Hemodynamics and Arterial Stiffness in Response to Oral Glucose Loading in Individuals with Type II Diabetes and Controlled Hypertension.

INTRODUCTION: Type 2 diabetes (T2D), the fastest growing pandemic, is typically accompanied by vascular complications. A central hallmark of both T2D and vascular disease is insulin resistance which causes impaired glucose transport and vasoconstriction concomitantly. Those with cardiometabolic disease display greater variation in central hemodynamics and arterial elasticity, both potent predictors of cardiovascular morbidity and mortality, which may be exacerbated by concomitant hyperglycemia and hyperinsulinemia during glucose testing. Thus, elucidating central and arterial responses to glucose testing in those with T2D may identify acute vascular pathophysiologies triggered by oral glucose loading. AIM: This study compared hemodynamics and arterial stiffness to an oral glucose challenge (OGC: 50g glucose) between individuals with and without T2D. 21 healthy (48 ± 10 years) and 20 participants with clinically diagnosed T2D and controlled hypertension (52 ± 8 years) were tested. METHODS: Hemodynamics and arterial compliance were assessed at baseline, and 10, 20, 30, 40, 50, and 60 min post-OGC. RESULTS: Heart rate increased between 20 and 60 post-OGC in both groups (p < 0.05). Central systolic blood pressure (SBP) decreased in the T2D group between 10 and 50 min post-OGC while central diastolic blood pressure (DBP) decreased in both groups from 20 to 60 post-OGC. Central SBP decreased in T2D between 10 and 50 min post-OGC and central DBP decreased in both groups between 20 and 60 min post-OGC. Brachial SBP decreased between 10 and 50 min in healthy participants, whereas both groups displayed decreases in brachial DBP between 20 and 60 min post-OGC. Arterial stiffness was unaffected. CONCLUSIONS: An OGC alters central and peripheral blood pressure in healthy and T2D participants similarly with no changes in arterial stiffness.

Impaired postprandial adipose tissue microvascular blood flow responses to a mixed-nutrient meal in first-degree relatives of adults with type 2 diabetes.

Adipose tissue microvascular blood flow (MBF) is stimulated postprandially to augment delivery of nutrients and hormones to adipocytes. Adipose tissue MBF is impaired in type 2 diabetes (T2D). Whether healthy individuals at-risk of T2D show similar impairments is unknown. We aimed to determine whether adipose tissue MBF is impaired in apparently healthy individuals with a family history of T2D. Overnight-fasted individuals with no family history of T2D for two generations (FH-, n = 13), with at least one parent with T2D (FH+, n = 14) and clinically diagnosed T2D (n = 11) underwent a mixed meal challenge (MMC). Metabolic responses [blood glucose, plasma insulin, plasma nonesterified fatty acids (NEFAs), and fat oxidation] were measured before and during the MMC. MBF in truncal subcutaneous adipose tissue was assessed by contrast ultrasound while fasting and 60 min post-MMC. FH+ had normal blood glucoses, increased adiposity, and impaired post-MMC adipose tissue MBF (Δ0.70 ± 0.22 vs. 2.45 ± 0.60 acoustic intensity/s, P = 0.007) and post-MMC adipose tissue insulin resistance (Adipo-IR index; Δ45.5 ± 13.9 vs. 7.8 ± 5.1 mmol/L × pmol/L, P = 0.007) compared with FH-. FH+ and T2D had an impaired ability to suppress fat oxidation post-MMC. Fat oxidation incremental area under the curve (iAUC) (35-55 min post-MMC, iAUC) was higher in FH+ and T2D than in FH- (P = 0.005 and 0.009, respectively). Postprandial MBF was negatively associated with postprandial fat oxidation iAUC (P = 0.01). We conclude that apparently healthy FH+ individuals display blunted postprandial adipose tissue MBF that occurs in parallel with adipose tissue insulin resistance and impaired suppression of fat oxidation, which may help explain their heightened risk for developing T2D.NEW & NOTEWORTHY Adipose tissue blood flow plays a key role in postprandial nutrient storage. People at-risk of type 2 diabetes have impaired postmeal adipose tissue blood flow. Impaired adipose tissue blood flow is associated with altered fat oxidation. Risk of type 2 diabetes may be elevated by poor adipose tissue blood flow.

Impaired postprandial skeletal muscle vascular responses to a mixed meal challenge in normoglycaemic people with a parent with type 2 diabetes.

