Oral glucose tolerance response curve predicts disposition index but not other cardiometabolic risk factors in healthy adolescents.

OBJECTIVES: In obese adults the shape of the glucose response curve during an oral glucose tolerance test (OGTT) predicts future type 2 diabetes. Patients with an incessant increase or monophasic curves have increased risk compared to those with biphasic curves. Since type 2 diabetes is associated with increased cardiometabolic risk, we studied whether differences in OGTT response curve are associated with differences in cardiometabolic risk factors in healthy adolescents across a wide body mass index (BMI) range. METHODS: Sixty-nine (33F/36M), white adolescents (age: 15.2 ± 1.7 years; BMI: 21.5 ± 4.7 kg/m2; mean ± SD) were studied. Risk factors measured included percent body fat, blood pressure, lipids, augmentation index, reactive hyperemia, endothelin 1, plasminogen activator 1, inflammatory markers (interleukin 6, c-reactive protein), insulin secretion, insulin sensitivity (Matusda index), and disposition index (DI). RESULTS: Thirty-two subjects had biphasic responses; 35 subjects had monophasic responses and two females had incessant increases. Sex did not affect the frequency of responses. Glucose area under the curve during OGTT was greater in those with a mono vs. biphasic curves (p=0.01). Disposition index was markedly lower in subjects with a monophasic curve than in those with a biphasic curve (3.6 [2.3-5.0] vs. 5.8 [3.8-7.6], median [25th, 75th%] p=0.003). Triglyceride to high-density lipoprotein cholesterol (HDL) ratio was higher in subjects with a monophasic curve (p=0.046). CONCLUSIONS: The decreased disposition index indicates that in healthy adolescents a monophasic response to OGTT is due to decreased insulin secretion relative to the degree of insulin resistance present. This was not associated with differences in most other cardiometabolic risk markers. TRIAL REGISTRATION: Clinical Trials.gov, NCT02821104.

Relationships of complement components C3 and C4 and their genetics to cardiometabolic risk in healthy, non-Hispanic white adolescents.

BACKGROUND: Complement promotes inflammatory and immune responses and may affect cardiometabolic risk. This study was designed to investigate the effect of complement components C3 and C4 on cardiometabolic risk in healthy non-Hispanic white adolescents. METHODS: Body mass index (BMI), BMI percentile, waist circumference, and percent body fat were assessed in 75 adolescents. Arterial stiffness was assessed using arterial tomography and endothelial function using reactive hyperemia. Fasting lipids, inflammatory markers, and complement levels were measured and oral glucose tolerance test was performed. A single C3 polymorphism and C4 gene copy number variations were assessed. RESULTS: C3 plasma levels increased with measures of obesity. Endothelial function worsened with increased C3 and C4 levels. Triglycerides and low-density lipoprotein increased and high-density lipoprotein (HDL) and insulin sensitivity decreased with increasing C3 levels, but the relationships were lost when body habitus was included in the model. C4 negatively related to HDL and positively to inflammatory markers. Subjects with at least one C3F allele had increased BMI and fat mass index. HDL was significantly related to C4L, C4S, C4A, and C4B gene copy number variation. CONCLUSIONS: C3 levels increase with increasing body mass and increased C4 levels and copy number are associated with increased cardiometabolic risk in healthy adolescents.

Increased body fat and reduced insulin sensitivity are associated with impaired endothelial function and subendocardial viability in healthy, non-Hispanic white adolescents.

BACKGROUND: Cardiovascular disease has its origins in adolescents. Endothelial dysfunction, arterial stiffness, and decreased endocardial oxygen supply: demand ratios are early functional markers of cardiovascular risk. The goal of this study was to determine the relationships of these markers to physical, inflammatory, and metabolic markers in healthy non-Hispanic, white adolescents. METHODS: Thirty-four of the 75 subjects were female. Mean age was 15.0 ± 1.7 years and mean body mass index (BMI) was 22.0 ± 5.8 kg/m2 (mean ± SD). Reactive hyperemia was measured using venous occlusion plethysmography. Arterial tonometry was used to measure the augmentation index (AIx75 ) and the Buckberg subendocardial viability ratio. Blood samples were taken to measure inflammatory and lipid markers and oral glucose tolerance test was used to assess insulin sensitivity. RESULTS: Reactive hyperemia decreased as body mass and fat mass increased. It also decreased with increasing neutrophil count. The Buckberg index was higher in males and was positively related to insulin sensitivity even when accounting for age, sex, and resting heart rate. AIx75 was not related to any of the other variables. CONCLUSIONS: These results demonstrate that increased fat mass and decreased insulin sensitivity are related to poorer vascular function and cardiac risk in adolescents before the development of actual cardiovascular disease.

Complement Components, C3 and C4, and the Metabolic Syndrome.

INTRODUCTION: Increased systemic inflammation plays a significant role in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis, and hypertension. The complement system is a part of the innate immune system and plays a key role in the regulation of inflammation. Of particular importance is the activation of complement components C3 and C4. C3 is produced primarily by the liver but is also produced in adipocytes, macrophages and endothelial cells, all of which are present in adipose tissues. Dietary fat and chylomicrons stimulate C3 production. Adipocytes in addition to producing C3 also have receptors for activated C3 and other complement components and thus also respond to as well as produce a target for complement. C3adesArg, also known as acylation stimulation factor, increases adipocyte triglyceride synthesis and release. These physiological effects play a significant role in the development of metabolic syndrome. Epidemiologically, obese adults and non-obese adults with cardiometabolic disease who are not obese have been shown to have increased complement levels. C4 levels also correlate with body mass index. Genetically, specific C3 polymorphisms have been shown to predict future cardiovascular events and. D decreased C4 long gene copy number is associated with increased longevity. CONCLUSION: Future research is clearly needed to clarify the role of complement in the development of cardiovascular disease and mechanisms for its action. The complement system may provide a new area for intervention in the prevention of cardiometabolic diseases.

Type 1 diabetes: where are we in 2017?

Type 1 diabetes mellitus is a chronic state of insulin deficiency which results from destruction of beta cells by the immune system. The long term microvascular and macrovascular complications can be devastating. Since the discovery of insulin almost 100 years ago new medical therapies have improved the long-term survival for people with type 1 diabetes. Each year we come closer to discovering a cure but much work still needs to be done to eliminate this disease.