background The prevalence and magnitude of childhood obesity are increasing dramatically. We examined the effect of varying degrees of obesity on the prevalence of the metabolic syndrome and its relation to insulin resistance and to C-reactive protein and adiponectin levels in a large, multiethnic, multiracial cohort of children and adolescents. methods We administered a standard glucose-tolerance test to 439 obese, 31 overweight, and 20 nonobese children and adolescents. Baseline measurements included blood pressure and plasma lipid, C-reactive protein, and adiponectin levels. Levels of triglycerides, high-density lipoprotein cholesterol, and blood pressure were adjusted for age and sex. Because the body-mass index varies according to age, we standardized the value for age and sex with the use of conversion to a z score. results The prevalence of the metabolic syndrome increased with the severity of obesity and reached 50 percent in severely obese youngsters. Each half-unit increase in the bodymass index, converted to a z score, was associated with an increase in the risk of the metabolic syndrome among overweight and obese subjects (odds ratio, 1.55; 95 percent confidence interval, 1.16 to 2.08), as was each unit of increase in insulin resistance as assessed with the homeostatic model (odds ratio, 1.12; 95 percent confidence interval, 1.07 to 1.18 for each additional unit of insulin resistance). The prevalence of the metabolic syndrome increased significantly with increasing insulin resistance (P for trend, <0.001) after adjustment for race or ethnic group and the degree of obesity. C-reactive protein levels increased and adiponectin levels decreased with increasing obesity. conclusions The prevalence of the metabolic syndrome is high among obese children and adolescents, and it increases with worsening obesity. Biomarkers of an increased risk of adverse cardiovascular outcomes are already present in these youngsters.

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Obesity and the metabolic syndrome in children and adolescents.

In this contribution we put forward a novel hypothesis concerning the aetiology of Type 2 (non-insulin dependent) diabetes mellitus. The concept underlying our hypothesis is that poor foetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. We propose that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes. In the first section we outline our research which has led to this hypothesis. We will then review the relevant literature. Finally we show that the hypothesis suggests a reinterpretation of some findings and an explanation of others which are at present not easy to understand.

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Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.

OBJECTIVE--To discover whether reduced fetal and infant growth is associated with non-insulin dependent diabetes and impaired glucose tolerance in adult life. DESIGN--Follow up study of men born during 1920-30 whose birth weights and weights at 1 year were known. SETTING--Hertfordshire, England. SUBJECTS--468 men born in east Hertfordshire and still living there. MAIN OUTCOME MEASURES--Fasting plasma glucose, insulin, proinsulin, and 32-33 split pro-insulin concentrations and plasma glucose and insulin concentrations 30 and 120 minutes after a 75 g glucose drink. RESULTS--93 men had impaired glucose tolerance or hitherto undiagnosed diabetes. They had had a lower mean birth weight and a lower weight at 1 year. The proportion of men with impaired glucose tolerance fell progressively from 26% (6/23) among those who had weighted 18 lb (8.16 kg) or less at 1 year to 13% (3/24) among those who had weighed 27 lb (12.25 kg) or more. Corresponding figures for diabetes were 17% (4/23) and nil (0/24). Plasma glucose concentrations at 30 and 120 minutes fell with increasing birth weight and weight at 1 year. Plasma 32-33 split proinsulin concentration fell with increasing weight at 1 year. All these trends were significant and independent of current body mass. Blood pressure was inversely related to birth weight and strongly related to plasma glucose and 32-33 split proinsulin concentrations. CONCLUSIONS--Reduced growth in early life is strongly linked with impaired glucose tolerance and non-insulin dependent diabetes. Reduced early growth is also related to a raised plasma concentration of 32-33 split proinsulin, which is interpreted as a sign of beta cell dysfunction. Reduced intrauterine growth is linked with high blood pressure, which may explain the association between hypertension and impaired glucose tolerance.

https://www.bmj.com/content/bmj/303/6809/1019.full.pdf

Fetal and infant growth and impaired glucose tolerance at age 64.