AIMS/HYPOTHESIS: Microvascular blood flow (MBF) increases in skeletal muscle postprandially to aid in glucose delivery and uptake in muscle. This vascular action is impaired in individuals who are obese or have type 2 diabetes. Whether MBF is impaired in normoglycaemic people at risk of type 2 diabetes is unknown. We aimed to determine whether apparently healthy people at risk of type 2 diabetes display impaired skeletal muscle microvascular responses to a mixed-nutrient meal. METHODS: In this cross-sectional study, participants with no family history of type 2 diabetes (FH-) for two generations (n = 18), participants with a positive family history of type 2 diabetes (FH+; i.e. a parent with type 2 diabetes; n = 16) and those with type 2 diabetes (n = 12) underwent a mixed meal challenge (MMC). Metabolic responses (blood glucose, plasma insulin and indirect calorimetry) were measured before and during the MMC. Skeletal muscle large artery haemodynamics (2D and Doppler ultrasound, and Mobil-O-graph) and microvascular responses (contrast-enhanced ultrasound) were measured at baseline and 1 h post MMC. RESULTS: Despite normal blood glucose concentrations, FH+ individuals displayed impaired metabolic flexibility (reduced ability to switch from fat to carbohydrate oxidation vs FH-; p < 0.05) during the MMC. The MMC increased forearm muscle microvascular blood volume in both the FH- (1.3-fold, p < 0.01) and FH+ (1.3-fold, p < 0.05) groups but not in participants with type 2 diabetes. However, the MMC increased MBF (1.9-fold, p < 0.01), brachial artery diameter (1.1-fold, p < 0.01) and brachial artery blood flow (1.7-fold, p < 0.001) and reduced vascular resistance (0.7-fold, p < 0.001) only in FH- participants, with these changes being absent in FH+ and type 2 diabetes. Participants with type 2 diabetes displayed significantly higher vascular stiffness (p < 0.001) compared with those in the FH- and FH+ groups; however, vascular stiffness did not change during the MMC in any participant group. CONCLUSIONS/INTERPRETATION: Normoglycaemic FH+ participants display impaired postprandial skeletal muscle macro- and microvascular responses, suggesting that poor vascular responses to a meal may contribute to their increased risk of type 2 diabetes. We conclude that vascular insulin resistance may be an early precursor to type 2 diabetes in humans, which can be revealed using an MMC.

Liver alanine catabolism promotes skeletal muscle atrophy and hyperglycaemia in type 2 diabetes.

Both obesity and sarcopenia are frequently associated in ageing, and together may promote the progression of related conditions such as diabetes and frailty. However, little is known about the pathophysiological mechanisms underpinning this association. Here we show that systemic alanine metabolism is linked to glycaemic control. We find that expression of alanine aminotransferases is increased in the liver in mice with obesity and diabetes, as well as in humans with type 2 diabetes. Hepatocyte-selective silencing of both alanine aminotransferase enzymes in mice with obesity and diabetes retards hyperglycaemia and reverses skeletal muscle atrophy through restoration of skeletal muscle protein synthesis. Mechanistically, liver alanine catabolism driven by chronic glucocorticoid and glucagon signalling promotes hyperglycaemia and skeletal muscle wasting. We further provide evidence for amino acid-induced metabolic cross-talk between the liver and skeletal muscle in ex vivo experiments. Taken together, we reveal a metabolic inter-tissue cross-talk that links skeletal muscle atrophy and hyperglycaemia in type 2 diabetes.

Postprandial microvascular blood flow in skeletal muscle: Similarities and disparities to the hyperinsulinaemic-euglycaemic clamp.

Skeletal muscle contributes to ~40% of total body mass and has numerous important mechanical and metabolic roles in the body. Skeletal muscle is a major site for glucose disposal following a meal. Consequently, skeletal muscle plays an important role in postprandial blood glucose homeostasis. Over the past number of decades, research has demonstrated that insulin has an important role in vasodilating the vasculature in skeletal muscle in response to an insulin infusion (hyperinsulinaemic-euglycaemic clamp) or following the ingestion of a meal. This vascular action of insulin is pivotal for glucose disposal in skeletal muscle, as insulin-stimulated vasodilation increases the delivery of both glucose and insulin to the myocyte. Notably, in insulin-resistant states such as obesity and type 2 diabetes, this vascular response of insulin in skeletal muscle is significantly impaired. Whereas the majority of work in this field has focussed on the action of insulin alone on skeletal muscle microvascular blood flow and myocyte glucose metabolism, there is less understanding of how the consumption of a meal may affect skeletal muscle blood flow. This is in part due to complex variations in glucose and insulin dynamics that occurs postprandially-with changes in humoral concentrations of glucose, insulin, amino acids, gut and pancreatic peptides-compared to the hyperinsulinaemic-euglycaemic clamp. This review will address the emerging body of evidence to suggest that postprandial blood flow responses in skeletal muscle may be a function of the nutritional composition of a meal.

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.

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).

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".

Short bouts of high-intensity resistance-style training produce similar reductions in fasting blood glucose of diabetic offspring and controls.

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, 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, 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.

Metabolic dysfunction in diabetic offspring: deviations in metabolic flexibility.

