Ryan D. Russell

Circulating zonulin levels in newly diagnosed Chinese type 2 diabetes patients

AIMS Studies suggest that type 2 diabetes mellitus is associated with increased gut permeability. Human zonulin is the only physiological mediator discovered to date that is known to regulate gut permeability reversibly by disassembling intestinal tight junctions. However, the relationship between zonulin and type 2 diabetes remains to be defined, and no Chinese population-based data were reported. The aim of this study was to investigate the association between serum zonulin levels and type 2 diabetes in a Chinese Han population. METHODS 143 newly diagnosed type 2 diabetes patients, 124 patients with impaired glucose tolerance and 121 subjects with normal glucose tolerance were enrolled in this study. Serum zonulin was measured by ELISA. RESULTS Patients with type 2 diabetes had higher serum zonulin levels than impaired or normal glucose tolerant subjects. Serum zonulin correlated with body mass index, waist-to-hip ratio, triglyceride, total cholesterol, HDL-C, fasting plasma glucose, 2h plasma glucose, HbA1c, tumor necrosis factor α, interleukin 6, HOMA-IR and QUICK index using correlation analysis (p < 0.05 for all). Multivariate stepwise regression analysis showed that zonulin levels were independently associated with insulin resistance (β = 0.024, p = 0.005). In logistic regression analysis, zonulin levels were an independent predictor of type 2 diabetes (OR = 1.080, p = 0.037). CONCLUSIONS Serum zonulin levels are significantly elevated in newly diagnosed Chinese Type 2 diabetes patients, and are associated with dyslipidemia, inflammation and insulin resistance, indicating a potential role of zonulin in the pathophysiology of type 2 diabetes in Chinese.

Variants of NLRP3 gene are associated with insulin resistance in Chinese Han population with type-2 diabetes

AIMS Nod like receptor pyrin domain containing 3 (NLRP3) is the best characterized member of nod like receptor family. Recent studies suggest that NLRP3 plays a crucial role in the pathogenesis of type-2 diabetes (T2DM), and variants in NLRP3 affect its mRNA stability and expression. Therefore, we hypothesize that the variants in NLRP3 gene may contribute to T2DM susceptibility. The aim of this study is to evaluate the association of NLRP3 SNPs with T2DM in Chinese Han patients. METHODS Two common variants in NLRP3 gene, rs10754558 and rs4612666, were detected using the polymerase chain reaction-restriction fragment length polymorphism procedure in 952 unrelated T2DM patients and 871 healthy controls. All participants were unrelated Chinese Hans. RESULTS The GG genotype and G allele frequencies of rs10754558 were significantly higher in T2DM patients than those in controls (for GG genotype, 19.6% vs. 14.5%, p=0.019; for G allele, 43.9% vs. 39.8%, p=0.013). The GG genotype of rs10754558 was significantly associated with higher LDL-C levels and more prone to insulin resistance, as evaluated by HOMA-IR or QUICK indexes. CONCLUSIONS The variant (rs10754558) in NLRP3 is related to insulin resistance and increased risk of T2DM in Chinese Han population.

Effect of Dietary Fat on Serum and Intramyocellular Lipids and Running Performance

PURPOSE This study evaluated whether lowering IMCL stores via 3-d consumption of very-low-fat (LFAT) diet impairs endurance performance relative to a moderate-fat diet (MFAT), and whether such a diet unfavorably alters lipid profiles. METHODS Twenty-one male and female endurance-trained runners followed a controlled diet and training regimen for 3 d prior to consuming either a LFAT (10% fat) or MFAT (35% fat) isoenergetic diet for another 3 d in random crossover fashion. On day 7, runners followed a glycogen normalization protocol (to equalize glycogen stores) and then underwent performance testing (90-min preload run at 62 +/- 1% VO2max followed by a 10-km time trial) on the morning of day 8. Muscle biopsies obtained from vastus lateralis before and after performance testing were analyzed for IMCL (via electron microscopy) and glycogen content (via enzymatic methodology). RESULTS Despite approximately 30% lower IMCL (0.220 +/- 0.032% LFAT, 0.316 +/- 0.049% MFAT; P = 0.045) and approximately 22% higher muscle glycogen stores at the start of performance testing (P = 0.10), 10-km performance time was not significantly different following the two diet treatments (43.5 +/- 1.4 min LFAT vs 43.7 +/- 1.2 min MFAT). However, LFAT produced less favorable lipid profiles (P < 0.01) by increasing fasting triglycerides (baseline = 84.9 +/- 8.6; LFAT = 118.7 +/- 10.0 mg.dL(-1)) and the total cholesterol:HDL cholesterol ratio (baseline = 3.42 +/- 0.13:1; LFAT = 3.75 +/- 0.20:1), whereas MFAT lowered triglycerides (baseline = 97.5 +/- 12.2; MFAT = 70.9 +/- 7.1 mg.dL(-1)) and the total cholesterol:HDL cholesterol ratio (baseline = 3.47 +/- 0.18:1; MFAT = 3.33 +/- 0.14:1). CONCLUSION The results suggest that reducing IMCL via 3-d consumption of a LFAT diet does not impair running performance lasting a little over 2 h (compared with 3-d consumption of a MFAT diet plus 1-d glycogen normalization), but that even short-term consumption of a LFAT diet may unfavorably alter serum lipids, even in healthy, endurance-trained runners.

