W. Todd Cade

Diabetes-Related Microvascular and Macrovascular Diseases in the Physical Therapy Setting

Physical therapists commonly treat people with diabetes for a wide variety of diabetes-associated impairments, including those from diabetes-related vascular disease. Diabetes is associated with both microvascular and macrovascular diseases affecting several organs, including muscle, skin, heart, brain, and kidneys. A common etiology links the different types of diabetes-associated vascular disease. Common risk factors for vascular disease in people with diabetes, specifically type 2 diabetes, include hyperglycemia, insulin resistance, dyslipidemia, hypertension, tobacco use, and obesity. Mechanisms for vascular disease in diabetes include the pathologic effects of advanced glycation end product accumulation, impaired vasodilatory response attributable to nitric oxide inhibition, smooth muscle cell dysfunction, overproduction of endothelial growth factors, chronic inflammation, hemodynamic dysregulation, impaired fibrinolytic ability, and enhanced platelet aggregation. It is becoming increasingly important for physical therapists to be aware of diabetes-related vascular complications as more patients present with insulin resistance and diabetes. The opportunities for effective physical therapy interventions (such as exercise) are significant.

Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome

Barth syndrome is a complex metabolic disorder caused by mutations in the mitochondrial transacylase tafazzin. Recently, an inducible tafazzin shRNA knockdown mouse model was generated to deconvolute the complex bioenergetic phenotype of this disease. To investigate the underlying cause of hemodynamic dysfunction in Barth syndrome, we interrogated the cardiac structural and signaling lipidome of this mouse model as well as its myocardial bioenergetic phenotype. A decrease in the distribution of cardiolipin molecular species and robust increases in monolysocardiolipin and dilysocardiolipin were demonstrated. Additionally, the contents of choline and ethanolamine glycerophospholipid molecular species containing precursors for lipid signaling at the sn-2 position were altered. Lipidomic analyses revealed specific dysregulation of HETEs and prostanoids, as well as oxidized linoleic and docosahexaenoic metabolites. Bioenergetic interrogation uncovered differential substrate utilization as well as decreases in Complex III and V activities. Transgenic expression of cardiolipin synthase or iPLA2γ ablation in tafazzin-deficient mice did not rescue the observed phenotype. These results underscore the complex nature of alterations in cardiolipin metabolism mediated by tafazzin loss of function. Collectively, we identified specific lipidomic, bioenergetic, and signaling alterations in a murine model that parallel those of Barth syndrome thereby providing novel insights into the pathophysiology of this debilitating disease.

Lower physical activity is associated with higher intermuscular adipose tissue in people with type 2 diabetes and peripheral neuropathy

Background Increased lipid accumulation in skeletal muscle has been linked to insulin resistance, impaired muscle performance, and impaired physical function. It is unclear whether physical activity is associated with lipid content in skeletal muscle, muscle performance, or overall physical function. Objective The purpose of this study was to characterize physical activity levels (average daily step count) in a sample of people with diabetes and peripheral neuropathy and to determine the relationship among step count, intermuscular adipose tissue volume (IMAT), muscle performance (peak torque, power), and physical function. Design A cross-sectional design was used in this study. Methods Twenty-two people with diabetes and peripheral neuropathy (15 men and 7 women, mean age=64.5 years [SD=12.7], and mean body mass index=33.2 kg/m2 [SD=6.4]) participated. Average daily step count, glycosylated hemoglobin, modified 9-item Physical Performance Test scores, Six-Minute Walk Test distance, calf intermuscular adipose tissue volume (via magnetic resonance imaging), and isokinetic dynamometry of the ankle muscles were recorded. Results Average daily step count was 7,754 (SD=4,678; range=3,088–20,079). Five participants had an average daily step count greater than 10,000. Average IMAT volume was 84 cm3 (SD=88). Greater average daily step count was associated with younger age (r=−.39, P<.05) and with lower IMAT volume in the calf (r=−.44, P<.05). Lower IMAT volume was associated with greater muscle performance (r=−.45) and physical function (r=−.43 to −.48). Limitations The sample in this study may be biased toward people with high levels of activity because participants were recruited for an exercise study. The results should not be generalized to people taking fewer than 3,000 steps/day or to those with a current foot ulcer, peripheral arterial disease, or severe foot deformity or amputation or who weigh more than 136 kg (300 lb). Conclusions Average daily step count was inversely related to IMAT, and IMAT was inversely related to muscle performance and overall physical function. In addition, we found that people with diabetes and peripheral neuropathy and without severe foot deformity appear to be able to take a large number of steps per day.

