Type 2 Diabetes in Youth: Epidemiology and Pathophysiology
TL;DR: The pathophysiology of type 2 diabetes and the natural history of this pathology in obese children and adolescents is explored, which is associated with an increased lipid accumulation in visceral compartments, liver and muscle tissues and by reduced sensitivity of I²-cell of first and second-phase insulin secretion.
Abstract: The prevalence of type 2 diabetes is significantly increased in the pediatric population, which is affected by obesity worldwide. The progression from normal glucose tolerance (NGT) to type 2 diabetes involves intermediate stages of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), also known as prediabetes. The pathophysiology underlying the development of these glucose metabolic alterations is multifactorial; however an alteration in the balance between insulin sensitivity and insulin secretion represents the most important player in the development of type 2 diabetes. Obese children and adolescents affected by IGT and type 2 diabetes are characterized by severe insulin resistance, which is associated with an increased lipid accumulation in visceral compartments, liver and muscle tissues and by reduced sensitivity of I²-cell of first and second-phase insulin secretion.
The progression in obese children of insulin resistance to type 2 diabetes has been shown to be faster than in adults; in addition, type 2 diabetes is already associated with several metabolic and cardiovascular complications in this age group.
In the present review, we summarize the most recent findings concerning the prevalence of type 2 diabetes in youth and in particular we explore the pathophysiology of type 2 diabetes and the natural history of this pathology in obese children and adolescents.
Concurrent with the worldwide epidemic increase of childhood obesity, type 2 diabetes and the two prediabetic conditions, IFG and IGT, are becoming increasingly more common in obese children and adolescents (1,2). Until 10 years ago, type 2 diabetes accounted for less than 3% of all cases of new-onset diabetes in adolescents. At present 45% of cases are attributed to it (3,4).
Type 2 diabetes occurs in youth more often during the second decade of life, coinciding with the physiological occurrence of pubertal insulin resistance (1). In addition, …
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TL;DR: Evidence is accumulating that young-onset type 2 diabetes has a more aggressive disease phenotype, leading to premature development of complications, with adverse effects on quality of life and unfavourable effects on long-term outcomes, raising the possibility of a future public health catastrophe.
415 citations
TL;DR: Paradigms in cardiovascular survival in patients with T2DM have contributed to patients surviving longer, allowing sufficient time to develop renal impairment, and this Review explores how the changing epidemiology of T2 DM has influenced the prevalence and incidence of associated CKD across different populations and clinical settings.
Abstract: Chronic kidney disease (CKD) is a common comorbidity in patients with type 2 diabetes mellitus (T2DM) and both conditions are increasing in prevalence. CKD is estimated to affect ∼50% patients with T2DM globally, and its presence and severity markedly influences disease prognosis. CKD is more common in certain patient populations, including the elderly, those with youth-onset diabetes mellitus, those who are obese, certain ethnic groups, and disadvantaged populations. These same settings have also seen the greatest increase in the prevalence of T2DM, as exemplified by the increasing prevalence of T2DM in low-to- middle income countries. Patients from low-to-middle income countries are often the least able to deal with the burden of T2DM and CKD and the health-care facilities of these countries least able to deal with the demand for equitable access to renal replacement therapies. The increasing prevalence of younger individuals with T2DM, in whom an accelerated course of complications can be observed, further adds to the global burden of CKD. Paradoxically, improvements in cardiovascular survival in patients with T2DM have contributed to patients surviving longer, allowing sufficient time to develop renal impairment. This Review explores how the changing epidemiology of T2DM has influenced the prevalence and incidence of associated CKD across different populations and clinical settings.
376 citations
TL;DR: Worldwide incidence and prevalence of type 2 diabetes in children and adolescents vary substantially among countries, age categories and ethnic groups and this can be explained by variations in population characteristics and methodological dissimilarities between studies.
Abstract: Aims/hypothesis
This study aimed to systematically review what has been reported on the incidence and prevalence of type 2 diabetes in children and adolescents, to scrutinise the methodological issues observed in the included studies and to prepare recommendations for future research and surveillances.
