Leryn J. Reynolds

Acute inactivity impairs glycemic control but not blood flow to glucose ingestion.

PURPOSE Insulin-stimulated increases in skeletal muscle blood flow play a role in glucose disposal. Indeed, 7 d of aerobic exercise in patients with Type 2 diabetes increased blood flow responses to an oral glucose tolerance test (OGTT) and improved insulin sensitivity. More recent work suggests that reduced daily physical activity impairs glycemic control (GC) in healthy individuals. Herein, we sought to determine whether an acute reduction in daily activity (from >10,000 to <5000 steps per day) for 5 d (RA5) in healthy individuals reduced insulin-stimulated blood flow and GC in parallel and if a 1-d return to activity (RTA1) improved these outcomes. METHODS OGTT were performed as a stimulus to increase insulin in 14 healthy, recreationally active men (24 ± 1.1 yr) at baseline, RA5, and RTA1. Measures of insulin sensitivity (Matsuda index) and femoral and brachial artery blood flow were made during the OGTT. Free-living measures of GC including peak postprandial glucose (peak PPG) were also made via continuous glucose monitoring. RESULTS Femoral and brachial artery blood flow increased during the OGTT but neither was significantly impacted by changes in physical activity (P > 0.05). However, insulin sensitivity was decreased by RA5 (11.3 ± 1.5 to 8.0 ± 1.0, P < 0.05). Likewise, free-living GC measures of peak PPG (113 ± 3 to 123 ± 5 mg·dL(-1), P < 0.05) was significantly increased at RA5. Interestingly, insulin sensitivity and GC as assessed by peak PPG were not restored after RTA1 (P > 0.05). CONCLUSIONS Thus, acute reductions in physical activity impaired GC and insulin sensitivity; however, blood flow responses to an OGTT were not affected. Further, a 1-d return to activity was not sufficient to normalize GC after 5 d of reduced daily physical activity.

Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow: role of skeletal muscle NO synthase and endothelin-1

Increased endothelin-1 (ET-1) and reduced endothelial nitric oxide phosphorylation (peNOS) are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), but studies examining these links in humans are limited. We sought to assess basal and insulin-stimulated endothelial signaling proteins (ET-1 and peNOS) in skeletal muscle from T2D patients. Ten obese T2D [glucose disposal rate (GDR): 6.6 ± 1.6 mg·kg lean body mass (LBM)-1·min-1] and 11 lean insulin-sensitive subjects (Lean GDR: 12.9 ± 1.2 mg·kg LBM-1·min-1) underwent a hyperinsulinemic-euglycemic clamp with vastus lateralis biopsies taken before and 60 min into the clamp. Basal biopsies were also taken in 11 medication-naïve, obese, non-T2D subjects. ET-1, peNOS (Ser1177), and eNOS protein and mRNA were measured from skeletal muscle samples containing native microvessels. Femoral artery blood flow was assessed by duplex Doppler ultrasound. Insulin-stimulated blood flow was reduced in obese T2D (Lean: +50.7 ± 6.5% baseline, T2D: +20.8 ± 5.2% baseline, P < 0.05). peNOS/eNOS content was higher in Lean under basal conditions and, although not increased by insulin, remained higher in Lean during the insulin clamp than in obese T2D (P < 0.05). ET-1 mRNA and peptide were 2.25 ± 0.50- and 1.52 ± 0.11-fold higher in obese T2D compared with Lean at baseline, and ET-1 peptide remained 2.02 ± 1.9-fold elevated in obese T2D after insulin infusion (P < 0.05) but did not increase with insulin in either group (P > 0.05). Obese non-T2D subjects tended to also display elevated basal ET-1 (P = 0.06). In summary, higher basal skeletal muscle expression of ET-1 and reduced peNOS/eNOS may contribute to a reduced insulin-stimulated leg blood flow response in obese T2D patients. NEW & NOTEWORTHY Although impairments in endothelial signaling are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), human studies examining these links are limited. We provide the first measures of nitric oxide synthase and endothelin-1 expression from skeletal muscle tissue containing native microvessels in individuals with and without T2D before and during insulin stimulation. Higher basal skeletal muscle expression of endothelin-1 and reduced endothelial nitric oxide phosphorylation (peNOS)/eNOS may contribute to reduced insulin-stimulated blood flow in obese T2D patients.