ContextComplications of atherosclerosis cause most morbidity and mortality
in patients with diabetes mellitus. Despite the frequency and severity of
disease, proven medical therapy remains incompletely understood and underused.ObjectiveTo review the epidemiology, pathophysiology, and medical and invasive
treatment of atherosclerosis in patients with diabetes mellitus.Data SourcesUsing the index terms diabetes mellitus, myocardial infarction, peripheral vascular
diseases, cerebrovascular accident, endothelium, vascular smooth muscle, platelets, thrombosis, cholesterol, hypertension, hyperglycemia, insulin, angioplasty, and coronary artery bypass, we
searched the MEDLINE and EMBASE databases from 1976 to 2001. Additional data
sources included bibliographies of identified articles and preliminary data
presented at recent cardiology conferences.Study SelectionWe selected original investigations and reviews of the epidemiology,
pathophysiology, and therapy of atherosclerosis in diabetes. We selected randomized,
double-blind, controlled studies, when available, to support therapeutic recommendations.
Criteria for data inclusion (168 of 396) included publication in a peer-reviewed
journal or presentation at a national cardiovascular society–sponsored
meeting.Data ExtractionData quality was determined by publication in peer-reviewed literature.
Data extraction was performed by one of the authors.Data SynthesisDiabetes mellitus markedly increases the risk of myocardial infarction,
stroke, amputation, and death. The metabolic abnormalities caused by diabetes
induce vascular dysfunction that predisposes this patient population to atherosclerosis.
Blood pressure control, lipid-lowering therapy, angiotensin-converting enzyme
inhibition, and antiplatelet drugs significantly reduce the risk of cardiovascular
events. Although diabetic patients undergo revascularization procedures because
of acute coronary syndromes or critical limb ischemia, the outcomes are less
favorable than in nondiabetic cohorts.ConclusionsSince most patients with diabetes die from complications of atherosclerosis,
they should receive intensive preventive interventions proven to reduce their
cardiovascular risk.

Diabetes and atherosclerosis: epidemiology, pathophysiology, and management.

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1053/jhep.2003.50161

Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome

The sulphonylurea receptor may be an ATP-sensitive potassium channel.

Poor fetal growth is linked with long-term detrimental effects on health in adulthood. Here we investigate whether the lifespan of male mice is affected by their growth rate when they were suckling and find that limiting growth during that period not only increases longevity but also protects against the life-shortening effect of an obesity-inducing diet later on. By contrast, we find that lifespan is considerably shortened if the postnatal period of growth is accelerated to make up for reduced growth in utero, and that, in addition, these mice are susceptible to the adverse effects on longevity of an obesity-inducing diet after weaning.

Lifespan: catch-up growth and obesity in male mice.

Insulin deficiency in non-insulin-dependent diabetes.

Epidemiological studies have revealed strong inverse relationships between birthweight and the risk of developing type 2 diabetes mellitus (T2DM) and the metabolic syndrome. The mechanistic basis of these relationships remains the subject of research and debate. Evidence for the importance of the fetal environment has been obtained from both human and rodent studies. Studies of monozygotic twins have shown that genetic effects cannot explain these relationships entirely, if at all. Fetal and early postnatal growth restriction produced by feeding a reduced protein diet to rat dams leads to T2DM in old male offspring and, if combined with an obesity-inducing diet after weaning, to all the features of the metabolic syndrome.

https://www.cell.com/trends/endocrinology-metabolism/pdf/S1043-2760(02)00666-5.pdf

Early programming of glucose–insulin metabolism

Restricted fetal growth is associated with increased risk for the future development of Type 2 diabetes in humans. The study aim was to assess the glucose tolerance of old (seventeen months) male rats, which were growth restricted in early life due to maternal protein restriction during gestation and lactation. Rat mothers were fed diets containing either 20% or 8% protein and all offspring weaned onto a standard rat diet. In old-age fasting plasma glucose concentrations were significantly higher in the low protein offspring: 8.4 (1.3)mmol/l v. 5.3 (1.3)mmol/l (p = 0.005), Areas under the curves were increased by 67% for glucose (p = 0.01) and 81% for insulin (p = 0.01) in these rats in intravenous glucose tolerance tests, suggesting (a degree of) insulin resistance. These results show that early growth retardation due to maternal protein restriction leads to the development of diabetes in old male rat offspring. The diabetes is predominantly associated with insulin resistance.

/pdf/diabetes-in-old-male-offspring-of-rat-dams-fed-a-reduced-4o7vcy8qjs.pdf

C. Nicholas Hales

Papers

The sulphonylurea receptor may be an ATP-sensitive potassium channel.

Lifespan: catch-up growth and obesity in male mice.

Insulin deficiency in non-insulin-dependent diabetes.

Early programming of glucose–insulin metabolism

Diabetes in Old Male Offspring of Rat Dams Fed a Reduced Protein Diet