Edward Park

Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo.

OBJECTIVE—An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma free fatty acids (FFAs), which induce insulin resistance and chronically decrease β-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in β-cell function. RESEARCH DESIGN AND METHODS—We used an in vivo model of 48-h intravenous oleate infusion in Wistar rats followed by hyperglycemic clamps or islet secretion studies ex vivo and in vitro models of 48-h exposure to oleate in islets and MIN6 cells. RESULTS—Forty-eight–hour infusion of oleate decreased the insulin and C-peptide responses to a hyperglycemic clamp (P < 0.01), an effect prevented by coinfusion of the antioxidants N-acetylcysteine (NAC) and taurine. Similar to the findings in vivo, 48-h infusion of oleate decreased glucose-stimulated insulin secretion ex vivo (P < 0.01) and induced oxidative stress (P < 0.001) in isolated islets, effects prevented by coinfusion of the antioxidants NAC, taurine, or tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl). Forty-eight–hour infusion of olive oil induced oxidative stress (P < 0.001) and decreased the insulin response of isolated islets similar to oleate (P < 0.01). Islets exposed to oleate or palmitate and MIN6 cells exposed to oleate showed a decreased insulin response to high glucose and increased levels of oxidative stress (both P < 0.001), effects prevented by taurine. Real-time RT-PCR showed increased mRNA levels of antioxidant genes in MIN6 cells after oleate exposure, an effect partially prevented by taurine. CONCLUSIONS—Our data are the first demonstration that oxidative stress plays a role in the decrease in β-cell secretory function induced by prolonged exposure to FFAs in vitro and in vivo.

Salicylate prevents hepatic insulin resistance caused by short-term elevation of free fatty acids in vivo

Recent evidence indicates that inflammatory pathways are causally involved in insulin resistance. In particular, Ikappa Balpha kinase beta (IKKbeta ), which can impair insulin signaling directly via serine phosphorylation of insulin receptor substrates (IRS) and/or indirectly via induction of transcription of proinflammatory mediators, has been implicated in free fatty acid (FFA)-induced insulin resistance in skeletal muscle. However, it is unclear whether liver IKKbeta activation plays a causal role in hepatic insulin resistance caused by acutely elevated FFA. In the present study, we wished to test the hypothesis that sodium salicylate, which inhibits IKKbeta , prevents hepatic insulin resistance caused by short-term elevation of FFA. To do this, overnight-fasted Wistar rats were subject to 7-h i.v. infusion of either saline or Intralipid plus 20 U/ml heparin (IH; triglyceride emulsion that elevates FFA levels in vivo) with or without salicylate. Hyperinsulinemic-euglycemic clamp with tracer infusion was performed to assess insulin-induced stimulation of peripheral glucose utilization and suppression of endogenous glucose production (EGP). Infusion of IH markedly decreased (P < 0.05) insulin-induced stimulation of peripheral glucose utilization and suppression of EGP, which were completely prevented by salicylate co-infusion. Furthermore, salicylate reversed IH-induced 1) decrease in Ikappa Balpha content; 2) increase in serine phosphorylation of IRS-1 (Ser 307) and IRS-2 (Ser 233); 3) decrease in tyrosine phosphorylation of IRS-1 and IRS-2; and 4) decrease in serine 473-phosphorylated Akt in the liver. These results demonstrate that inhibition of IKKbeta prevents FFA-induced impairment of hepatic insulin signaling, thus implicating IKKbeta as a causal mediator of hepatic insulin resistance caused by acutely elevated plasma FFA.

FFA-induced hepatic insulin resistance in vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress

Fat-induced hepatic insulin resistance plays a key role in the pathogenesis of type 2 diabetes in obese individuals. Although PKC and inflammatory pathways have been implicated in fat-induced hepatic insulin resistance, the sequence of events leading to impaired insulin signaling is unknown. We used Wistar rats to investigate whether PKCδ and oxidative stress play causal roles in this process and whether this occurs via IKKβ- and JNK-dependent pathways. Rats received a 7-h infusion of Intralipid plus heparin (IH) to elevate circulating free fatty acids (FFA). During the last 2 h of the infusion, a hyperinsulinemic-euglycemic clamp with tracer was performed to assess hepatic and peripheral insulin sensitivity. An antioxidant, N-acetyl-L-cysteine (NAC), prevented IH-induced hepatic insulin resistance in parallel with prevention of decreased IκBα content, increased JNK phosphorylation (markers of IKKβ and JNK activation, respectively), increased serine phosphorylation of IRS-1 and IRS-2, and impaired insulin signaling in the liver without affecting IH-induced hepatic PKCδ activation. Furthermore, an antisense oligonucleotide against PKCδ prevented IH-induced phosphorylation of p47(phox) (marker of NADPH oxidase activation) and hepatic insulin resistance. Apocynin, an NADPH oxidase inhibitor, prevented IH-induced hepatic and peripheral insulin resistance similarly to NAC. These results demonstrate that PKCδ, NADPH oxidase, and oxidative stress play a causal role in FFA-induced hepatic insulin resistance in vivo and suggest that the pathway of FFA-induced hepatic insulin resistance is FFA → PKCδ → NADPH oxidase and oxidative stress → IKKβ/JNK → impaired hepatic insulin signaling.

Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats

Stress-activated systems and oxidative stress are involved in insulin resistance, which, along with beta-cell failure, contribute to the development of type 2 diabetes mellitus (T2DM). Exercise improves insulin resistance and glucose tolerance, and these adaptations may, in part, be related to reductions in inflammation and oxidative stress. We investigated circulating and tissue-specific markers of inflammation and oxidative stress and insulin-signaling pathways in a rodent model of T2DM, the Zucker diabetic fatty rat, with and without voluntary exercise. At 5 wk of age, Zucker diabetic fatty rats (n = 8-9/group) were divided into basal (B), voluntary exercise (E), and sedentary control (S) groups. B rats were euthanized at 6 wk of age, and S and E rats were euthanized 10 wk later. E rats ran approximately 5 km/day, which improved insulin sensitivity and maintained fed and fasted glucose levels and glucose tolerance. Ten weeks of exercise also decreased whole body markers of inflammation and oxidative stress in plasma and liver, including lowered circulating IL-6, haptoglobin, and malondialdehyde levels, hepatic protein oxidation, and phosphorylated JNK, the latter indicating decreased JNK activity. Hepatic phosphoenolpyruvate carboxykinase levels and Ser(307)-phosphorylated insulin receptor substrate-1 were also reduced in E compared with S rats. In summary, we show that, in a rodent model of T2DM, voluntary exercise decreases circulating markers of inflammation and oxidative stress and lowers hepatic JNK activation and Ser(307)-phosphorylated insulin receptor substrate-1. These changes in oxidative stress markers and inflammation are associated with decreased hyperglycemia and insulin resistance and reduced expression of the main gluconeogenic enzyme phosphoenolpyruvate carboxykinase.

Three-dimensional localization of thin-walled sheet metal parts for robotic assembly

This article presents a technical demonstration of a system for determining the three-dimensional spatial location of complexly shaped, thin-walled sheet metal parts grasped by robots during assembly. For successful part assembly, the precise location of grasped parts (essential for successful mating of parts) must be achieved. A localization system is implemented to determine the accurate position and orientation of a sheet metal part that has been picked up by a robot from an arbitrary location. The proposed localization system employs a novel sensing method, utilizing laser-based proximity and edge detectors, to extract the part feature data in real time. These geometrical feature data are incorporated into an existing localization algorithm, which is based on the singular value decomposition formulation of the part localization problem. The sensing method is particularly effective in measuring 3-D feature geometry (i.e., thin edges) of sheet metal parts. An experimental single-robot test bed has been developed to demonstrate the feasibility of the part localization concept for a single sheet metal part. The experimental results obtained from the test bed demonstrate that the system can be effectively used for the localization of thin-walled sheet metal parts.

