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Introduction: Hudda-Index is a prediction model for fat mass (FM) based on simple anthropometric measures. FM is a crucial factor in the development of comorbidities, i.e., type 2 diabetes. Hence, Hudda-Index is a promising tool to facilitate the identification of children at risk for metabolic comorbidities. It has been validated against deuterium dilution assessments; however, independent validation against the gold standard for body composition analysis, magnetic resonance imaging (MRI), is lacking. The aim of this study was to validate FM calculated by Hudda-Index against FM measured by MRI. The secondary aim was to compare Hudda-Index to other anthropometric measures including body mass index (BMI), BMI-standard deviation score (BMI-SDS), waist/hip-ratio, waist circumference (WC), and skinfold thickness.

Methods: The study cohort consists of 115 individuals between the age of 9 and 15 years, recruited at Paracelsus Medical University Hospital in Salzburg (Austria) and Uppsala University Children’s Hospital (Sweden). Anthropometry, blood samples, and oral glucose tolerance tests followed standard procedures. MRI examinations were performed to determine visceral adipose tissue (VAT) and subcutaneous adipose tissue.

Results: BMI and WC showed slightly stronger associations with the reference standard VAT (r = 0.72 and 0.70, p < 0.01, respectively) than Hudda-Index (r = 0.67, p < 0.01). There is an almost perfect linear association between BMI and Hudda-Index. Accordingly, BMI and Hudda-Index both showed an acceptable association with cardiometabolic parameters. VAT was strongly associated with markers of liver status (LFF r = 0.59, p < 0.01) and insulin resistance (HOMA-IR r = 0.71, p < 0.01) and predicted metabolic dysfunction-associated steatotic liver disease.

Conclusion: BMI, although an imperfect measure, remains the most reliable tool and estimates cardiometabolic risk more reliably than other anthropometry-based measures.

IntroductionChildhood obesity is associated with maternal obesity, but the link to gestational weight gain (GWG) is not fully elucidated. We examined the relationship between early pregnancy maternal body mass index (BMI) and GWG on early childhood growth.Material and MethodsData from 30 197 mother-child pairs from Uppsala County Mother and Child Cohort were divided into 15 groups according to maternal BMI and GWG, based on World Health Organization classification and Institute of Medicine guidelines, respectively. Postnatal growth patterns were analyzed with linear mixed regression models within maternal BMI groups. Odds ratios of overweight and obesity at 4 years of age were assessed with logistic regression analyses. We treated children of mothers with normal weight and adequate GWG as the reference group, and all analyses were adjusted for potential confounders.ResultsGWG was associated with infant BMI z-score at birth, independent of potential confounding factors. Independent of GWG, we observed an overall decrease in BMI z-score from 18 months to 5 years in children of mothers who were underweight, while an increase in BMI z-score was seen in children of mothers who were overweight or obese. In children of normal- and overweight mothers, the risk of childhood overweight and obesity was associated with excessive compared to adequate GWG (adjusted odds ratio [aOR] 1.17, 95% confidence interval [CI] 1.01-1.36 for normal-weight mothers, and aOR 1.25, 95% CI 1.04-1.51 for overweight mothers, respectively). Children of mothers with obesity and excessive GWG had the highest risk of being overweight or obese at 4 years (aOR 2.88, 95% CI 2.40-3.44, and 4.38, 95% CI 3.37-5.67, respectively). Associations did not differ between children of mothers with obesity class 1 and 2-3 when comparing excessive and adequate GWG (aOR 1.33, 95% CI 0.96-1.85, and 1.12, 95% CI 0.74-1.70, respectively).ConclusionsMaternal GWG affects infant birth size and growth until 18 months, although maternal BMI is more crucial for childhood growth beyond 18 months. Further, children of mothers who are normal- or overweight and experience excessive GWG have an increased risk of obesity at 4 years. Maternal gestational weight gain (GWG) affects growth patterns in early childhood. Excessive GWG increases the risk of overweight and obesity in children of mothers with normal weight and overweight, while children of mothers with obesity are at increased risk of childhood overweight and obesity independent of GWG.image

Background:  Fasting levels of glucagon are known to be elevated in youth and adults with type 2 diabetes mellitus (T2D). Children and adolescents with obesity were previously reported to show increasing fasting and post-glucose-challenge hyperglucagonemia across the spectrum of glucose tolerance, while no data are available in those with impaired fasting glucose (IFG).

