The severity and frequency of childhood obesity has increased significantly over the past three to four decades. The health effects of increased body mass index as a child may significantly impact obese youth as they age. However, many of the long-term outcomes of childhood obesity have yet to be studied. This article examines the currently available longitudinal data evaluating the effects of childhood obesity on adult outcomes. Consequences of obesity include an increased risk of developing the metabolic syndrome, cardiovascular disease, type 2 diabetes and its associated retinal and renal complications, nonalcoholic fatty liver disease, obstructive sleep apnea, polycystic ovarian syndrome, infertility, asthma, orthopedic complications, psychiatric disease, and increased rates of cancer, among others. These disorders can start as early as childhood, and such early onset increases the likelihood of early morbidity and mortality. Being obese as a child also increases the likelihood of being obese as an adult, and obesity in adulthood also leads to obesity-related complications. This review outlines the evidence for childhood obesity as a predictor of adult obesity and obesity-related disorders, thereby emphasizing the importance of early intervention to prevent the onset of obesity in childhood.

Whether asymptomatic hyperuricemia in the absence of comorbidities increases the risk for cardiometabolic disorders and chronic kidney disease remains controversial. This study was conducted to clarify the association between asymptomatic hyperuricemia and cardiometabolic conditions. Subjects consisted of Japanese adults between 30 and 85 years of age were enrolled in the study at Center for Preventive Medicine, St. Luke's International Hospital, Tokyo, and available at enrollment (2004) and at 5-year follow-up (2009). Subjects were excluded if they were overweight or obese, hypertensive, diabetic, dyslipidemic, had a history of gout or hyperuricemia on medications, or if they had chronic kidney disease as estimated glomerular filtration rate <60 ml/min/1.73m2. Linear and logistic regression analyses were used to examine the relationship between hyperuricemia and development of hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, and overweight/obesity (unadjusted and adjusted for age, sex, smoking, drinking habits, baseline estimated glomerular filtration rate and body mass index). 5,899 subjects without comorbidities (mean age of 47 ± 10 years, 1,864 men) were followed for 5 years. Hyperuricemia (defined as >7 mg/dL in men and ≥6 mg/dL in women) was associated with increased cumulative incidence rates of hypertension (14.9% vs 6.1%, p<0.001), dyslipidemia (23.1% vs 15.5%, p<0.001), chronic kidney disease (19.0% vs 10.7%, p<0.001), and overweight/obesity (8.9% vs 3.0%, p<0.001), while diabetes mellitus (1.7% vs 0.9%, p=0.087) showed a trend but did not reach statistical significance. In conclusion, asymptomatic hyperuricemia carries a significant risk for developing cardiometabolic conditions in Japanese individual without comorbidities.

Background: Cardiovascular disease (CVD) is the leading cause of mortality in type 1 diabetes (T1D) and relates strongly to insulin resistance (IR). Lean and obese T1D adolescents have marked IR. Metformin improves surrogate markers of IR in T1D, but its effect on directly-measured IR and vascular health in T1D youth is unclear. We hypothesized that 1) T1D adolescents have impaired vascular function, and 2) metformin improves this IR and vascular dysfunction. Methods: T1D adolescents and controls underwent MRI of the ascending (AA) and descending aorta (DA) to assess pulse wave velocity (PWV), relative area change (RAC), maximal (WSSMAX) and time-averaged wall shear stress (WSSTA). T1D participants also underwent assessment of carotid intima-media thickness (cIMT) by ultrasound, brachial distensibility (BrachD) by DynaPulse, fat and lean mass by DXA, fasting labs following overnight glycemic control, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (glucose infusion rate/insulin, [M/I]). T1D adolescents were randomized 1:1 to 3 months of 2000 mg metformin or placebo daily, after which baseline measures were repeated. Results: Forty-eight T1D adolescents ages 12–21 years (40% BMI ≥ 90th%ile; 56% female) and twenty-four nondiabetic controls of similar age, BMI and sex distribution were enrolled. T1D adolescents demonstrated impaired aortic health vs. controls, including elevated AA and DA PWV, reduced AA and DA RAC and elevated AA and DA WSSMAX and WSSTA. T1D adolescents in the metformin vs. placebo group had improved M/I (12.2±3.2 vs. −2.4±3.6 [mg/kg/min]/uIU/uL, p=0.005; 18.6±4.8 vs. −3.4±5.6 [mg/lean kg/min]/uIU/uL, p=0.005) and reduced weight (−0.5±0.5 vs. 1.6±0.5 kg, p=0.004), BMI (−0.2±0.15 vs. 0.4±0.15 kg/m2, p=0.005) and fat mass (−0.7±0.3 vs. 0.6±0.4 kg, p=0.01). M/I also improved in normal-weight participants (11.8±4.4 vs. −4.5±4.4 [mg/kg/min]/uIU/uL, p=0.02, 17.6±6.7 vs. −7.0±6.7 [mg/lean kg/min]/uIU/uL, p=0.02). The metformin group had reduced AA WSSMAX (−0.3±0.4 vs. 1.5±0.5 dyne/cm2, p=0.03), AA PWV, (−1.1±1.20 vs. 4.1±1.6 m/s, p=0.04) and far-wall diastolic cIMT (−0.04±0.01 vs. −0.00±0.01 mm, p=0.049) vs. placebo. Conclusions: T1D adolescents demonstrate IR and impaired vascular health vs. controls. Metformin improves IR, regardless of baseline BMI, and BMI, weight, fat mass, insulin dose, aortic and carotid health in T1D adolescents. Metformin may hold promise as a cardioprotective intervention in T1D.

