Muscle fatigue is an exercise-induced reduction in maximal voluntary muscle force. It may arise not only because of peripheral changes at the level of the muscle, but also because the central nervous system fails to drive the motoneurons adequately. Evidence for “central” fatigue and the neural mechanisms underlying it are reviewed, together with its terminology and the methods used to reveal it. Much data suggest that voluntary activation of human motoneurons and muscle fibers is suboptimal and thus maximal voluntary force is commonly less than true maximal force. Hence, maximal voluntary strength can often be below true maximal muscle force. The technique of twitch interpolation has helped to reveal the changes in drive to motoneurons during fatigue. Voluntary activation usually diminishes during maximal voluntary isometric tasks, that is central fatigue develops, and motor unit firing rates decline. Transcranial magnetic stimulation over the motor cortex during fatiguing exercise has revealed focal cha...

Spinal and Supraspinal Factors in Human Muscle Fatigue

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1 ) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2 ) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3 ) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function.

The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in (17,18). Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by …

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From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus

Pathogenesis of type 2 diabetes mellitus

Over the last 20 years, heart rate monitors (HRMs) have become a widely used training aid for a variety of sports. The development of new HRMs has also evolved rapidly during the last two decades. In addition to heart rate (HR) responses to exercise, research has recently focused more on heart rate variability (HRV). Increased HRV has been associated with lower mortality rate and is affected by both age and sex. During graded exercise, the majority of studies show that HRV decreases progressively up to moderate intensities, after which it stabilises. There is abundant evidence from cross-sectional studies that trained individuals have higher HRV than untrained individuals. The results from longitudinal studies are equivocal, with some showing increased HRV after training but an equal number of studies showing no differences. The duration of the training programmes might be one of the factors responsible for the versatility of the results. HRMs are mainly used to determine the exercise intensity of a training session or race. Compared with other indications of exercise intensity, HR is easy to monitor, is relatively cheap and can be used in most situations. In addition, HR and HRV could potentially play a role in the prevention and detection of overtraining. The effects of overreaching on submaximal HR are controversial, with some studies showing decreased rates and others no difference. Maximal HR appears to be decreased in almost all ‘overreaching’ studies. So far, only few studies have investigated HRV changes after a period of intensified training and no firm conclusions can be drawn from these results. The relationship between HR and oxygen uptake (VO2) has been used to predict maximal oxygen uptake (VO2max). This method relies upon several assumptions and it has been shown that the results can deviate up to 20% from the true value. The HR-VO2 relationship is also used to estimate energy expenditure during field conditions. There appears to be general consensus that this method provides a satisfactory estimate of energy expenditure on a group level, but is not very accurate for individual estimations. The relationship between HR and other parameters used to predict and monitor an individual’s training status can be influenced by numerous factors. There appears to be a small day-to-day variability in HR and a steady increase during exercise has been observed in most studies. Furthermore, factors such as dehydration and ambient temperature can have a profound effect on the HR-VO2 relationship.

Heart rate monitoring: applications and limitations.

Skin blood flow in adult human thermoregulation: how it works, when it does not, and why.

Local warming of skin induces vasodilation by unknown mechanisms. To test whether nitric oxide (NO) is involved, we examined effects of NO synthase (NOS) inhibition with NG-nitro-L-arginine methyl ester (L-NAME) on vasodilation induced by local warming of skin in six subjects. Two adjacent sites on the forearm were instrumented with intradermal microdialysis probes for delivery of L-NAME and sodium nitroprusside. Skin blood flow was monitored by laser-Doppler flowmetry (LDF) at microdialysis sites. Local temperature (Tloc) of the skin at both sites was controlled with special LDF probe holders. Mean arterial pressure (MAP; Finapres) was measured and cutaneous vascular conductance calculated (CVC = LDF/MAP = mV/mmHg). Data collection began with a control period (Tloc at both sites = 34 degrees C). One site was then warmed to 41 degrees C while the second was maintained at 34 degrees C. Local warming increased CVC from 1.44 +/- 0.41 to 4.28 +/- 0.60 mV/mmHg (P < 0.05). Subsequent L-NAME administration reduced CVC to 2.28 +/- 0.47 mV/mmHg (P < 0.05 vs. heating), despite the continued elevation of Tloc. At a Tloc of 34 degrees C, L-NAME reduced CVC from 1.17 +/- 0.23 to 0.75 +/- 0.11 mV/mmHg (P < 0.05). Administration of sodium nitroprusside increased CVC to levels no different from those induced by local warming. Thus NOS inhibition attenuated, and sodium nitroprusside restored, the cutaneous vasodilation induced by elevation of Tloc; therefore, the mechanism of cutaneous vasodilation by local warming requires NOS generation of NO.