183 citations
North Shore-LIJ Health System1, Autonomous University of Barcelona2, Aalborg University3, Rutgers University4, King's College London5, National Health Service6, Katholieke Universiteit Leuven7, Columbia University8, Hannover Medical School9, Yale University10, University of Cincinnati11, China Medical University (Taiwan)12, Hospital General Universitario Gregorio Marañón13, Hofstra University14, The Feinstein Institute for Medical Research15
TL;DR: Although T2DM seems rare in antipsychotic-exposed youth, cumulative risk and exposure-adjusted incidences and IRRs were significantly higher than in healthy controls and psychiatric controls.
Abstract: Importance Antipsychotics are used increasingly in youth for nonpsychotic and off-label indications, but cardiometabolic adverse effects and (especially) type 2 diabetes mellitus (T2DM) risk have raised additional concern. Objective To assess T2DM risk associated with antipsychotic treatment in youth. Data Sources Systematic literature search of PubMed and PsycINFO without language restrictions from database inception until May 4, 2015. Data analyses were performed in July 2015, and additional analyses were added in November 2015. Study Selection Longitudinal studies reporting on T2DM incidence in youth 2 to 24 years old exposed to antipsychotics for at least 3 months. Data Extraction and Synthesis Two independent investigators extracted study-level data for a random-effects meta-analysis and meta-regression of T2DM risk. Main Outcomes and Measures The coprimary outcomes were study-defined T2DM, expressed as cumulative T2DM risk or as T2DM incidence rate per patient-years. Secondary outcomes included the comparison of the coprimary outcomes in antipsychotic-treated youth with psychiatric controls not receiving antipsychotics or with healthy controls Results Thirteen studies were included in the meta-analysis, including 185 105 youth exposed to antipsychotics and 310 438 patient-years. The mean (SD) age of patients was 14.1 (2.1) years, and 59.5% were male. The mean (SD) follow-up was 1.7 (2.3) years. Among them, 7 studies included psychiatric controls (1 342 121 patients and 2 071 135 patient-years), and 8 studies included healthy controls (298 803 patients and 463 084 patient-years). Antipsychotic-exposed youth had a cumulative T2DM risk of 5.72 (95% CI, 3.45-9.48; P P P P P P P P P = .002) ( r 2 = 1.00, P P ≤ .050) and less autism spectrum disorder diagnosis ( P = .048) ( r 2 = 0.21, P = .044). Conclusions and Relevance Although T2DM seems rare in antipsychotic-exposed youth, cumulative risk and exposure-adjusted incidences and IRRs were significantly higher than in healthy controls and psychiatric controls. Olanzapine treatment and antipsychotic exposure time were the main modifiable risk factors for T2DM development in antipsychotic-exposed youth. Antipsychotics should be used judiciously and for the shortest necessary duration, and their efficacy and safety should be monitored proactively.
173 citations
TL;DR: A review on the impact of early onset T2DM provides the latest insights into this emerging epidemic with a need for multidisciplinary care of complications and comorbidities, in addition to adequate educational and psychological support.
Abstract: Early onset type 2 diabetes mellitus (T2DM) is increasingly prevalent with a significant impact on the individual, healthcare service delivery and planning. The individuals are likely to be obese, lead a sedentary lifestyle, have a strong family history of T2DM, be of black and minority ethnic (BME) origin and come from a less affluent socioeconomic group. They have a heightened risk of developing microvascular and macrovascular complications, often at an earlier stage and with greater frequency than seen in type 1 diabetes. As such, early and aggressive risk factor management is warranted. Early onset T2DM is complex and impacts on service delivery with a need for multidisciplinary care of complications and comorbidities’, in addition to adequate educational and psychological support. This review on the impact of early onset T2DM provides the latest insights into this emerging epidemic.
159 citations
References
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TL;DR: In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance.
Abstract: Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells - the cells that release insulin - failure to control blood glucose levels results Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention
4,515 citations
"Type 2 Diabetes in Youth: Epidemiol..." refers background in this paper
...The ability of the b-cell to secrete sufficient insulin to adequately respond to the peripheral insulin resistance state depends on multiple factors, including b-cell mass (14) and secretory capacity (14), which are influenced by genetic (15) and environmental factors (15)....
