Speaker's Bureau; Novo Nordisk. M.Salehi: None.
Funding
National Institute of Diabetes, Digestive, and Kidney Diseases (DK105379)
•CFRD is more prevalent in non-Hispanic Blacks compared to non-Hispanic whites.•Non-Hispanic Black women and youth with obesity are particularly at risk for CFRD.•CFRD emerges earlier in non-Hispanic ...Blacks and Hispanics.•CFRD is more common in individuals with public health insurance.
CF-related diabetes (CFRD) is a common, life-expectancy limiting complication of CF. While Black race and Hispanic ethnicity in youth-onset type 1 and type 2 diabetes are well-recognized risk factors for worse diabetes complications, the potential for racial/ethnic disparities in CFRD has received limited attention.
We conducted a retrospective cohort study utilizing the CF Foundation Patient Registry from 2010 to 2019 to determine the prevalence and incidence of CFRD by race/ethnicity. Three age cohorts were identified at baseline in 2010 (11–20y, 21–30y, and 31–40y). Logistic regression and Cox regression stratified by age group were used to determine the prevalence and incidence, respectively, among Hispanic, non-Hispanic Blacks (NHB), and non-Hispanic whites (NHW) after adjustment for relevant confounders, including demographics, socioeconomic status, clinical factors, and chronic medication use.
Among 14,660 registry participants, 510 were NHB and 890 Hispanic. NHB associated with higher odds of CFRD baseline prevalence in all age cohorts (11–20y: OR 2.53 (95 % CI: 1.88–3.41, P < 0.05), 21–30y: OR 1.80 (1.25–2.59, P < 0.05), and 31–40y: OR 1.93 (1.00–3.73, P < 0.05)) relative to NHW. In the 11–20y cohort, the hazard of new-onset CFRD was 40 % higher in NHB (HR 1.40 (1.09–1.8, P < 0.05)) and 19 % higher in Hispanics (HR 1.19 (1.01–1.41, P < 0.05)).
NHB had a higher prevalence of CFRD across all age groups, with NHB and Hispanics showing higher incidence of CFRD in the youngest group. Multicenter studies performed in diverse CF populations are warranted to identify modifiable factors influencing earlier CFRD development in minoritized groups and their potential contribution to diabetes complication disparities.
ABSTRACT
Objectives:
Nonalcoholic fatty liver disease (NAFLD) can develop in lean subjects referred to as lean NAFLD. We aim to evaluate the prevalence and risk factors of NAFLD in lean adolescents ...in the United States (US).
Methods:
Cross sectional data from 1482 lean subjects (body mass index <85th percentile) ages between 12 and 18 years, who were enrolled in the National Health and Examination Survey during the 2005 to 2014 cycles were included. We defined suspected NAFLD as alanine aminotransferase >25.8 U/L for boys and >22.1 U/L for girls; hypertriglyceridemia as triglycerides ≥150 mg/dL; low HDL as HDL <40 mg/dL and insulin resistance (IR) as homeostatic model assessment of IR ≥3.
Results:
The mean weighted prevalence of suspected NAFLD among lean adolescents during 2005 to 2014 cycles was 8% (95% CI 6.2–9.9). Lean subjects with suspected NAFLD were significantly older compared with lean non‐NAFLD subjects (15.5 vs 15 years, P value <0.05). Low HDL (15.5% vs 6.8%; P value 0.016) and hypertriglyceridemia (10% vs 3.9%; P value 0.028) were also found to be more common among lean NAFLD subjects compared with their non‐NAFLD counterparts. Presence of IR increased the risk of having suspected NAFLD by 4‐fold among lean adolescents. Non‐Hispanic black lean adolescents were less likely to have suspected NAFLD compared with non‐Hispanic white lean adolescents.
Conclusions:
The estimated prevalence of suspected NAFLD among lean adolescents in the US was found to be 8% with evidence of metabolic derangements such as low HDL, hypertriglyceridemia, and IR.