UNLABELLED: In type 2 diabetes (T2D), insulin resistance is related to comorbidities, including high lipotoxicity, poor glucoregulation, and loss of metabolic flexibility. Controversy exists regarding whether reduced metabolic flexibility precedes insulin resistance or vice versa. PURPOSE: The purpose of this study was to determine whether a family history of T2D leads to metabolic inflexibility. METHODS: To examine potential loss of metabolic flexibility at early stages, we used a hooded metabolic cart to compare metabolic characteristics in people with T2D, family history of T2D (FH+), and controls (FH-) 1) at rest, 2) with passive stretching (PS) and recovery, and 3) with oral glucose load. Testing of 9 T2D, 11 FH+, and 9 FH- occurred after a 12-h fast under resting conditions. Expired gas and blood glucose (BG) were measured before and after each condition. RESULTS: PS lowered BG (P < 0.05) in FH- and FH+ (mean ± SD, -2.7 ± 5.9 and -5.8 ± 7.5 mg·mL(-1)) compared with T2D (-0.9 ± 7.7). CHO use (kcal·min(-1)) increased with PS in all groups (0.04 ± 0.18, 0.03 ± 0.26, and 0.22 ± 1.6 mg·mL(-1) in FH-, FH+, and T2D, respectively). For oral glucose load, different metabolic flexibility existed between FH- as well as FH+ (0.16 ± 0.07) as well as T2D (0.16 ± 0.07), with no difference between FH- and T2D. CONCLUSION: PS increases glycolytic activity without affecting BG in T2D, and reductions in metabolic flexibility exist in T2D and FH+ without glucoregulatory impairment in FH+, indicating early stage of mitochondrial dysfunction in FH+. Findings indicate PS is an important tool for assessing metabolic flexibility.

Physical activity level and physical functionality in nonagenarians compared to individuals aged 60-74 years.

BACKGROUND: Functional dependence and the risks of disability increase with age. The loss of independence is thought to be partially due to a decrease in physical activity. However, in populations, accurate measurement of physical activity is challenging and may not provide information on functional impairment. METHODS: This study therefore assessed physical functionality and physical activity level in a group of nonagenarians (11 men/11 women; 93+/-1 years, 66.6+/-2.4 kg, body mass index [BMI]=24+/-1 kg/m2) and a group of participants aged 60-74 years (17 men/15 women; 70+/-1 years, 83.3+/-3.0 kg, BMI=29+/-1 kg/m2) from the Louisiana Healthy Aging Study. Physical activity level was calculated from total energy expenditure (TEE) and resting metabolic rate (RMR). Physical functionality was assessed using the Reduced Continuous Scale Physical Functional Performance Test (CS-PFP10). RESULTS: Nonagenarians had lower absolute (p<.001) and adjusted (p<.007) TEE compared to participants aged 60-74 years which was attributed to a reduction in both RMR and physical activity level. Nonagenarians also had reduced functional performance (p<.001) which was correlated with activity level (r=0.68, p<.001). CONCLUSIONS: When compared to individuals aged 60-74 years, 73% of the reduction in TEE in nonagenarians can be attributed to a reduction in physical activity level, the remaining being accounted for by a reduction in RMR. The reduced physical activity in nonagenarians is associated with less physical functionality. This study provides the first objective comparison of physical functionality and actual levels of physical activity in older individuals.

Reproducibility of endurance performance on a treadmill using a preloaded time trial.

PURPOSE: The purpose of this study was to establish a highly reproducible test to measure endurance performance in runners. METHODS: We evaluated the reproducibility of endurance performance during a 10-km time trial performed on a treadmill after a 90-min preload run at 65% of maximal oxygen uptake VO2max). After screening and a practice test, eight endurance runners (4 men, 4 women, 33.4 +/- 10.1 yr, VO2max = 60.3 +/- 6.3 mL x kg(-1) x min(-1) in men and 51.8 +/- 2.2 mL x kg(-1) x min(-1) in women, mean +/- SD) completed two preloaded time trial tests spaced 3-4 wk apart in men and one menstrual cycle apart in women. A high-carbohydrate diet (15% protein, 10% fat, 75% carbohydrate) was provided the day before both tests. RESULTS: Runners completed time trial 1 and time trial 2 in 45:41 +/- 4:45 and 45:24 +/- 5:03 min:s, respectively (43:29 +/- 5:02 and 43:12 +/- 5:14 min:s for men and 47:53 +/- 3:47 and 47:35 +/- 4:23 min:s for women, trials 1 and 2, respectively). The within-subject coefficient of variation for 10-km time was 1.00% +/- 0.25% (point estimate +/- estimated standard error) (0.54% +/- 0.19% for men and 1.26% +/- 0.45% for women). CONCLUSION: These results suggest that performance measured as time to complete a 10-km time trial on a treadmill after a 90-min preload is extremely reliable and may be useful for future research assessing the effect of diet, ergogenic substances, or training methods on endurance running performance.