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TL;DR: It is shown that commonly accepted models that attempt to explain the association of insulin resistance and obesity are incompatible with recent findings and an alternative model is proposed that appears to fit these and other available data.
Abstract: It is estimated that by the year 2020 there will be approximately 250 million people affected by type 2 diabetes mellitus worldwide (1). Although the primary factors causing this disease are unknown, it is clear that insulin resistance plays a major role in its development. Evidence for this comes from (a) the presence of insulin resistance 10–20 years before the onset of the disease (2, 3); (b) cross-sectional studies demonstrating that insulin resistance is a consistent finding in patients with type 2 diabetes (3–6); and (c) prospective studies demonstrating that insulin resistance is the best predictor of whether or not an individual will later become diabetic (2, 3). Here, I focus on some recent advances in our understanding of human insulin resistance that have been made using nuclear magnetic resonance spectroscopy (NMR). This technique takes advantage of the spin properties of the nuclei of certain isotopes, such as 1H, 13C, and 31P, which endow the isotopes with a magnetic component that can be used to measure the concentration of intracellular metabolites noninvasively and to assess biochemical differences between normal and diabetic subjects. Drawing on NMR studies from my laboratory and others, I first consider the control of glucose phosphorylation and transport in regulating muscle responses to insulin. I then turn to the effects of fatty acids on insulin responses, showing that commonly accepted models that attempt to explain the association of insulin resistance and obesity are incompatible with recent findings. Finally, I propose an alternative model that appears to fit these and other available data.
2,650 citations
"Type 2 Diabetes in Youth: Epidemiol..." refers background in this paper
...Evidence of this comes from cross-sectional and longitudinal studies demonstrating that insulin resistance occurs 10–20 years before the onset of the disease and that it is the best predictor of whether or not an individual will later become diabetic (22)....
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TL;DR: Eight players comprise the ominous octet and dictate that treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects.
Abstract: Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1 ) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2 ) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3 ) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function.
The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in (17,18). Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by …
2,184 citations
TL;DR: Insulin resistance was greater in the affected cohort and was the best predictor of impaired glucose tolerance and Overt type 2 diabetes was linked to beta-cell failure.
Abstract: Background Childhood obesity, epidemic in the United States, has been accompanied by an increase in the prevalence of type 2 diabetes among children and adolescents. We determined the prevalence of impaired glucose tolerance in a multiethnic cohort of 167 obese children and adolescents. Methods All subjects underwent a two-hour oral glucose-tolerance test (1.75 mg of glucose per kilogram of body weight), and glucose, insulin, and C-peptide levels were measured. Fasting levels of proinsulin were obtained, and the ratio of proinsulin to insulin was calculated. Insulin resistance was estimated by homeostatic model assessment, and beta-cell function was estimated by calculating the ratio between the changes in the insulin level and the glucose level during the first 30 minutes after the ingestion of glucose. Results Impaired glucose tolerance was detected in 25 percent of the 55 obese children (4 to 10 years of age) and 21 percent of the 112 obese adolescents (11 to 18 years of age); silent type 2 diabetes wa...
1,784 citations
"Type 2 Diabetes in Youth: Epidemiol..." refers background in this paper
...In particular, 25% of children and 21% adolescents with severe degree of obesity, irrespective of ethnicity, were found to have IGT (10)....
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TL;DR: It is not clear whether NAFLD causes metabolic dysfunction or whether metabolic dysfunction is responsible for IHTG accumulation, or possibly both, but it is likely that abnormalities in fatty acid metabolism are key factors involved in the development of insulin resistance, dyslipidemia, and other cardiometabolic risk factors associated withNAFLD.
1,668 citations
"Type 2 Diabetes in Youth: Epidemiol..." refers background in this paper
...Although it remains unclear whether hepatic steatosis is a consequence or a cause of derangements in insulin sensitivity, the presence of steatosis is an important marker of multiorgan insulin resistance (29); moreover, insulin resistance is directly related to percent liver fat (29)....
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