No abstract

Prehypertension frequently progresses to hypertension, a condition associated with high morbidity and mortality from cardiovascular diseases and stroke. However, the risk factors for developing hypertension from prehypertension remain poorly understood. We conducted a retrospective cohort study using the data from 3584 prehypertensive Japanese adults (52.1±11.0 years, 2081 men) found to be prehypertensive in 2004 and reexamined in 2009. We calculated the cumulative incidences of hypertension over 5 years, examined risk factors, and calculated odds ratios (ORs) for developing hypertension after adjustments for age, sex, body mass index, smoking and drinking habits, baseline systolic and diastolic blood pressure, pulse rate, diabetes mellitus, dyslipidemia, chronic kidney disease, and serum uric acid levels. The additional analysis evaluated whether serum uric acid (hyperuricemia) constituted an independent risk factor for developing hypertension. The cumulative incidence of hypertension from prehypertension over 5 years was 25.3%. There were no significant differences between women and men (24.4% versus 26.0%; =0.28). The cumulative incidence of hypertension in subjects with hyperuricemia (n=726) was significantly higher than those without hyperuricemia (n=2858; 30.7% versus 24.0%;<0.001). After multivariable adjustments, the risk factors for developing hypertension from prehypertension were age (OR, 1.023; <0.001), female sex (OR, 1.595; <0.001), higher body mass index (OR, 1.051; <0.001), higher baseline systolic (OR, 1.072; <0.001) and diastolic blood pressure (OR, 1.085; <0.001), and higher serum uric acid (OR, 1.149; <0.001). Increased serum uric acid is a strong risk marker for developing hypertension from prehypertension. Further studies are needed to determine whether treatment of hyperuricemia in prehypertensive subjects could impede the onset of hypertension.

Asymptomatic hyperuricemia affects approximately 20 percent of the general population in the USA, with variable rates in other countries. Historically asymptomatic hyperuricemia was considered a benign laboratory abnormality with little clinical significance in the absence of gout or kidney stones. Yet, there is increasing evidence that asymptomatic hyperuricemia can predict the development of hypertension, obesity, diabetes mellitus and chronic kidney disease. One potential mechanism by which asymptomatic hyperuricemia may contribute to disease is by stimulating inflammation. While urate has been classically viewed as an anti-oxidant with beneficial effects, more recent studies suggest both crystalline and soluble urate may activate various inflammatory pathways. Herein we review the role of urate in the inflammatory response. Further research is needed to define the role of asymptomatic hyperuricemia in these proinflammatory pathways.

Despite current established therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide. Novel therapeutic targets are therefore needed to improve the prognosis of patients with HF. The EMPA-REG OUTCOME trial demonstrated significant reductions in mortality and HF hospitalization risk in patients with type 2 diabetes (T2D) and cardiovascular disease with the antihyperglycemic agent, empagliflozin – a sodium glucose co-transporter 2 (SGLT2) inhibitor. The CANVAS trial subsequently reported a reduction in 3-point MACE (major adverse cardiovascular events) and HF hospitalization risk. While SGLT2 inhibition may have potential application beyond T2D, including HF, the mechanisms responsible for the cardioprotective effects of SGLT2 inhibitors remain incompletely understood. SGLT2 inhibition promotes natriuresis and osmotic diuresis, leading to plasma volume contraction and reduced preload, as well as decreases in blood pressure, arterial stiffness and afterload, thereby improving subendocardial blood flow in patients with HF. SGLT2 inhibition is also associated with preservation of renal function. Based on data from mechanistic studies and clinical trials, large clinical trials with SGLT2 inhibitors are now investigating the potential use of SGLT2 inhibition in patients with HF with and without T2D. Accordingly, in this review, we summarize key pharmacodynamic effects of SGLT2 inhibitors and the clinical evidence which support the rationale for the use of SGLT2 inhibitors in HF patients with T2D. Since presumably these favorable effects occur independent of blood-glucose lowering, we also explore the potential use of SGLT2 inhibition in patients without T2D with HF or at risk of HF, such as in patients with coronary artery disease or hypertension. Finally, we provide a detailed overview and summary of ongoing cardiovascular outcome trials with SGLT2 inhibitors.

Clinical studies have reported associations between serum uric acid levels and the development of diabetic nephropathy, but the underlying mechanisms remain elusive. There is evidence from animal studies that blocking uric acid production protects the kidney from tubulointerstitial injury, which may suggest a causal role for uric acid in the development of diabetic tubular injury. In turn, when fructose, which is endogenously produced in diabetes via the polyol pathway, is metabolised, uric acid is generated from a side-chain reaction driven by ATP depletion and purine nucleotide turnover. For this reason, uric acid derived from endogenous fructose could cause tubulointerstitial injury in diabetes. Accordingly, our research group recently demonstrated that blocking fructose metabolism in a diabetic mouse model mitigated the development of tubulointerstitial injury by lowering tubular uric acid production. In this review we discuss the relationship between uric acid and fructose as a novel mechanism for the development of diabetic tubular injury.