Serum zonulin is elevated in women with polycystic ovary syndrome and correlates with insulin resistance and severity of anovulation.

OBJECTIVE Evidence suggests that increased gut permeability may be associated with polycystic ovary syndrome (PCOS). Human zonulin is currently the only physiological mediator known to reversibly regulate gut permeability by disassembling intestinal tight junctions. So far, no data on serum zonulin levels in patients with PCOS are available. This study aimed to determine circulating serum zonulin levels in women with PCOS and discuss the relationship between zonulin, insulin resistance, and menstrual disorders in this group. DESIGN A case-control study. METHODS The study includes 78 women recently diagnosed with PCOS and 63 age-matched healthy controls recruited. Serum zonulin levels were determined by ELISA. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda and DeFronzos insulin sensitivity index (ISI). RESULTS PCOS women had higher serum zonulin levels (P=0.022). After adjustment for age and BMI, zonulin levels significantly correlated with HOMA-IR and ISI. Furthermore, PCOS women with more severe menstrual disorders had significantly higher zonulin levels and displayed an inverse correlation between zonulin and the number of menstrual cycles per year (r=-0.398, P<0.001). CONCLUSIONS Serum zonulin, a biomarker for gut permeability, is increased in PCOS women and correlates with insulin resistance and severity of menstrual disorders. It suggests that alterations in gut permeability may play a role in the pathophysiology of PCOS, and serum zonulin might be used as a biomarker for both risk stratification and therapeutic outcomes in PCOS women.

SHORT BOUTS OF HIGH-INTENSITY RESISTANCE-STYLE TRAINING PRODUCE SIMILAR REDUCTIONS IN FASTING BLOOD GLUCOSE OF DIABETIC OFFSPRING AND CONTROLS

Abstract Russell, RD, Nelson, AG, and Kraemer, RR. Short bouts of high-intensity resistance-style training produce similar reductions in fasting blood glucose of diabetic offspring and controls. J Strength Cond Res 28(10): 2760–2767, 2014—Family history of diabetes (FH) is associated with impaired cardiometabolic function. Aerobic exercise improves insulin sensitivity, though resistance training studies on fasting glucose (FG) in FH are lacking. This study examined the effects of 7 weeks of high-intensity-resistance-focused training (HIRFT), including circuit, core, and plyometric resistance training on FG in FH and matched controls (CON). We hypothesized that HIRFT would reduce FG levels, with greater reductions in CON. Thirty-eight healthy men and women (23.5 ± 2 years; 171 ± 7.4 cm; 71 ± 14 kg) participated in 7 weeks of HIRFT including full-body, plyometric, and core resistance training on alternate days. Fasting glucose was analyzed before and after the 7-week training before and after workouts. One repetition maximum was calculated for bench press, squat, and deadlift before and after training. Body mass index and resting HR remained unchanged. Fasting glucose declined similarly between groups with training (−0.23 ± 0.08 vs. −0.20 ± 0.07 mmol·L−1, p < 0.01 for FH and CON, respectively), whereas strength increased (kg) (bench: 8.0 ± 1.8, squat: 19.4 ± 4.6, deadlift: 16.4 ± 3.6, overall mean percent increase: 38.9 ± 9.2, p < 0.001). Ten-minute postexercise glucose decreased (−0.65 mmol·L−1, p = 0.05) with training, with no differences between groups. Changes in FG and strength increase were inversely correlated (r = −0.519, p = 0.05). Strength increased equally between groups. Data indicate that HIRFT reduces FG concentrations similarly in FH and CON, making it effective for improving FG in FH.

