Therefore, although we concur that in type 2 diabetes there are endocrine cells with altered cell identity, this process does not account for the deficit in β-cells in type 2 diabetes but may reflect, in part, attempted β-cell regeneration.

(VNS) has been proposed as a cardioprotective intervention. However, regional ventricular electrophysiological effects of VNS are not well characterized. The purpose of this study was to evaluate effects of right and left VNS on electrophysiological properties of the ventricles and hemodynamic parameters. In Yorkshire pigs, a 56-electrode sock was used for epicardial (n ϭ 12) activation recovery interval (ARI) recordings and a 64-electrode catheter for endocardial (n ϭ 9) ARI recordings at baseline and during VNS. Hemodynamic recordings were obtained using a conductance catheter. Right and left VNS decreased heart rate (84 Ϯ 5 to 71 Ϯ 5 beats/min and 84 Ϯ 4 to 73 Ϯ 5 beats/min), left ventricular pressure (89 Ϯ 9 to 77 Ϯ 9 mmHg and 91 Ϯ 9 to 83 Ϯ 9 mmHg), and dP/dt max (1,660 Ϯ 154 to 1,490 Ϯ 160 mmHg/s and 1,595 Ϯ 155 to 1,416 Ϯ 134 mmHg/s) and prolonged ARI (327 Ϯ 18 to 350 Ϯ 23 ms and 327 Ϯ 16 to 347 Ϯ 21 ms, P Ͻ 0.05 vs. baseline for all parameters and P ϭ not significant for right VNS vs. left VNS). No anteriorposterior-lateral regional differences in the prolongation of ARI during right or left VNS were found. However, endocardial ARI prolonged more than epicardial ARI, and apical ARI prolonged more than basal ARI during both right and left VNS. Changes in dP/dt max showed the strongest correlation with ventricular ARI effects (R 2 ϭ 0.81, P Ͻ 0.0001) than either heart rate (R 2 ϭ 0.58, P Ͻ 0.01) or left ventricular pressure (R 2 ϭ 0.52, P Ͻ 0.05). Therefore, right and left VNS have similar effects on ventricular ARI, in contrast to sympathetic stimulation, which shows regional differences. The decrease in inotropy correlates best with ventricular electrophysiological effects.vagal nerve stimulation; ventricle; repolarization THE AUTONOMIC NERVOUS SYSTEM plays a significant role in the genesis and persistence of ventricular arrhythmias (54, 59). Sympathetic activation is proarrhythmic (16,32,53), whereas parasympathetic activation is thought to be cardioprotective (17, 31). The vagal nerve trunk provides important cardiomotor efferent fibers to the heart and also carries afferent signals from the heart. Vagal nerve stimulation (VNS) has been shown to decrease infarct size (48), reduce the ventricular fibrillation (VF) threshold (39), and decrease the incidence of ventricular arrhythmias and mortality during ischemia (13,27,38,52). Furthermore, a preserved parasympathetic reflex has been reported to be protective during myocardial infarction (46). Stimulation of the right vagal nerve (RVN) has shown benefits in a series of patients with cardiomyopathy and is undergoing evaluation in clinical trials (20,47). The mechanisms of the antiarrhythmic effects of VNS are less clear and are thought to be multifactorial, with a decrease in heart rate (HR) (15), release of nitric oxide (9), and antagonism of the sympathetic nervous system all thought to play a role (8,30,49).Modulation of repolarization by sympathetic nerve stimulation has been well characterized (1,25,41,55,58). However, the effects of parasympatheti...

Circadian disruption and obesity synergize to predispose to development of type 2 diabetes mellitus (T2DM), signifying that therapeutic targeting of both circadian and metabolic dysfunctions should be considered as a potential treatment approach. To address this hypothesis, we studied rats concomitantly exposed to circadian disruption and diet-induced obesity (CDO), a rat model recently shown to recapitulate phenotypical aspects of obese T2DM (eg, circadian disruption, obesity, insulin resistance, and islet failure). CDO rats were subsequently treated daily (for 12 wk) by timed oral gavage with vehicle, melatonin (a known chronobiotic), metformin, or combination treatment of both therapeutics. Melatonin treatment alone improved circadian activity rhythms, attenuated induction of β-cell failure, and enhanced glucose tolerance. Metformin alone did not modify circadian activity but enhanced insulin sensitivity and glucose tolerance. Importantly, the combination of melatonin and metformin had synergistic actions to modify progression of metabolic dysfunction in CDO rats through improved adiposity, circadian activity, insulin sensitivity, and islet cell failure. This study suggests that management of both circadian and metabolic dysfunctions should be considered as a potential preventative and therapeutic option for treatment of obesity and T2DM.

The islet in type 2 diabetes is characterized by β-cell loss, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). When protein misfolding protective mechanisms are overcome, human IAPP (h-IAPP) forms membrane permeant toxic oligomers that induce β-cell dysfunction and apoptosis. In humans with type 2 diabetes (T2D) and mice transgenic for h-IAPP, endoplasmic reticulum (ER) stress has been inferred from nuclear translocation of CCAAT/enhancer-binding protein homologous protein (CHOP), an established mediator of ER stress. To establish whether h-IAPP toxicity is mediated by ER stress, we evaluated diabetes onset and β-cell mass in h-IAPP transgenic (h-TG) mice with and without deletion of CHOP in comparison with wild-type controls. Diabetes was delayed in h-TG CHOP(-/-) mice, with relatively preserved β-cell mass and decreased β-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy/lysosomal pathway in β-cells of h-TG mice, uncovering a role for CHOP in mediating h-IAPP-induced dysfunction of autophagy. As deletion of CHOP delayed but did not prevent h-IAPP-induced β-cell loss and diabetes, we examined CHOP-independent stress pathways. JNK, a target of the IRE-1pTRAF2 complex, and the Bcl-2 family proapoptotic mediator BIM, a target of ATF4, were comparably activated by h-IAPP expression in the presence and absence of CHOP. Therefore, although these studies affirm that CHOP is a mediator of h-IAPP-induced ER stress, it is not the only one. Therefore, suppression of CHOP alone is unlikely to be a durable therapeutic strategy to protect against h-IAPP toxicity because multiple stress pathways are activated.

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