The two most commonly performed bariatric surgical procedures, gastric bypass (GB) and sleeve gastrectomy (SG), induce diabetes remission before any significant weight loss. While the role of ...entero-insular axis after SG remains unknown, weight-independent glycemic effects of GB have been attributed to larger systemic appearance of glucose and incretin effect. We examined the effect of increasing endogenous incretins 2-3 fold with a DPP-4 inhibitor on glycemic effects of GB and SG. Glucose and islet-cell secretory responses were measured in 4 subjects with a history of GB, 4 with SG and 4 non-surgical controls (CN) during 50-gram oral glucose ingestion with and without 200 mg sitagliptin orally on two separate days. GB, SG, and CN groups were matched for BMI, FFM, HbA1c, age, fasting glucose and insulin levels; GB and SG were matched for weight loss and time postsurgery; none had diabetes. Compared to SG-treated subjects and controls, subjects with prior GB had lower prandial glycemia (AUCGlucose 3hr) (P < 0.001), and higher AUCGlucagon 3hr (P < 0.0001). The expected differences in prandial insulin response pattern to glucose ingestion among surgical and controls was observed; however, AUCInsulin 3hr and AUCC-peptide 3hr were similar between groups. Sitagliptin did not change AUCGlucose 3hr in GB-treated subjects, whereas the prandial glucose response was reduced by 21 ± 13 % in SG-treated and non-surgical controls by sitagliptin. Enhanced endogenous incretins diminished early glucagon (AUCGlucagon 1hr) in all 3 groups (P < 0.05), improved β-cell glucose sensitivity in CN (P < 0.05), but it had no effect on beta-cell function in GB or SG subjects. Sitagliptin had no effect on insulin clearance or insulin sensitivity in fasting or fed states. These findings indicate that glucose metabolism after SG, similar to non-operated controls, is enhanced by incretins, which are at maximum in GB group and thus not influenced by DPP-4 inhibition.
Disclosure
H. Honka: None. M. S. Rayas: Research Support; Self; National Center for Advancing Translational Sciences. R. A. Defronzo: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. A. Gastaldelli: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Consultant; Self; Eli Lilly and Company, Inventiva Pharma, Research Support; Self; Gilead Sciences, Inc., Speaker’s Bureau; Self; Novo Nordisk. M. Salehi: None.
Funding
National Institutes of Health (TR002646); National Institute of Diabetes and Digestive and Kidney Diseases (DK105379)
Protein ingestion increases the plasma insulin and glucagon responses, but the enteral factors involved are entirely unknown. We hypothesized that glucagon-like peptide 1 (GLP-1) signaling regulates ...glucose metabolism after protein ingestion, and that this effect may be amplified after Roux-en Y gastric bypass (GB) and sleeve gastrectomy (SG). We examined the glucose and islet-cell secretory responses to 50 g protein ingestion with and without GLP-1 receptor antagonist, exendin-(9-39) Ex-9, in 4 GB-treated subjects, 4 SG-treated, and 4 non-operated controls (CN). The groups were matched for age, BMI, fat-free mass, fasting glucose and insulin, and HbA1c. The surgical groups also were matched for weight loss and time post-surgery; none had diabetes. Protein ingestion resulted in an early rise in glycemia (AUCGlucose 1hr) in GB and SG compared to CN (p<0.05), whose glucose values remained at basal concentrations. Both β- and α-cell hormonal responses were enhanced by protein ingestion in all 3 groups. GLP-1 receptor blockade increased fasting and prandial glycemia in all 3 groups, but to a greater extent in GB (p<0.05, interaction). This glycemic effect of Ex-9 was associated with a ~25% reduction in prandial insulin secretion in GB and SG and ~25% increase in prandial insulin response in CN (p<0.05, interaction). The prandial glucagon responses were larger during studies with Ex-9 compared to those without (p<0.05). Blocking the GLP-1R increased prandial insulin clearance (p<0.05) in all groups, but to a much larger extent in surgical subjects (p=0.1, interaction). Our findings indicate that glucose metabolism after protein ingestion is altered after GB and SG. To our knowledge, this is the first report demonstrating that endogenous GLP-1 contributes to glucose and islet-cell secretory response to protein ingestion, and that GB and SG exaggerate GLP-1 contribution to insulin secretion and clearance after protein ingestion.