The influence of reduced insulin sensitivity via short-term reductions in physical activity on cardiac baroreflex sensitivity during acute hyperglycemia

Reduced insulin sensitivity and impaired glycemic control are among the consequences of physical inactivity and have been associated with reduced cardiac baroreflex sensitivity (BRS). However, the effect of reduced insulin sensitivity and acute hyperglycemia following glucose consumption on cardiac BRS in young, healthy subjects has not been well characterized. We hypothesized that a reduction in insulin sensitivity via reductions in physical activity would reduce cardiac BRS at rest and following an oral glucose tolerance test (OGTT). Nine recreationally active men (23 ± 1 yr; >10,000 steps/day) underwent 5 days of reduced daily physical activity (RA5) by refraining from planned exercise and reducing daily steps (<5,000 steps/day). Spontaneous cardiac BRS (sequence technique) was compared at rest and for 120 min following an OGTT at baseline and after RA5. A substudy (n = 8) was also performed to independently investigate the influence of elevated insulin alone on cardiac BRS using a 120-min hyperinsulinemic-euglycemic clamp. Insulin sensitivity (Matsuda index) was significantly reduced following RA5 (BL 9.2 ± 1.3 vs. RA5 6.4 ± 1.1, P < 0.001). Resting cardiac BRS was unaffected by RA5 and significantly reduced during the OGTT similarly at baseline and RA5 (baseline 0 min, 28 ± 4 vs. 120 min, 18 ± 4; RA5 0 min, 28 ± 4 vs. 120 min, 21 ± 3 ms/mmHg). Spontaneous cardiac BRS was also reduced during the hyperinsulinemic-euglycemic clamp (P < 0.05). Collectively, these data demonstrate that acute elevations in plasma glucose and insulin can impair spontaneous cardiac BRS in young, healthy subjects, and that reductions in cardiac BRS following acute hyperglycemia are unaffected by reduced insulin sensitivity via short-term reductions in physical activity.

A pilot study examining the effects of consuming a high-protein vs normal-protein breakfast on free-living glycemic control in overweight/obese ‘breakfast skipping’ adolescents

To examine whether the daily consumption of normal-protein (NP) vs higher-protein (HP) breakfasts improve free-living glycemic control in overweight/obese, ‘breakfast skipping’ adolescents. Twenty-eight healthy, but overweight, teens (age: 19±1 year; BMI: 29.9±0.8 kg m−2) completed a 12-week randomized parallel-arm study in which the adolescents consumed either a 350 kcal NP breakfast (13 g protein) or HP breakfast (35 g protein). Pre- and post-study 24-h blood glucose measures were assessed using continuous glucose monitoring. Although no main effects of time or group were detected, time by group interactions were observed. Post hoc pairwise comparisons assessing the post–pre changes revealed that the daily consumption of the HP breakfasts tended to reduce the 24-h glucose variability (s.d.) vs NP (−0.17±0.09 vs +0.09±0.10 s.d.; P=0.06) and tended to reduce the time spent above the high glucose limit (−292±118 vs −24±80 min; P=0.09). The consumption of the HP breakfasts also reduced the 24-h maximal (peak) glucose response (−0.94±0.36 vs +0.30±0.18 mmol l−1; P<0.01) and reduced postprandial glucose fluctuations (−0.88±0.44 vs +0.49±0.34 mmol l−1; P<0.03) vs NP. These data suggest that the daily addition of a HP breakfast, containing 35 g of high-quality protein, has better efficacy at improving free-living glycemic control compared with a NP breakfast in overweight/obese, but otherwise healthy, ‘breakfast skipping’ adolescents.