https://www.physiology.org/doi/pdf/10.1152/jappl.1999.86.4.1185

Role of nitric oxide in the vascular effects of local warming of the skin in humans

This review focuses on the neural and local mechanisms that have been demonstrated to effect cutaneous vasodilation and vasoconstriction in response to heat and cold stress in vivo in humans. First, our present understanding of the mechanisms by which sympathetic cholinergic nerves mediate cutaneous active vasodilation during reflex responses to whole body heating is discussed. These mechanisms include roles for cotransmission as well as nitric oxide (NO). Next, the mechanisms by which sympathetic noradrenergic nerves mediate cutaneous active vasoconstriction during whole body cooling are reviewed, including cotransmission by neuropeptide Y (NPY) acting through NPY Y1 receptors. Subsequently, current concepts for the mechanisms that effect local cutaneous vascular responses to direct skin warming are examined. These mechanisms include the roles of temperature-sensitive afferent neurons as well as NO in causing vasodilation during local heating of skin. This section is followed by a review of the mechanisms that cause local cutaneous vasoconstriction in response to direct cooling of the skin, including the dependence of these responses on intact sensory and sympathetic, noradrenergic innervation as well as roles for nonneural mechanisms. Finally, unresolved issues that warrant further research on mechanisms that control cutaneous vascular responses to heating and cooling are discussed.

In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges

During heat stress, increases in blood flow in nonglabrous skin in humans are mediated through active vasodilation by an unknown neurotransmitter mechanism. To investigate this mechanism, a three-part study was performed to determine the following: (1) Is muscarinic receptor activation necessary for active cutaneous vasodilation? We iontophoretically applied atropine to a small area of forearm skin. At that site and an untreated control site, we measured the vasomotor (laser-Doppler blood flow [LDF]) and sudomotor (relative humidity) responses to whole-body heat stress. Blood pressure was monitored. Cutaneous vascular conductance (CVC) was calculated (LDF÷mean arterial pressure). Sweating was blocked at treated sites only. CVC rose at both sites ( P P P >.05). Active vasodilator and sudomotor responses to heat stress were abolished by botulinum toxin. We conclude that cholinergic nerve activation mediates cutaneous active vasodilation through release of an unknown cotransmitter, not through ACh.

Cutaneous Active Vasodilation in Humans Is Mediated by Cholinergic Nerve Cotransmission

In this review, we focus on significant developments in our understanding of the mechanisms that control the cutaneous vasculature in humans, with emphasis on the literature of the last half-century To provide a background for subsequent sections, we review methods of measurement and techniques of importance in elucidating control mechanisms for studying skin blood flow In addition, the anatomy of the skin relevant to its thermoregulatory function is outlined The mechanisms by which sympathetic nerves mediate cutaneous active vasodilation during whole body heating and cutaneous vasoconstriction during whole body cooling are reviewed, including discussions of mechanisms involving cotransmission, NO, and other effectors Current concepts for the mechanisms that effect local cutaneous vascular responses to local skin warming and cooling are examined, including the roles of temperature sensitive afferent neurons as well as NO and other mediators Factors that can modulate control mechanisms of the cutaneous vasculature, such as gender, aging, and clinical conditions, are discussed, as are nonthermoregulatory reflex modifiers of thermoregulatory cutaneous vascular responses

Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation.

Whether nitric oxide (NO) is involved in cutaneous active vasodilation during hyperthermia in humans is unclear. We tested for a role of NO in this process during heat stress (water-perfused suits)...

Dean L. Kellogg

Papers

Role of nitric oxide in the vascular effects of local warming of the skin in humans

In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges

Cutaneous Active Vasodilation in Humans Is Mediated by Cholinergic Nerve Cotransmission

Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation.

Nitric oxide and cutaneous active vasodilation during heat stress in humans