Materials and methods: Individuals from the Beta-JUDO study population (Uppsala and Salzburg 2010-2016) (n=101, age 13.3 +/- 2.8, m/f =50/51) were included (90 with overweight or obesity, 11 with normal weight). Standardized OGTT were performed and plasma glucose, glucagon and insulin concentrations assessed at baseline, 5, 10, 15, 30, 60, 90 and 120 minutes. Patients were grouped according to their glycemic state in six groups with normal glucose metabolism (NGM) and normal weight (NG-NW), NGM with obesity or overweight (NG-O), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), IGT+IFG and T2D, and in two groups with NGM and impaired glucose metabolism (IGM), for statistical analysis.

Results and conclusion:  Glucagon concentrations were elevated in young normoglycemic individuals with overweight or obesity (NG-O) compared to normoglycemic individuals with normal weight. Glucagon levels, fasting and dynamic, increased with progressing glycemic deterioration, except in IFG, where levels were comparable to those in NG-O. All glycemic groups showed an overall suppression of glucagon during OGTT. An initial increase of glucagon could be observed in T2D. In T2D, glucagon showed a strong direct linear correlation with plasma glucose levels during OGTT. Glucagon in adolescents, as in adults, may play a role in the disease progression of T2D.

Aim: To investigate the prevalence and possible risk factors for the development of impaired glucose metabolism in children and adolescents with obesity.

Methods: This was a cross-sectional retrospective cohort study, including 634 patients with obesity and 98 normal weight controls aged 4-18 years from the Beta-cell function in Juvenile Diabetes and Obesity (Beta-JUDO) cohort, a dual-centre study at Uppsala University Hospital (Sweden) and Paracelsus Medical University Hospital (Salzburg, Austria) conducted between 2012 and 2021. A longitudinal subgroup analysis, including 188 of these subjects was performed. Impaired glucose metabolism was diagnosed by oral glucose tolerance tests according to American Diabetes Association criteria.

Results: The prevalence of impaired glucose metabolism was 72% in Uppsala patients, 24% in Salzburg patients, 30% in Uppsala controls and 13% in Salzburg controls. The prevalence was lower at the follow-up visits compared with baseline both in Uppsala and Salzburg patients. A family history of type 2 diabetes showed the strongest association with impaired glucose metabolism at the follow-up visits besides belonging to the Uppsala cohort.

Conclusion: The prevalence of impaired glucose metabolism was extraordinarily high in Swedish children and adolescents with obesity, but decreased during the follow-up period.

Background: GLP-1 receptor agonists (GLP-1RA) are increasingly used to treat adolescent obesity. However, the effect on endogenous GLP-1 secretory patterns following treatment in adolescents is unknown. The GLP-1RA exenatide was shown to significantly lower BMI and 2-hour glucose in adolescents with obesity, in the placebo-controlled, randomized controlled trial Combat-JUDO. The aim of this study was to evaluate effects of weekly injections of 2 mg exenatide extended release on secretory patterns of endogenous hormones during OGTT.

Subjects and Measurements: This study was a pre-planned sub-study of the Combat-JUDO trial, set at the Pediatric clinic at Uppsala University Hospital, Sweden and Paracelsus Medical University, Austria. 44 adolescents with obesity were included and randomized 1:1 to treatment:placebo. 19 patients in the treatment group and 18 in the placebo group completed the trial. Before and after treatment, GLP-1, glucose, insulin, glucagon and glicentin levels were measured during OGTT; DPP-4 and proinsulin were measured at fasting. A per-protocol approach was used in the analyses.

Results: Exenatide treatment did not affect GLP-1 levels during OGTT. Treatment significantly lowered DPP-4, proinsulin and the proinsulin-to-insulin ratio at fasting, increased glicentin levels but did not affect insulin, C-peptide or glucagon levels during OGTT.

Conclusion: Weekly s.c. injections with 2 mg of exenatide maintains endogenous total GLP-1 levels and lowers circulating DPP-4 levels. This adds an argument in favor of using exenatide in the treatment of pediatric obesity.

In children with obesity, insulin hypersecretion is proposed to precede insulin resistance. We investigated if metformin could be used to attenuate insulin secretion from palmitate-treated isolated islets and its implication for children with obesity. Human islets were exposed to palmitate for 0.5 or 1 day, when metformin was introduced. After culture, glucose-stimulated insulin secretion (GSIS) was measured. Children with obesity, who had received metformin for over six months (n = 21, age 13.9 +/- 1.8), were retrospectively evaluated. Children were classified as either "reducing" or "increasing" based on the difference between AUC(0-120) of insulin during OGTT before and after metformin treatment. In human islets, GSIS increased after culture in palmitate for up to 1 day but declined with continued palmitate exposure. Whereas adding metformin after 1 day of palmitate exposure increased GSIS, adding metformin after 0.5 days reduced GSIS. In children with "reducing" insulin AUC(0-120) (n = 9), 2 h glucose and triglycerides decreased after metformin treatment, which was not observed in patients with "increasing" insulin AUC(0-120) (n = 12). In isolated islets, metformin attenuated insulin hypersecretion if introduced when islet secretory capacity was maintained. In children with obesity, improved glycemic and lipid levels were accompanied by reduced insulin levels during OGTT after metformin treatment.