Skeletal Muscle Microvascular-Linked Improvements in Glycemic Control From Resistance Training in Individuals With Type 2 Diabetes

OBJECTIVE Insulin increases glucose disposal in part by enhancing microvascular blood flow (MBF) and substrate delivery to myocytes. Insulin’s microvascular action is impaired with insulin resistance and type 2 diabetes. Resistance training (RT) improves glycemic control and insulin sensitivity, but whether this improvement is linked to augmented skeletal muscle microvascular responses in type 2 diabetes is unknown. RESEARCH DESIGN AND METHODS Seventeen (11 male and 6 female; 52 ± 2 years old) sedentary patients with type 2 diabetes underwent 6 weeks of whole-body RT. Before and after RT, participants who fasted overnight had clinical chemistries measured (lipids, glucose, HbA1c, insulin, and advanced glycation end products) and underwent an oral glucose challenge (OGC) (50 g × 2 h). Forearm muscle MBF was assessed by contrast-enhanced ultrasound, skin MBF by laser Doppler flowmetry, and brachial artery flow by Doppler ultrasound at baseline and 60 min post-OGC. A whole-body DEXA scan before and after RT assessed body composition. RESULTS After RT, muscle MBF response to the OGC increased, while skin microvascular responses were unchanged. These microvascular adaptations were accompanied by improved glycemic control (fasting blood glucose, HbA1c, and glucose area under the curve [AUC] during OGC) and increased lean body mass and reductions in fasting plasma triglyceride, total cholesterol, advanced glycation end products, and total body fat. Changes in muscle MBF response after RT significantly correlated with reductions in fasting blood glucose, HbA1c, and OGC AUC with adjustment for age, sex, % body fat, and % lean mass. CONCLUSIONS RT improves OGC-stimulated muscle MBF and glycemic control concomitantly, suggesting that MBF plays a role in improved glycemic control from RT.

Regulation of microvascular flow and metabolism: an overview

Skeletal muscle is an important site for insulin to regulate blood glucose levels. It is estimated that skeletal muscle is responsible for ~80% of insulin‐mediated glucose disposal in the post‐prandial period. The classical action of insulin to increase muscle glucose uptake involves insulin binding to insulin receptors on myocytes to stimulate glucose transporter 4 (GLUT 4) translocation to the cell surface membrane, enhancing glucose uptake. However, an additional role of insulin that is often under‐appreciated is its action to increase muscle perfusion thereby improving insulin and glucose delivery to myocytes. Either of these responses (myocyte and/or vascular) may be impaired in insulin resistance, and both impairments are apparent in type 2 diabetes, resulting in diminished glucose disposal by muscle. The aim of this review is to report on the growing body of literature suggesting that insulin‐mediated control of skeletal muscle perfusion is an important regulator of muscle glucose uptake and that impairment of microvascular insulin action has important physiological consequences early in the pathogenesis of insulin resistance. This work was discussed at the 2015 Australian Physiological Society Symposium “Physiological mechanisms controlling microvascular flow and muscle metabolism”.

Impairments in Adipose Tissue Microcirculation in Type 2 Diabetes Mellitus Assessed by Real-Time Contrast-Enhanced Ultrasound

Background: In obesity and type 2 diabetes mellitus (T2D), adipose tissue expansion (because of larger adipocytes) results in reduced microvascular density which is thought to lead to adipocyte hypoxia, inflammation, and reduced nutrient delivery to the adipocyte. Adipose tissue microvascular responses in humans with T2D have not been extensively characterized. Furthermore, it has not been determined whether impaired microvascular responses in human adipose tissue are most closely associated with adiposity, inflammation, or altered metabolism. Methods and Results: Overnight-fasted healthy controls (n=24, 9 females/15 males) and people with T2D (n=21, 8 females/13 males) underwent a body composition scan (dual-energy X-ray absorptiometry), an oral glucose challenge (50 g glucose) and blood analysis of clinical chemistries and inflammatory markers. Abdominal subcutaneous adipose tissue microvascular responses were measured by contrast-enhanced ultrasound at baseline and 1-hour post-oral glucose challenge. Adipose tissue microvascular blood volume was significantly elevated in healthy subjects 1-hour post-oral glucose challenge; however, this effect was absent in T2D. Adipose tissue microvascular blood flow was lower in people with T2D at baseline and was significantly blunted post-oral glucose challenge compared with controls. Adipose tissue microvascular blood flow was negatively associated with truncal fat (%), glucoregulatory function, fasting triglyceride and nonesterified fatty acid levels, and positively associated with insulin sensitivity. Truncal fat (%), systolic blood pressure, and insulin sensitivity were the only correlates with microvascular blood volume. Systemic inflammation was not associated with adipose tissue microvascular responses. Conclusions: Impaired microvascular function in adipose tissue during T2D is not conditionally linked to systemic inflammation but is associated with other characteristics of the metabolic syndrome (obesity, insulin resistance, hyperglycemia, and dyslipidemia).