Disclosure
M. S. Rayas: Research Support; Self; National Center for Advancing Translational Sciences. H. Honka: None. R. A. Defronzo: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. A. Gastaldelli: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Consultant; Self; Eli Lilly and Company, Inventiva Pharma, Research Support; Self; Gilead Sciences, Inc., Speaker’s Bureau; Self; Novo Nordisk. M. Salehi: None.
Funding
National Institutes of Health (DK105379)
Biofertilizer production and application for sustainable agriculture is already a reality. The methods for biofertilizers delivery in crop fields are diverse. Although foliar spray is gaining wide ...acceptance, little is known about the influence that the biochemical features of leaves have on the microbial colonization. Arthrobacter agilis UMCV2 is a rhizospheric and endophytic bacteria that promotes plant growth and health. In this study, we determined the capacity of the UMCV2 strain to colonize different leaves from Medicago truncatula in a foliar inoculation system. By using two powerful analytical methods based on mass spectrometry, we determined the chemical profile of the leaves in 15-d old plants. The metabolic signatures between the unifoliate leaf (m1) and the metameric units developing above (m2 and m3) were different, and interestingly, the highest colony forming units (CFU) was found in m1. The occurrence of the endophyte strongly affects the sugar composition in m1 and m2 leaves. Our results suggest that A. agilis UMCV2 colonize the leaves under a foliar inoculation system independently of the phenological age of the leaf and it is capable of modulating the carbohydrate metabolism without affecting the rest of the metabolome.
Insulin deficiency largely underlies cystic fibrosis related diabetes (CFRD). CF liver disease (CFLD) is a risk factor for CFRD development, but the mechanisms linking these mortality-increasing ...comorbidities are unknown. This pilot study sought to characterize prandial glucose metabolism and islet function in youth across glycemia and CFLD spectrums.
Glucose, insulin, c-peptide (CP) and glucagon were obtained during a 3-hr oral glucose tolerance test in youth (9M/11F, ages 12-21y) with pancreatic insufficient CF from two centers. Fasting insulin sensitivity (HOMA-IR) and insulin clearance (CP:insulin), and prandial glucose and glucagon excursion (AUC180), insulin sensitivity (Matsuda index), β-cell sensitivity to glucose, insulin secretory rates (ISR; by parametric deconvolution of CP kinetics) and disposition index (DI, composite of insulin secretion and insulin sensitivity) were calculated. CFLD status was defined using CFLD guidelines: CFLD with portal hypertension (CFLDPH), CFLD without portal hypertension (CFLD) and no liver disease (CFnoLD).
CFLDPH (n=3), CFLD (n=3) CFnoLD (n=14) did not differ in age, BMI-Z, or HbA1c. CFRD was present in 2 CFLDPH, 0 CFLD, 4 CFnoLD. Fasting glucose was greater in CFLDPH vs. CFLD or CFnoLD (p<0.05). HOMA-IR and fasting CP:insulin were reduced in CFLDPH vs. CFLD and CFnoLD, but post-meal glucose-AUC180 and indices of insulin sensitivity and clearance were similar. ISR and DI tended to be lower in CFLDPH vs. CFLD (p=0.008 and p=0.077) and CFnoLD (p=0.071 and p=0.058), respectively. β-cell sensitivity was reduced in CFLDPH vs. CFLD (p<0.05). Fasting and AUC180 glucagon did not differ among groups.
In this limited group of youth, reduced fasting insulin sensitivity and magnified insulin secretory defects are present in CFLDPH, the more severe form of CFLD, and may explain their heightened CFRD risk. Larger studies are warranted to define pathogenesis and inform glycemic treatment targets in individuals with severe CFLD.