Resveratrol Prevents Insulin Resistance Caused by Short - Term Elevation of Free Fatty Acids In Vivo

Elevated levels of plasma free fatty acids (FFA), which are commonly found in obesity, induce insulin resistance. FFA activate protein kinases including the proinflammatory IκBα kinase β (IKKβ), leading to serine phosphorylation of insulin receptor substrate 1 (IRS-1) and impaired insulin signaling. To test whether resveratrol, a polyphenol found in red wine, prevents FFA-induced insulin resistance, we used a hyperinsulinemic-euglycemic clamp with a tracer to assess hepatic and peripheral insulin sensitivity in overnight-fasted Wistar rats infused for 7 h with saline, Intralipid plus 20 U·mL(-1) heparin (IH; triglyceride emulsion that elevates FFA levels in vivo; 5.5 μL·min(-1)) with or without resveratrol (3 mg·kg(-1)·h(-1)), or resveratrol alone. Infusion of IH significantly decreased glucose infusion rate (GIR; P < 0.05) and peripheral glucose utilization (P < 0.05) and increased endogenous glucose production (EGP; P < 0.05) during the clamp compared with saline infusion. Resveratrol co-infusion, however, completely prevented the effects induced by IH infusion: it prevented the decreases in GIR (P < 0.05 vs. IH), peripheral glucose utilization (P < 0.05 vs. IH), and insulin-induced suppression of EGP (P < 0.05 vs. IH). Resveratrol alone had no effect. Furthermore, IH infusion increased serine (307) phosphorylation of IRS-1 in soleus muscle (∼30-fold, P < 0.001), decreased total IRS-1 levels, and decreased IκBα content, consistent with activation of IKKβ. Importantly, all of these effects were abolished by resveratrol (P < 0.05 vs. IH). These results suggest that resveratrol prevents FFA-induced hepatic and peripheral insulin resistance and, therefore, may help mitigate the health consequences of obesity.

Dynamic modeling of flexible payloads grasped by actuated grippers using component mode synthesis

This paper presents an improved method of modeling the linear dynamics of a flexible payload grasped by an actuated robotic gripper. The component mode synthesis (CMS) method is employed to explicitly model the coupling between the payload and actuators, and to reduce the system order. With the addition of quasi-static modes to vibration normal modes and constraint or attachment modes, as pre-selected component modes, a new component mode representation is defined. In this study, it is found that the inclusion of quasi-static modes and attachment modes in the CMS formulation results in increased accuracy for simulation of dynamic responses of flexible payloads subject to both static and dynamic external forces. Numerical examples are presented to demonstrate the effectiveness of the new component mode representation for the given problem.

Calibration-based absolute localization of parts for multi-robot assembly

In multi-robot assembly of parts, for successful mating, the grasped parts must be located with sufficiently small position and orientation errors so that assembly can be achieved. This paper describes a new approach for determining the absolute three-dimensional spatial location of parts grasped by robots during assembly. Through a combination of robot pose calibration and part-sensor calibration, the robot, used to grasp the part, is calibrated to accurately position and orient parts to a designated mating location. First, by employing a robot pose measurement system, the 6 DOF robot pose errors relative to a reference coordinate frame are compensated. Second, with the implementation of a part pose measurement, the 6 DOF part pose errors, relative to the robot tool frame, are estimated in real time. An experimental verification of the proposed methodology using a single FANUC S–110 robot manipulating an automotive sheet metal part is described.

Mechanisms underlying fat-induced hepatic insulin resistance

Free fatty acids (FFAs), which are often elevated in obesity, cause insulin resistance. While the effects of FFAs on muscle glucose metabolism are well known, the mechanisms by which FFAs cause hepatic insulin resistance are incompletely understood. Recent evidence points to an accumulation of fat metabolites that activates various serine/threonine kinases, such as protein kinase C, c-Jun NH2-terminal kinase 1 and IκBα kinase, as a key event in the pathway of fat-induced hepatic insulin resistance. In this review, we present recent progress regarding the potential causal mediators of fat-induced hepatic insulin resistance and discuss the possible pathways by which they interact to induce impairment of hepatic insulin signaling.

Development of a smart robotic gripper for shape and vibration control of flexible payloads: theory and experiments

This paper presents the development and demonstration of a robotic gripper for active control of shape and vibration of thin-walled flexible payloads. The gripper is a smart gripper, which is configured with multiple actuated fingers that are comprised of linear actuators with DC motors, and laser proximity sensors to enable control of both shape and vibration of thin-walled flexible payloads. A detailed description of the proof-of-concept smart gripper is presented, followed by an experimental demonstration using an automotive front quarter body panel.