Metabolic inflexibility in youth with obesity: Is it a feature of obesity or distinctive of youth who are metabolically unhealthy?

Individuals with obesity have metabolic inflexibility with diminished fasting fat oxidation and blunted increase in respiratory quotient (RQ) in insulin-stimulated states. However, it is unclear if metabolic inflexibility is a characteristic of obesity per se or is unique to youth who have metabolically unhealthy obesity (MUO) compared with metabolically healthy obesity (MHO). We investigated metabolic flexibility in youth with MUO, MHO and normal weight (NW) and compared their metabolic characteristics. Youth (n = 188) were divided, based on cut-off points for in vivo insulin sensitivity (IS) of adolescents with NW, into 137 with MUO and 51 with MHO. Fasting hepatic IS (HIS) from hepatic glucose production by [6,6-2 H2 ]glucose, adipose tissue IS (ATIS) from whole-body lipolysis by [2 H5 ]glycerol, RQ (indirect calorimetry) during fasting and a hyperinsulinemic (80 mU/m2 /min)-euglycemic clamp were measured. Youth with MUO versus MHO had blunted ΔRQ (p = .035) and lower HIS and ATIS (both p < .0001), while ΔRQ, HIS and ATIS were not different between youth with MHO and NW. In a pair-matched sub-analyses of 30 MUO and 30 MHO the results were similar to the total cohort. Metabolic inflexibility, does not appear to be a feature of obesity per se rather distinctive of youth with MUO, who also have worse HIS and ATIS compared with youth with MHO.

Youth prediabetes and type 2 diabetes: Risk factors and prevalence of dysglycaemia.

BACKGROUND: The American Diabetes Association recommends risk-based screening for dysglycaemia (prediabetes and type 2 diabetes) in youth with overweight/obesity plus ≥1 risk factor. However, evidence for these recommendations is lacking. OBJECTIVES: Examine the association between the number of risk factors and the prevalence of dysglycaemia in youth with overweight/obesity at initial presentation. METHODS: In a paediatric obesity registry, youth (>10 and <20 years old, body mass index ≥85th percentile) were categorized into four groups according to number of risk factors (1, 2, 3 and ≥4). Based on oral glucose tolerance test, participants were classified into normal glucose tolerance or dysglycaemia. RESULTS: Of 635 youth, 31.5% had prediabetes and 6.1% had type 2 diabetes. The prevalence of dysglycaemia was 23.1% with 1 risk factor and increased to 44.9% with ≥4 risk factors (p = 0.025). Dyslipidaemia, family history of type 2 diabetes and maternal history of gestational diabetes were significantly associated with dysglycaemia. Fasting and 2-h insulin, 2-h glucose increased (all p < 0.0001) and ALT increased (p = 0.001) with increasing risk factors. Insulin sensitivity and ß-cell function deteriorated significantly with increasing risk factors. CONCLUSION: Screening for dysglycaemia in youth with obesity and any additional risk factor is warranted to target early management.

ß-cell impairment and clinically meaningful alterations in glycemia in obese youth across the glucose tolerance spectrum.

BACKGROUND/AIMS: In obese youth, it is not clear what degree of ß-cell impairment translates to glucose dysregulation commensurate with shifts from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes. We aimed to investigate the quantitative relationship between ß-cell (clamp-measured disposition index [DI]) and OGTT glucose area under the curve (G-AUC) in obese youth across the spectrum of glucose tolerance. METHODS: Data from 152 youth (58 African-American [AA] and 94 American-White [AW]; 73 NGT, 48 IGT, and 31 type 2 diabetes) who completed a 3-h hyperinsulinemic (80 mu/m2/min)-euglycemic clamp, and a 2-h hyperglycemic (225 mg/dL) clamp synchronized with a 2-h OGTT were examined. RESULTS: In IGT vs. NGT, 36% lower DI corresponded to 27% higher G-AUC; in type 2 diabetes vs. IGT, 65% lower DI related to 25% higher G-AUC, and in type 2 diabetes vs. NGT, 78% lower DI paralleled 59% higher G-AUC. Although AA vs. AW youth had larger decrements in DI, from NGT to IGT and from NGT to type 2 diabetes, they displayed comparable increments in G-AUC. CONCLUSION: At least ~35-50% recovery in ß-cell function might be needed to have clinically meaningful improvement in G-AUC commensurate with conversion to better glucose tolerance. Mechanism(s) protective against dysglycemia might be operative in AA vs. AW youth despite greater declines in DI. Treatments aiming to improve ß-cell function should focus on degree of change in DI commensurate with clinically meaningful changes in glycemia, reflective of restoration of glucose tolerance.