Aim: To elucidate how proinsulin synthesis and insulin was affected by metformin under conditions of nutrient overstimulation.

Materials and methods: Isolated human pancreatic islets from seven donors were cultured at 5.5 mmol/L glucose and 0.5 mmol/L palmitate for 12, 24 or 72 h. Metformin (25 μmol/L) was introduced after initial 12 h with palmitate. Proinsulin and insulin were measured. Expression of prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE), was determined by western blot. Adolescents with obesity, treated with metformin and with normal glucose tolerance (n = 5), prediabetes (n = 14), or type 2 diabetes (T2DM; n = 7) were included. Fasting proinsulin, insulin, glucose, 2-h glucose and glycated haemoglobin were measured. Proinsulin/insulin ratio (PI/I) was calculated.

Results: In human islets, palmitate treatment for 12 and 24 h increased proinsulin and insulin proportionally. After 72 h, proinsulin but not insulin continued to increase which was coupled with reduced expression of PC1/3 and CPE. Metformin normalized expression of PC1/3 and CPE, and proinsulin and insulin secretion. In adolescents with obesity, before treatment, fasting proinsulin and insulin concentrations were higher in subjects with T2DM than with normal glucose tolerance. PI/I was reduced after metformin treatment in subjects with T2DM as well as in subjects with prediabetes, coupled with reduced 2-h glucose and glycated haemoglobin.

Conclusions: Metformin normalized proinsulin and insulin secretion after prolonged nutrient-overstimulation, coupled with normalization of the converting enzymes, in isolated islets. In adolescents with obesity, metformin treatment was associated with improved PI/I, which was coupled with improved glycaemic control.

Introduction: Obesity is associated with chronic inflammation. Chronic inflammation has also been linked to insulin resistance and type 2 diabetes, non-alcoholic fatty liver disease and cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor analogs (GLP-1RA) are clinically used to treat obesity, with known anti-inflammatory properties. How the GLP-1RA exenatide effects inflammation in adolescents with obesity is not fully investigated.

Methods: 44 patients were randomized to receive weekly subcutaneous injections with either 2 mg exenatide or placebo for 6 months. Plasma samples were collected at baseline and at the end of the study, and 90 inflammatory proteins were measured.

Results: Following treatment with exenatide, 15 out of the 90 proteins were decreased, and one was increased. However, after adjustment for multiple testing, only IL18-R alpha was significantly lowered following treatment.

Conclusions: Weekly injections with 2 mg of exenatide lowers circulating IL18-R alpha in adolescents with obesity, which may be a potential link between exenatide and its anti-inflammatory effect in vivo. This contributes to exenatide's pharmaceutical potential as a treatment for obesity beyond weight control and glucose tolerance, and should be further studied mechanistically.

Background

Decreasing hyperinsulinemia is crucial in preventing laminitis in insulin dysregulated (ID) horses. Complementary pharmacological treatments that efficiently decrease postprandial hyperinsulinemia in ID horses are needed.

Objectives

Compare short-term effects of canagliflozin vs placebo on glucose and insulin responses to an oral sugar test (OST) as well as the effects on body weight and triglyceride concentrations in horses with ID.

Animals

Sixteen privately-owned ID horses.

Methods

A single-center, randomized, double-blind, placebo-controlled, parallel design study. The horses were randomized (ratio 1:1) to either once daily PO treatment with 0.6 mg/kg canagliflozin or placebo. The study consisted of an initial 3-day period for obtaining baseline data, a 3-week double-blind treatment period at home, and a 3-day follow-up period similar to the initial baseline period but with continued double-blind treatment. Horses were subjected to an 8-sample OST in the morning of the third day on both visits.

Results

Maximal geometric least square (LS) mean insulin concentration (95% confidence interval [CI]) during the OST decreased after 3 weeks of canagliflozin treatment compared with placebo (83.2; 55.4-125.0 vs 215.2; 143.2-323.2 μIU/mL). The geometric LS mean insulin response (insulin AUC_0-180) for canagliflozin-treated horses was >66% lower compared with placebo. Least square mean body weight decreased by 11.1 (4-18.1) kg and LS mean triglyceride concentrations increased by 0.99 (0.47-1.5) mmol/L with canagliflozin treatment.

Conclusions and Clinical Importance

Canagliflozin is a promising drug for treatment of ID horses that requires future studies.