The growing number of obese children and adolescents affected by type 2 diabetes and the rapid development of glucose homeostasis dysregulation in this age group explain why type 2 diabetes is ...becoming one of the most important public health problems. ... identifying obese children at risk for type 2 diabetes is of primary importance in order to interrupt its progression and the diabetes-related cardiovascular complications in this age group.
As a consequence of the global rise in the prevalence of adolescent obesity, an unprecedented phenomenon of type 2 diabetes has emerged in pediatrics. At the heart of the development of type 2 ...diabetes lies a key metabolic derangement: insulin resistance (IR). Despite the widespread occurrence of IR affecting an unmeasurable number of youths worldwide, its pathogenesis remains elusive. IR in obese youth is a complex phenomenon that defies explanation by a single pathway. In this review we first describe recent data on the prevalence, severity, and racial/ethnic differences in pediatric obesity. We follow by elucidating the initiating events associated with the onset of IR, and describe a distinct “endophenotype” in obese adolescents characterized by a thin superficial layer of abdominal subcutaneous adipose tissue, increased visceral adipose tissue, marked IR, dyslipidemia, and fatty liver. Further, we provide evidence for the cellular and molecular mechanisms associated with this peculiar endophenotype and its relations to IR in the obese adolescent.
Summary Diabetes is a much more heterogeneous disease than the present subdivision into types 1 and 2 assumes; type 1 and type 2 diabetes probably represent extremes on a range of diabetic disorders. ...Both type 1 and type 2 diabetes seem to result from a collision between genes and environment. Although genetic predisposition establishes susceptibility, rapid changes in the environment (ie, lifestyle factors) are the most probable explanation for the increase in incidence of both forms of diabetes. Many patients have genetic predispositions to both forms of diabetes, resulting in hybrid forms of diabetes (eg, latent autoimmune diabetes in adults). Obesity is a strong modifier of diabetes risk, and can account for not only a large proportion of the epidemic of type 2 diabetes in Asia but also the ever-increasing number of adolescents with type 2 diabetes. With improved characterisation of patients with diabetes, the range of diabetic subgroups will become even more diverse in the future.
Childhood obesity is one of the most serious global public-health challenges of the twenty-first century. Over the past four decades, the number of children and adolescents with obesity has risen ...more than tenfold. Worldwide, an increasing number of youth are facing greater exposure to obesity throughout their lives, and this increase will contribute to the early development of type 2 diabetes, fatty liver and cardiovascular complications. Herein, we provide a brief overview of trends in the global shifts in, and environmental and genetic determinants of, childhood obesity. We then discuss recent progress in the elucidation of the central role of insulin resistance, the key element linking obesity and cardiovascular-risk-factor clustering, and the potential mechanisms through which ectopic lipid accumulation leads to insulin resistance and its associated cardiometabolic complications in obese adolescents. In the absence of effective prevention and intervention programs, childhood obesity will have severe public-health consequences for decades to come.
Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains ...unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin’s ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D.
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•Insulin inhibits gluconeogenesis by suppressing lipolysis and hepatic acetyl CoA•Hyperglycemia associated with HFD is due to increased WAT-derived hepatic acetyl CoA•ATGL KOs are protected from HFD-induced insulin resistance due to decreased lipolysis•mφJNK KOs are protected from HFD-induced insulin resistance due to decreased lipolysis
Metabolic abnormalities associated with a high-fat diet are found to be driven by increased hepatic acetyl CoA levels, which are shown to be a consequence of white adipose tissue inflammation and inappropriately increased lipolysis.
OBJECTIVE: Hemoglobin A₁c (A1C) has emerged as a recommended diagnostic tool for identifying diabetes and subjects at risk for the disease. This recommendation is based on data in adults showing the ...relationship between A1C with future development of diabetes and microvascular complications. However, studies in the pediatric population are lacking. RESEARCH DESIGN AND METHODS: We studied a multiethnic cohort of 1,156 obese children and adolescents without a diagnosis of diabetes (male, 40%/female, 60%). All subjects underwent an oral glucose tolerance test (OGTT) and A1C measurement. These tests were repeated after a follow-up time of ~2 years in 218 subjects. RESULTS: At baseline, subjects were stratified according to A1C categories: 77% with normal glucose tolerance (A1C <5.7%), 21% at risk for diabetes (A1C 5.7-6.4%), and 1% with diabetes (A1C >6.5%). In the at risk for diabetes category, 47% were classified with prediabetes or diabetes, and in the diabetes category, 62% were classified with type 2 diabetes by the OGTT. The area under the curve receiver operating characteristic for A1C was 0.81 (95% CI 0.70-0.92). The threshold for identifying type 2 diabetes was 5.8%, with 78% specificity and 68% sensitivity. In the subgroup with repeated measures, a multivariate analysis showed that the strongest predictors of 2-h glucose at follow-up were baseline A1C and 2-h glucose, independently of age, ethnicity, sex, fasting glucose, and follow-up time. CONCLUSIONS: The American Diabetes Association suggested that an A1C of 6.5% underestimates the prevalence of prediabetes and diabetes in obese children and adolescents. Given the low sensitivity and specificity, the use of A1C by itself represents a poor diagnostic tool for prediabetes and type 2 diabetes in obese children and adolescents.