Developmental Origins of Health Span and Life Span: A Mini-Review

Background: A vast body of research has demonstrated that disease susceptibility and offspring health can be influenced by perinatal factors, which include both paternal and maternal behavior and environment. Offspring disease risk has the potential to affect the health span and life span of offspring. Key Findings: Various maternal factors, such as environmental toxicant exposure, diet, stress, exercise, age at conception, and longevity have the potential to influence age-associated diseases such as cardiovascular disease, obesity, diabetes, and cancer risk in offspring. Paternal factors such as diet, age at conception, and longevity can potentially impact offspring health span and life span-reducing traits as well. Practical Implications: Continued research could go a long way toward defining mechanisms of the developmental origins of life span and health span, and eventually establishing regimens to avoid negative developmental influences and to encourage positive interventions to potentially increase life span and improve health span in offspring.

Influence of physical inactivity on arterial compliance during a glucose challenge

What is the central question of this study? To understand better the effects of acute hyperglycaemia on arterial stiffness in healthy young individuals, we assessed arterial stiffness in physically active men before and after reduced ambulatory physical activity to decrease insulin sensitivity. What is the main finding and its importance? During an oral glucose tolerance test, we identified an increase in leg arterial stiffness (i.e. reduced femoral artery compliance) only when subjects were inactive for 5 days (<5000 steps day−1) and not when they were engaging in regular physical activity (>10,000 steps day−1). These results demonstrate the deleterious consequence of acute reductions in daily physical activity on the response of the peripheral vasculature to acute hyperglycaemia.

Using neonatal skin to study the developmental programming of aging

&NA; Numerous studies have examined how both negative and positive maternal exposures (environmental contaminants, nutrition, exercise, etc.) impact offspring risk for age‐associated diseases such as obesity, type 2 diabetes, hypertension, and others. The purpose of this study was to introduce the foreskin as a novel model to examine developmental programming in human neonates, particularly in regard to adipogenesis and insulin receptor signaling, major contributors to age‐associated diseases such as obesity and diabetes. Neonatal foreskin was collected following circumcision and primary dermal fibroblasts were isolated to perform adipocyte differentiation and insulin stimulation experiments. Human neonatal foreskin primary fibroblasts take up lipid when stimulated with a differentiation cocktail and demonstrate insulin signaling when stimulated with insulin. Thus, we propose that foreskin tissue can be used to study developmental exposures and programming that occur in the neonate as it relates to age‐associated diseases such as obesity and diabetes. HighlightsForeskin primary fibroblasts accumulate lipid in response to an adipogenic cocktail.Insulin stimulation increases insulin signaling in foreskin primary fibroblasts.Foreskin is a useful tissue to study the developmental programming of aging.

Increased birth weight is associated with altered gene expression in neonatal foreskin

Elevated birth weight is linked to glucose intolerance and obesity health-related complications later in life. No studies have examined if infant birth weight is associated with gene expression markers of obesity and inflammation in a tissue that comes directly from the infant following birth. We evaluated the association between birth weight and gene expression on fetal programming of obesity. Foreskin samples were collected following circumcision, and gene expression analyzed comparing the 15% greatest birth weight infants (n=7) v. the remainder of the cohort (n=40). Multivariate linear regression models were fit to relate expression levels on differentially expressed genes to birth weight group with adjustment for variables selected from a list of maternal and infant characteristics. Glucose transporter type 4 (GLUT4), insulin receptor substrate 2 (IRS2), leptin receptor (LEPR), lipoprotein lipase (LPL), low-density lipoprotein receptor-related protein 1 (LRP1), matrix metalloproteinase 2 (MMP2), plasminogen activator inhibitor-1 (PAI-1) and transcription factor 7-like 2 (TCF7L2) were significantly upregulated and histone deacetylase 1 (HDAC1) and thioredoxin (TXN) downregulated in the larger birth weight neonates v. CONTROLS Multivariate modeling revealed that the estimated adjusted birth weight group difference exceeded one standard deviation of the expression level for eight of the 10 genes. Between 25 and 50% of variation in expression level was explained by multivariate modeling for eight of the 10 genes. Gene expression related to glycemic control, appetite/energy balance, obesity and inflammation were altered in tissue from babies with elevated birth weight, and these genes may provide important information regarding fetal programming in macrosomic babies.