Several investigators have reported that carbohydrate metabolism is suppressed in blood vessels from diabetic (Db) rats. However, it is not known if metabolites from the reciprocal increase in oxidation of long-chain fatty acids that accompanies insulin-deficiency exacerbates the suppression of this pathway in the Db blood vessels. Such inhibition may have particularly deleterious consequences in vascular smooth muscle since aerobic glycolysis is believed to preferentially fuel the sarcolemmal Na/K ATPase in this tissue. Therefore, this study evaluated the effect of physiological (0.4 mM) and elevated (1.2 mM) concentrations of the long-chain fatty acid palmitate on both carbohydrate utilization and Na/K-ATPase activity in aorta from insulin-deficient Db rat. Thoracic aorta were removed from 10 week Db (streptozotocin 60 mg/Kg , i.v.) or control (C) rats and intima-media aortic preparations were incubated in the absence or presence of palmitate. Glycolysis (microM/g dry wt/h) and glucose oxidation (microM/g dry wt/h) were quantified using 3H-glucose and 14C-glucose, respectively. Na/K-ATPase activity was estimated by the measurement of 86rubidium uptake in the absence and presence of 2 mM ouabain. In the absence of exogenous palmitate, glycolysis (p < 0.05), glucose oxidation (p < 0.01) and the estimated ATP production from exogenous glucose were decreased in aorta from Db rat. However, despite this diminished rate of glycolysis, Na/K ATPase activity was similar in Db and C aorta. Palmitate (0.4 mM) inhibited Na/K ATPase activity and glucose oxidation to a similar extent in both Db and C but had no effect on glycolysis in either group. Elevation of palmitate to 1.2 mM had no additional inhibitory effect on glucose oxidation, Na/K ATPase activity or glycolysis in either the Db or C aorta. The metabolism of exogenous palmitate restored the ATP production in Db to control values. These data demonstrate that, despite the diminished glycolysis and glucose oxidation demonstrated in the Db tissue, Na/K ATPase activity was comparable in the C and Db aorta, in the absence or presence of exogenous long-chain fatty acid. Therefore, the accelerated oxidation of palmitate in diabetic vascular smooth muscle had no additional inhibitory effect on glycolysis or Na/K ATPase activity. These data suggest that Na/K ATPase activity in vascular smooth muscle is not impaired by the altered pattern of substrate utilization that occurs in insulin-deficient Db rats.

Consumption of a high fat/high sugar (HFHS) diet has not only been identified as risk factor for obesity, but it also predisposes towards type 2 diabetes mellitus (T2DM), by resulting in hyperglycemia and impaired insulin signaling. A targeted metabolic pathway for treatment of T2DM is hepatic gluconeogenesis. Gluconeogenesis is responsible for maintaining blood glucose levels during times of exercise, fasting, and stress. Insulin is responsible for suppressing gluconeogenic activity. However, as the liver becomes insulin resistant, hepatic gluconeogenesis becomes over activated exacerbating T2DM pathology. We aimed to assess whether genistein and/or exercise regulate hepatic gluconeogenesis. C57BL/6J male and female mice aged 5–6 weeks were randomly assigned to one of the following groups (n=8–10/group): lean control (Ln), high fat/high sucrose diet (HFHS), HFHS+Gen (genistein), HFHS+Ex (exercise), and HFHS+Gen+Ex. The HFD consisted of 60% saturated fat, 20% carbohydrate, 20% protein and included sucrose and fructose (42 g/L) in the drinking water. Exercise consisted of daily moderate treadmill running for a total duration of 150 minutes/week for 12 weeks. Genistein dose was 600 mg genistein/kg HF diet. C57BL/6J mice fed HFHS exhibited phenotypes seen in T2DM pathology; including rapid weight gain, hyperinsulinemia and hyperglycemia. Our results demonstrate that serum glucose and insulin levels in males were rescued by Gen+Ex treatment combined compared to controls. Corticosterone levels were significantly elevated in females fed HFHS diet (2755±375 pg/mL, n=6) compared to Ln controls (1449 ± 275 pg/mL, n=7), with significant recovery by Gen+Ex (964±234 pg/mL, n=7). Measures of total protein expression of renal 11βHSD2 (responsible for the conversion of active cortisol to inactive cortisone) however, showed no significant difference indicating that 11βHSD2 may not be playing a role in corticosterone deactivation. We are currently determining total protein expression levels of hepatic 11βHSD1 (responsible for the conversion of corticosterone to its active form). Current studies are also evaluating the roles of two rate limiting enzymes; phosphoenolpyruvate carboxykinase (PEPCK) and glucose‐6‐phosphotase (G6Pase). These studies provide evidence of the protective role that genistein and exercise may provide to ameliorate diabetic‐obesity induced by HFHS diet.Support or Funding InformationSupport: Layla Al‐Nakkash, Tom Broderick were supported by Midwestern‐Arizona Alzheimer's Consortium and Midwestern University Intramural Funds. Chaheyla St Aubin and Amy Fisher were supported by the Department of Biomedical Sciences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Diabetes is often associated with chronic foot ulcers leading to limb amputations. Ulcerations appear to develop, in part, because of increased pressures on the plantar aspect of the foot due to an equinus deformity (limitation of ankle joint dorsiflexion). Equinus deformity may be due to changes in the elastic properties of the Achilles tendon. Elevated blood glucose levels result in glycation induced collagen cross‐linking and studies of rat tail tendon suggest that hyperglycemia alters the content of tendon collagen and normal cross‐links. To our knowledge collagen content has not been assessed in the Achilles tendon of diabetic rats. Twenty male Sprague‐Dawley rats (8 weeks) were randomly assigned to control (n=7) or streptozotocin‐induced diabetic (n=11, 55 mg•kg body weight) groups. After 10 weeks tendons were evaluated for collagen content via HPLC. Weight gained was higher in the control rats (control: 162.7±14.9 g, diabetic: 62.3±10.1 g). Hyperglycemia did not alter the content of collagen in the Achilles tendon (control: 305.3±14.9, diabetic: 301.4±18.9 μg collagen/mg wet weight and control: 682.3±31.7 and 692.2±58.0 μg collagen/mg dry weight). It does not appear that changes in total collagen can explain the functional changes noted in the Achilles tendon of diabetics. Although total collagen was unaffected additional studies of cross‐link content and collagen I to III ratios are warranted.Funding: Midwestern University

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Aortic aneurysm is the leading cause of death in Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin‐1 gene. MFS aneurysm is characterized by weakening of the aortic wall due to elastin fibers fragmentation and aortic aneurysm. The above‐average height and distinct physical features make young adults with MFS, desirable candidates for competitive sports; but little is known about the exercise limit at which they will be at risk for aortic rupture. On the other hand, voluntary cardiovascular exercise has been shown to have a protective effect on the aortic wall structure and function. In this study, we investigated whether a voluntary aerobic exercise routine would have any effects on structure and function of the aorta in a mouse model of MFS. Four‐week old MFS and control mice were subjected to voluntary wheel exercise or sedentary life‐style for five months. Aortic tissue were isolated at the age of 24‐weeks, and subjected to structural and functional studies using histological staining and myography. During the study period, running activity (Km/day) in MFS mice was reduced by 37 percent, as compared to control mice. However, compared to non‐exercise MFS mice, their aortic wall structure (elastin fibers organization) and blood vessel function (contractility and vasodilation) were significantly improved. These findings provide new insights into the potential protective effects of a mild exercise routine in Marfan patients, especially in young adults affected by cardiovascular complications and aortic aneurysm. This work was funded by Midwestern University Graduate Research Fund.