Disclosure
M.S. Rayas: None. K.S. Hughan: Research Support; Self; Novo Nordisk Inc. R. Javaid: None. D. leung: None. D. Stefanovski: None. A. Kelly: None. M. Salehi: None.
Funding
Cystic Fibrosis Foundation (RAYAS16GEO, HUGHAN16GE0, MOR16CFF); National Institutes of Health (5T32DK00772923)
•Severe CF-liver disease may exaggerate glucose abnormalities in patients with CFRD.•CF-liver disease may decrease insulin clearance that fosters insulin resistance.•Patients with CFRD and liver ...disease may warrant treatment other than insulin.
Diabetes and liver disease are life-threatening complications of cystic fibrosis (CF). CF-liver disease is a risk factor for CF related diabetes (CFRD) development, but the underlying mechanisms linking the two co-morbidities are not known. The objective of this pilot study was to characterize glucose metabolism in youth with CF with and without liver disease.
In this two-center cross-sectional study, 20 youth with CF with and without liver disease underwent a 3-hour oral glucose tolerance test. Subjects were categorized by liver disease (LD) status no LD, mild LD, severe LD and diabetes status. Measures of glucose excursion, islet cell secretory responses, insulin sensitivity and clearance were obtained.
Participants with severe LD had the highest fasting, peak, and glucose area under the curve over 3 h (AUC3h) among individuals with CFRD (interaction p < 0.05). In parallel with glycemic changes, prandial β-cell secretory response (AUC C-peptide 3h) was lower in those with severe LD compared to mild or no LD (p < 0.01). There was a trend of higher HOMA-IR in those with severe LD (p = 0.1) as well as lower fasting insulin clearance in those with mild and severe LD compared to no LD (p = 0.06) and lower prandial insulin clearance in severe LD among those with CFRD (interaction p = 0.1).
In this small cohort, subjects with severe LD tended to have more impaired glycemia, insulin secretion, insulin sensitivity and clearance. Larger studies are imperative to define the pathogenesis to inform clinical care guidelines in terms of CFRD screening, diagnosis, and treatment options.
OBJECTIVES/GOALS: In this study we sought to determine the role of glucagon-like peptide-1 (GLP-1), one of the main gut hormones in regulating glucose metabolism, after protein ingestion in patients ...with a history of Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG). METHODS/STUDY POPULATION: We examined the glucose and islet-cell secretory responses to 50 g protein ingestion with and without a potent GLP-1 receptor antagonist, exendin-(9-39) Ex-9, in 10 GB-treated subjects, 9 SG-treated, and 7 non-operated controls (CN). The groups were matched for age, BMI, fat-free mass, fasting glucose and insulin, and HbA1c. The surgical groups also were matched for weight loss and time post-surgery. No subjects had diabetes. RESULTS/ANTICIPATED RESULTS: Protein ingestion resulted in an early rise in glycemia (AUCGlucose1hr) in GB and SG, whereas CN had minimal change in glucose (p<0.05). Protein ingestion enhanced C-peptide responses in all groups, but to a larger extent in GB and SG when compared to CN (p<0.05). Early glucagon response to protein ingestion (AUCGlucagon1hr) tended to be larger in GB and SG subjects when compared to CN (p=0.07). Ex-9 increased premeal and prandial glycemia in all groups (p<0.05), but increase in early glycemia (AUCGlucose1hr) was most notable in GB (p=0.1, interaction). This glycemic effect of Ex-9 was associated with a ~25% reduction in prandial C-peptide secretion in GB and SG and ~8% increase in CN (p<0.05, interaction). Early prandial glucagon responses were larger during studies with Ex-9 compared to those without (p<0.05). DISCUSSION/SIGNIFICANCE: Our findings indicate that glucose metabolism after protein ingestion is altered after GB and SG. To our knowledge, this is the first report to demonstrate that endogenous GLP-1 contributes to glucose and islet-cell secretory response to protein ingestion, and that GB and SG exaggerate GLP-1 contribution to insulin secretion after protein ingestion.
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