ß-cell function, incretin response, and insulin sensitivity of glucose and fat metabolism in obese youth: Relationship to OGTT-time-to-glucose-peak.

BACKGROUND: In adults, the time-to-glucose-peak at or after 30 minutes during an oral glucose tolerance test (OGTT) identifies physiologically distinct groups with differences in insulin sensitivity, ß-cell function and risk for type 2 diabetes. In obese non-diabetic adolescents, we investigated if the OGTT-time-to-glucose-peak also reflects incretin and free fatty acid (FFA) responses besides insulin sensitivity and ß-cell function, measured by the clamp. METHODS: Obese adolescents (n = 278) were categorized according to their OGTT-time-to-glucose-peak by Early-peak (at 30 minutes) vs Late-peak (>30 minutes) groups. Body composition, visceral adipose tissue, oral disposition index and OGTT-area under the curve (AUC) were examined. A subset of 102 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and ß-cell function relative to insulin sensitivity. RESULTS: Compared with the Early-peak group, the Late-peak group had impaired ß-cell function relative to insulin sensitivity, lower glucose-dependent insulinotropic polypeptide-AUC, and higher FFA-AUC despite higher insulin- and C-peptide-AUC. They also had lower hepatic and peripheral insulin sensitivity despite similar percent body fat and visceral adipose tissue, and had higher prevalence of impaired glucose tolerance (all P < .05). CONCLUSIONS: In obese non-diabetic youth, those with a Late-peak vs an Early-peak glucose during an OGTT showed diminished ß-cell function, blunted incretin secretion, and lower insulin sensitivity of glucose and FFA metabolism. It remains to be determined if Late-peak glucose predicts the future development of type 2 diabetes in these high-risk youth.

HIV-1 elite controllers: an immunovirological review and clinical perspectives.

HIV type 1 (HIV-1) elite controllers (ECs) represent a rare group of individuals with an ability to maintain an undetectable HIV-1 viral load overtime in the absence of previous antiretroviral therapy. The mechanisms associated with this paradigm remain not clearly defined. However, loss of virological control, morbidity and mortality persist in these individuals, such as progress to AIDS-defining conditions together with persistent high rate of immune activation. Further insight into potential therapeutic options is therefore warranted. In this review, we discuss recent data on the type of immune responses understood to be associated with chronic virological control, the potential for disease progression and therapeutic options in ECs.

Delayed sleep phase syndrome and bipolar disorder: Pathogenesis and available common biomarkers.

Circadian rhythm disturbances are common in bipolar affective disorder (BD). Delayed sleep-wake phase syndrome (DSWPD) is the most prevalent circadian rhythm sleep-wake disorder (CRSWDs) and is frequently observed in BD. It is unclear whether DSWPD in BD is an independent process or is a consequence of BD. In this hypothetical review, we discuss the overlap between BD and DSWPD and potential common biomarkers for DSWPD and BD. The review will include a discussion of the genetics of DSWPD and BD. Biomarkers elucidating the pathophysiological processes occurring in these two disorders may offer insight into the etiology and prognosis of both conditions.

Neuroproteomics and microRNAs studies in multiple sclerosis: transforming research and clinical knowledge in biomarker research.

Multiple sclerosis (MS) is a complex disease characterized by extensive phenotypic variability. Biomarkers to capture the different aspects of MS heterogeneity, and to help make a diagnosis and monitor disease progression, while providing insights into etiopathogenesis and response to treatment, are urgently needed. Omics technologies and research efforts with microRNAs have provide unparalleled opportunities for exploring altered protein profiles associated with molecular mechanisms of disease, substantially expanding the list of candidate biomarkers for MS. This review presents evidence from proteomic studies that have focused on identification of biomarkers released in biofluids as a result of the different pathophysiological processes of MS. Also discussed is the emerging role of miRNAs as complementary biomarkers related to cellular processes occurring in MS patients. Also provided is an overview of candidate biomarkers that have been proposed for elucidating pathophysiological processes and disease activity and for guiding clinical diagnosis and/or therapeutic interventions in MS.