Impaired cardiac reserve and severely diminished skeletal muscle O2 utilization mediate exercise intolerance in Barth syndrome

Barth syndrome (BTHS) is a mitochondrial myopathy characterized by reports of exercise intolerance. We sought to determine if 1) BTHS leads to abnormalities of skeletal muscle O(2) extraction/utilization and 2) exercise intolerance in BTHS is related to impaired O(2) extraction/utilization, impaired cardiac function, or both. Participants with BTHS (age: 17 ± 5 yr, n = 15) and control participants (age: 13 ± 4 yr, n = 9) underwent graded exercise testing on a cycle ergometer with continuous ECG and metabolic measurements. Echocardiography was performed at rest and at peak exercise. Near-infrared spectroscopy of the vastus lateralis muscle was continuously recorded for measurements of skeletal muscle O(2) extraction. Adjusting for age, peak O(2) consumption (16.5 ± 4.0 vs. 39.5 ± 12.3 ml·kg(-1)·min(-1), P < 0.001) and peak work rate (58 ± 19 vs. 166 ± 60 W, P < 0.001) were significantly lower in BTHS than control participants. The percent increase from rest to peak exercise in ejection fraction (BTHS: 3 ± 10 vs. control: 19 ± 4%, P < 0.01) was blunted in BTHS compared with control participants. The muscle tissue O(2) saturation change from rest to peak exercise was paradoxically opposite (BTHS: 8 ± 16 vs. control: -5 ± 9, P < 0.01), and the deoxyhemoglobin change was blunted (BTHS: 0 ± 12 vs. control: 10 ± 8, P < 0.09) in BTHS compared with control participants, indicating impaired skeletal muscle extraction in BTHS. In conclusion, severe exercise intolerance in BTHS is due to both cardiac and skeletal muscle impairments that are consistent with cardiac and skeletal mitochondrial myopathy. These findings provide further insight to the pathophysiology of BTHS.

Development of Appropriate Coronary Heart Disease Risk Prediction Models in HIV-Infected Patients

Prediction equations for coronary heart disease (CHD) risk are useful tools that inform clinicians and patients about the absolute risk for developing CHD. A basic principle in CHD prevention is that the intensity of risk-reducing interventions should be based on the individual patient’s absolute CHD risk. In the current era of human immunodeficiency virus (HIV) infection and highly active antiretroviral therapy (HAART), knowing one’s CHD risk and acting to reduce it have become imperative to long-term survival. Given the increased life expectancy as a result of HAART, more HIV-infected persons will experience complications not related to HIV per se and will reach an age at which they are at increased risk for developing CHD. However, existing CHD risk prediction equations were not developed in HIV-infected adults or children. In the general population, CHD risk prediction models derived from the Framingham Heart Study estimate the risk of total CHD (angina pectoris, myocardial infarction [MI], CHD death)1 or estimate the risk for hard CHD end points (MI, CHD).2 The traditional risk factors used to predict CHD risk and how risk factor alterations affect CHD outcomes in HIV-infected and HIV-seronegative people are summarized in the Table. The estimates of the relative effects of traditional risk factors on CHD outcomes appear similar between HIV- and non–HIV-infected patients. However, they are based on only 2 studies in HIV-infected patients. Although traditional CHD risk factors may operate in the same manner in HIV patients as in the general population, there may still be a need to identify and evaluate HIV-specific CHD risk factors and equations, to refine existing CHD prediction equations, and to develop new HIV-specific CHD prediction equations for adults, adolescents, and children. To date, Framingham CHD risk predictions have performed reasonably well when applied to HIV-infected patients. We need to evaluate …

HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus

Insulin resistance, hyperglycemia, and type 2 diabetes are among the sequelae of metabolic syndromes that occur in 60-80% of human immunodeficiency virus (HIV)-positive patients treated with HIV-protease inhibitors (PIs). Studies to elucidate the molecular mechanism(s) contributing to these changes, however, have mainly focused on acute, in vitro actions of PIs. Here, we examined the chronic (7 wk) in vivo effects of the PI indinavir (IDV) in male Zucker diabetic fatty (fa/fa) (ZDF) rats. IDV exposure accelerated the diabetic state and dramatically exacerbated hyperglycemia and oral glucose intolerance in the ZDF rats, compared with vehicle-treated ZDF rats. Oligonucleotide gene array analyses revealed upregulation of suppressor of cytokine signaling-1 (SOCS-1) expression in insulin-sensitive tissues of IDV rats. SOCS-1 is a known inducer of insulin resistance and diabetes, and immunoblotting analyses revealed increases in SOCS-1 protein expression in adipose, skeletal muscle, and liver tissues of IDV-administered ZDF rats. This was associated with increases in the upstream regulator TNF-alpha and downstream effector sterol regulatory element-binding protein-1 and a decrease in IRS-2. IDV and other PIs currently in clinical use induced the SOCS-1 signaling cascade also in L6 myotubes and 3T3-L1 adipocytes exposed acutely to PIs under normal culturing conditions and in tissues from Zucker wild-type lean control rats administered PIs for 3 wk, suggesting an effect of these drugs even in the absence of background hyperglycemia/hyperlipidemia. Our findings therefore indicate that induction of the SOCS-1 signaling cascade by PIs could be an important contributing factor in the development of metabolic dysregulation associated with long-term exposures to HIV-PIs.

Whole-Body Proteolysis Rate Is Elevated in HIV-Associated Insulin Resistance

Type 2 diabetes is characterized by impaired glucose tolerance (IGT) and insulin resistance with respect to glucose metabolism but not amino acid metabolism. We examined whether whole-body leucine and protein metabolism are dysregulated in HIV-infected individuals with IGT. Glucose and leucine kinetics were measured under fasting insulin conditions and during euglycemic hyperinsulinemia using primed-constant infusions of 2H2-glucose and 13C-leucine in 10 HIV-seronegative control subjects, 16 HIV+ subjects with normal glucose tolerance, and 21 HIV+IGT subjects. Glucose disposal rate during hyperinsulinemia was lower in HIV+IGT than the other two groups. Absolute plasma leucine levels and rate of appearance (whole-body proteolysis) were higher in HIV+IGT at all insulin levels but declined in response to hyperinsulinemia in parallel to those in the other two groups. HIV+IGT had greater visceral adiposity, fasting serum interleukin (IL)-8 and free fatty acid levels, and higher lipid oxidation rates during the clamp than the other two groups. These findings implicate several factors in the insulin signaling pathway, which may be further dysregulated in HIV+IGT, and support the notion that insulin signaling pathways for glucose and leucine metabolism may be disrupted by increased proinflammatory adipocytokines (IL-8) and increased lipid oxidation. Increased proteolysis may provide amino acids for gluconeogenesis, exacerbating hyperglycemia in HIV.

A comparison of Qt and a-vO2 in individuals with HIV taking and not taking HAART

PURPOSE The aim of this study was to determine whether highly active antiretroviral therapy (HAART), rather than the direct effect of HIV infection, limits peripheral muscle oxygen extraction-utilization (a-vO(2)) in individuals infected with the human immunodeficiency virus (HIV). METHODS Fifteen subjects (6 female and 9 male) with HIV taking HAART, 15 subjects infected with HIV not taking HAART, and 15 healthy gender and activity level matched non-HIV infected controls (N = 45) performed an maximal treadmill exercise test to exhaustion. Noninvasive cardiac output Qt was measured at each stage and at peak exercise using the indirect Fick method based on the exponential rise carbon dioxide rebreathing method. Intergroup comparisons were adjusted for interactions of peak oxygen consumption ([V02), body surface area, and [V02]t using ANCOVA. RESULTS Peak a-vO(2) was significantly lower (P < 0.05) in subjects with HIV taking HAART (10.0 +/- 0.5 vol%) compared with subjects with HIV not taking HAART (11.7 +/- 0.5 vol%) and noninfected controls (12.7 +/- 0.5 vol%). In subjects with HIV taking HAART, peak heart rate (HR) (170.5 +/- 3.9 bpm) was lower than (P < 0.05) and stroke volume (Vs) (123.0 +/- 3.9 mL x beat-1) at peak exercise was higher (P < 0.05) than subjects with HIV not taking HAART (179.9 +/- 3.5 bpm) (106.6 +/- 3.9 mL x beat-1) and noninfected controls (185.4 +/- 3.8 bpm) (100.6 +/- 4.0 mL.beat-1) upon ANCOVA. There were no significant differences in peak [VO2]t between groups. CONCLUSION Peak a-vO(2) was diminished in subjects infected with HIV taking HAART compared with HIV-infected subjects not taking HAART and noninfected controls matched for age, gender, and physical activity level. Findings of the current study implicated HAART as a primary contributor to decreased muscle oxygen extraction-utilization in individuals infected with HIV.