Are the metabolic benefits of resistance training in type 2 diabetes linked to improvements in adipose tissue microvascular blood flow

The microcirculation in adipose tissue is markedly impaired in type 2 diabetes (T2D). Resistance training (RT) often increases muscle mass and promotes a favorable metabolic profile in people with T2D, even in the absence of fat loss. Whether the metabolic benefits of RT in T2D are linked to improvements in adipose tissue microvascular blood flow is unknown. Eighteen sedentary people with T2D (7 women/11 men, 52 ± 7 yr) completed 6 wk of RT. Before and after RT, overnight-fasted participants had blood sampled for clinical chemistries (glucose, insulin, lipids, HbA1c, and proinflammatory markers) and underwent an oral glucose challenge (OGC; 50 g glucose × 2 h) and a DEXA scan to assess body composition. Adipose tissue microvascular blood volume and flow were assessed at rest and 1 h post-OGC using contrast-enhanced ultrasound. RT significantly reduced fasting blood glucose ( P = 0.006), HbA1c ( P = 0.007), 2-h glucose area under the time curve post-OGC ( P = 0.014), and homeostatic model assessment of insulin resistance ( P = 0.005). This was accompanied by a small reduction in total body fat ( P = 0.002), trunk fat ( P = 0.023), and fasting triglyceride levels ( P = 0.029). Lean mass ( P = 0.003), circulating TNF-α ( P = 0.006), and soluble VCAM-1 ( P < 0.001) increased post-RT. There were no significant changes in adipose tissue microvascular blood volume or flow following RT; however those who did have a higher baseline microvascular blood flow post-RT also had lower fasting triglyceride levels ( r = -0.476, P = 0.045). The anthropometric, glycemic, and insulin-sensitizing benefits of 6 wk of RT in people with T2D are not associated with an improvement in adipose tissue microvascular responses; however, there may be an adipose tissue microvascular-linked benefit to fasting triglyceride levels.

Oral glucose challenge impairs skeletal muscle microvascular blood flow in healthy people

Skeletal muscle microvascular (capillary) blood flow increases in the postprandial state or during insulin infusion due to dilation of precapillary arterioles to augment glucose disposal. This effect occurs independently of changes in large artery function. However, acute hyperglycemia impairs vascular function, causes insulin to vasoconstrict precapillary arterioles, and causes muscle insulin resistance in vivo. We hypothesized that acute hyperglycemia impairs postprandial muscle microvascular perfusion, without disrupting normal large artery hemodynamics, in healthy humans. Fifteen healthy people (5 F/10 M) underwent an oral glucose challenge (OGC, 50 g glucose) and a mixed-meal challenge (MMC) on two separate occasions (randomized, crossover design). At 1 h, both challenges produced a comparable increase (6-fold) in plasma insulin levels. However, the OGC produced a 1.5-fold higher increase in blood glucose compared with the MMC 1 h postingestion. Forearm muscle microvascular blood volume and flow (contrast-enhanced ultrasound) were increased during the MMC (1.3- and 1.9-fold from baseline, respectively, P < 0.05 for both) but decreased during the OGC (0.7- and 0.6-fold from baseline, respectively, P < 0.05 for both) despite a similar hyperinsulinemia. Both challenges stimulated brachial artery flow (ultrasound) and heart rate to a similar extent, as well as yielding comparable decreases in diastolic blood pressure and total vascular resistance. Systolic blood pressure and aortic stiffness remained unaltered by either challenge. Independently of large artery hemodynamics, hyperglycemia impairs muscle microvascular blood flow, potentially limiting glucose disposal into skeletal muscle. The OGC reduced microvascular blood flow in muscle peripherally and therefore may underestimate the importance of skeletal muscle in postprandial glucose disposal.