The innate immune cell sensor leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome controls the activation of caspase-1, and the release of proinflammatory cytokines ...interleukin (IL)-1β and IL-18. The NLRP3 inflammasome is implicated in adipose tissue inflammation and the pathogenesis of insulin resistance. Herein, we tested the hypothesis that adipose tissue inflammation and NLRP3 inflammasome are linked to the downregulation of subcutaneous adipose tissue (SAT) adipogenesis/lipogenesis in obese adolescents with altered abdominal fat partitioning. We performed abdominal SAT biopsies on 58 obese adolescents and grouped them by MRI-derived visceral fat to visceral adipose tissue (VAT) plus SAT (VAT/VAT+SAT) ratio (cutoff 0.11). Adolescents with a high VAT/VAT+SAT ratio showed higher SAT macrophage infiltration and higher expression of the NLRP3 inflammasome-related genes (i.e., TLR4, NLRP3, IL1B, and CASP1). The increase in inflammation markers was paralleled by a decrease in genes related to insulin sensitivity (ADIPOQ, GLUT4, PPARG2, and SIRT1) and lipogenesis (SREBP1c, ACC, LPL, and FASN). Furthermore, SAT ceramide concentrations correlated with the expression of CASP1 and IL1B. Infiltration of macrophages and upregulation of the NLRP3 inflammasome together with the associated high ceramide content in the plasma and SAT of obese adolescents with a high VAT/VAT+SAT may contribute to the limited expansion of the subcutaneous abdominal adipose depot and the development of insulin resistance.
OBJECTIVE: We evaluated the role of fatty liver in the alteration of insulin sensitivity and β-cell function in two groups of obese adolescents, differing in hepatic fat content (hepatic fat fraction ...HFF) but with similar intrabdominal intramyocellular lipid content (IMCL) and overall degree of obesity. RESEARCH DESIGN AND METHODS: We studied 23 obese adolescents with high HFF (HFF >5.5%) and 20 obese adolescents with low HFF (HFF <5.5%), matched for age, Tanner stage, BMI z score, and percentages of body fat, visceral fat, and IMCL. All subjects underwent an oral glucose tolerance test and a two-step hyperinsulinemic-euglycemic clamp, magnetic resonance imaging and ¹H nuclear magnetic resonance to assess abdominal fat distribution, HFF, and IMCL, respectively. RESULTS: The high HFF group showed significantly lower whole-body insulin sensitivity index (P = 0.001) and estimates of insulin secretion (P = 0.03). The baseline hepatic glucose production (EGP) rate was not different between the two groups. Suppression of EGP was significantly lower (P = 0.04) in the high HFF group during low-dose insulin; no differences were observed during the second step. Baseline fatty acids, glycerol concentrations, and clamp suppression of glycerol turnover did not differ between the groups. During the second step, the glucose disposal rate was significantly lower (P = 0.01) in the high HFF group. CONCLUSIONS: Fatty liver, independent of visceral fat and IMCL, plays a central role in the insulin-resistant state in obese adolescents.
To determine if beneficial effects of a weight-management program could be sustained for up to 24 months in a randomized trial in an ethnically diverse obese population.
There were 209 obese children ...(BMI > 95th percentile), ages 8 to 16 of mixed ethnic backgrounds randomly assigned to the intensive lifestyle intervention or clinic control group. The control group received counseling every 6 months, and the intervention group received a family-based program, which included exercise, nutrition, and behavior modification. Lifestyle intervention sessions occurred twice weekly for the first 6 months, then twice monthly for the second 6 months; for the last 12 months there was no active intervention. There were 174 children who completed the 12 months of the randomized trial. Follow-up data were available for 76 of these children at 24 months. There were no statistical differences in dropout rates among ethnic groups or in any other aspects.
Treatment effect was sustained at 24 months in the intervention versus control group for BMI z score (-0.16 95% confidence interval: -0.23 to -0.09), BMI (-2.8 kg/m(2) 95% confidence interval: -4.0-1.6 kg/m(2)), percent body fat (-4.2% 95% confidence interval: -6.4% to -2.0%), total body fat mass (-5.8 kg 95% confidence interval: -9.1 kg to -2.6 kg), total cholesterol (-13.0 mg/dL 95% confidence interval: -21.7 mg/dL to -4.2 mg/dL), low-density lipoprotein cholesterol (-10.4 mg/dL 95% confidence interval: -18.3 mg/dL to -2.4 mg/dL), and homeostasis model assessment of insulin resistance (-2.05 95% confidence interval: -2.48 to -1.75).
This study, unprecedented because of the high degree of obesity and ethnically diverse backgrounds of children, reveals that benefits of an intensive lifestyle program can be sustained 12 months after completing the active intervention phase.
The prevalence of childhood obesity is increasing worldwide, as is the prevalence of obesity-related co-morbidity. Altered glucose metabolism, manifested as impaired glucose tolerance (IGT), appears ...early in obese children and adolescents. Obese young people with IGT are characterized by marked peripheral insulin resistance and a relative β-cell failure. Lipid deposition in muscle and the visceral compartment, and not only adiposity per se, is related to increased peripheral insulin resistance, the ‘driving force’ of the metabolic syndrome. Other elements of the metabolic syndrome, such as dyslipidemia and hypertension, are already present in obese youngsters and worsen with the degree of obesity. Similarly, markers of systemic ‘low-grade inflammation’ worsen with increasing adiposity. The long-term impact on cardiovascular and liver morbidity of obesity-related insulin resistance in young people is expected to emerge as these youngsters become young adults.
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