Exercise training augments the peripheral insulin sensitizing effects of pioglitazone in HIV-infected adults with insulin resistance and central adiposity

The prevalence and incidence of insulin resistance and type 2 diabetes mellitus (DM) are higher in people treated for human immunodeficiency virus-1 (HIV) infection than in the general population. Identifying safe and effective interventions is a high priority. We evaluated whether the peroxisome proliferator-activated receptor-γ agonist pioglitazone with exercise training improves central and peripheral insulin sensitivity more than pioglitazone alone in HIV-infected adults with insulin resistance and central adiposity. Forty-four HIV-infected adults with baseline insulin resistance and central adiposity were randomly assigned to 4 mo of pioglitazone (30 mg/day) with or without supervised, progressive aerobic, and resistance exercise training (1.5-2 h/day, 3 days/wk). The hyperinsulinemic euglycemic clamp was used to evaluate alterations in central and peripheral insulin sensitivity. Thirty-nine participants completed the study. Hepatic insulin sensitivity improved similarly in both groups. Exercise training augmented the beneficial effects of pioglitazone on peripheral insulin sensitivity. Greater improvements in peripheral insulin sensitivity were associated with reductions in total body and limb adipose content rather than increases in limb adiposity or pioglitazone-induced increases in adiponectin concentration. We conclude that supplementing pioglitazone with increased physical activity improved insulin sensitivity more effectively than pioglitazone alone in HIV-infected adults with insulin resistance and central adiposity. Pioglitazone alone did not significantly increase limb adipose content. Potential cardiovascular benefits of these interventions in HIV need investigation.

Protease inhibitors used in the treatment of HIV+ induce β-cell apoptosis via the mitochondrial pathway and compromise insulin secretion

Inclusion of HIV protease inhibitors (PIs) in the treatment of people living with HIV+ has markedly decreased mortality but also increased the incidence of metabolic abnormalities, causes of which are not well understood. Here, we report that insulinopenia is exacerbated when Zucker fa/fa rats are exposed to a PI for 7 wk, suggesting that chronic PI exposure adversely affects pancreatic islet beta-cell function. In support of this possibility, we find increased apoptosis, as reflected by TUNEL fluorescence analyses, and reduced insulin-secretory capacity in insulinoma cells and human pancreatic islet cells after in vitro exposures (48-96 h) to clinically relevant PIs (ritonavir, lopinavir, atazanavir, or tipranavir). Furthermore, pancreatic islets isolated from rats administered an HIV-PI for 3 wk exhibit greater cell death than islets isolated from vehicle-administered rats. The higher incidence of HIV-PI-induced cell death was associated with cleavage and, hence, activation of caspase-3 and poly(ADP)-ribose polymerase but not with activation of phospho-pancreatic endoplasmic reticulum (ER) kinase or induction of ER stress apoptotic factor C/EBP homologous protein. Exposure to the HIV-PIs, however, led to activation of mitochondria-associated caspase-9, caused a loss in mitochondrial membrane potential, and promoted the release of cytochrome c, suggesting that HIV-PIs currently in clinically use can induce beta-cell apoptosis by activating the mitochondrial apoptotic pathway. These findings therefore highlight the importance of considering beta-cell viability and function when assessing loss of glycemic control and the course of development of diabetes in HIV+ subjects receiving a protease inhibitor.