Assessment: symptomatic treatment for muscle cramps (an evidence-based review): report of the therapeutics and technology assessment subcommittee of the American academy of neurology.

BACKGROUND: A Food and Drug Administration advisory in 2006 warned against the off-label use of quinine sulfate and its derivatives in the treatment of muscle cramps. Physicians are faced with a difficult scenario in choosing a treatment regimen for patients with muscle cramps. This American Academy of Neurology assessment systematically reviews the available evidence on the symptomatic treatment of muscle cramps. METHODS: A total of 563 potential articles were reviewed, of which 24 met the inclusion criteria of prospective trials evaluating the efficacy of a particular treatment on muscle cramps as a primary or secondary outcome. RESULTS: There are Class I studies showing the efficacy of quinine derivatives for treatment of muscle cramps. However, the benefit is modest and there are adverse effects from published prospective trials as well as case reports. There is one Class II study each to support the use of Naftidrofuryl, vitamin B complex, lidocaine, and diltiazem in the treatment of muscle cramps. RECOMMENDATIONS: Although likely effective (Level A), quinine derivatives should be avoided for routine use in the management of muscle cramps because of the potential of toxicity, but in select patients they can be considered for an individual therapeutic trial once potential side effects are taken into account. Vitamin B complex, Naftidrofuryl, and calcium channel blockers such as diltiazem are possibly effective and may be considered in the management of muscle cramps (Level C). Further studies are needed to identify agents that are effective and safe for the treatment of muscle cramps.

Cytomegalovirus infection with MRI signal abnormalities affecting the optic nerves, optic chiasm, and optic tracts.

A 49-year-old woman who had been immunosuppressed after a renal transplant developed bilateral severe visual loss. Visual acuities were finger counting and hand movements in the two eyes. Both optic nerves were pale. There were no other ophthalmic abnormalities. Brain MRI disclosed marked signal abnormalities involving the optic nerves, optic chiasm, and optic tracts. Cerebrospinal fluid polymerase chain reaction (PCR) was positive for cytomegalovirus. Treatment did not restore vision. Such extensive clinical and imaging involvement of the anterior visual pathway, which has been previously reported with other herpes viruses, illustrates the propensity for this family of viruses to track along axons.

Entry of newly synthesized GLUT4 into the insulin-responsive storage compartment is dependent upon both the amino terminus and the large cytoplasmic loop.

We have recently reported that following initial biosynthesis, the GLUT4 protein exits the Golgi apparatus and directly enters the insulin-responsive compartment(s) without transiting the plasma membrane. To investigate the structural motifs involved in these initial sorting events, we have generated a variety of loss-of-function and gain-of-function GLUT4/GLUT1 chimera proteins. Substitution of the GLUT4 carboxyl-terminal domain with GLUT1 had no significant effect on the acquisition of insulin responsiveness. In contrast, substitution of either the GLUT4 amino-terminal domain or the large cytoplasmic loop between transmembrane domains 6 and 7 resulted in the rapid default of GLUT4 to the plasma membrane with blunted insulin response. Consistent with these findings, substitution of the amino-terminal, cytoplasmic loop, or carboxyl-terminal domains individually into GLUT1 backbone did not recapitulate normal GLUT4 trafficking. Similarly, dual substitutions of the GLUT1 amino and carboxyl termini with GLUT4 domains or the combination of the cytoplasmic loop plus the carboxyl terminus failed to display normal GLUT4 trafficking. However, the dual replacement of the amino terminus plus the cytoplasmic loop of GLUT4 in the GLUT1 backbone resulted in a complete restoration of normal GLUT4 trafficking. Alanine-scanning mutagenesis of the GLUT4 amino terminus demonstrated that Phe(5) and Ile(8) within the FQQI motif and, to a lesser extent, Asp(12)/Gly(13) were necessary for the appropriate initial trafficking following biosynthesis. In addition, amino acids 229-271 in the large intracellular loop between transmembrane domains 6 and 7 functionally cooperated with the amino-terminal domain. These data demonstrate that initial trafficking of GLUT4 from the Golgi to the insulin-responsive GLUT4 compartment requires the functional interaction of two distinct domains.

Entry of newly synthesized GLUT4 into the insulin-responsive storage compartment is GGA dependent.

Following biosynthesis, both GLUT1 and VSV-G proteins appear rapidly (2-3 h) at the plasma membrane, whereas GLUT4 is retained in intracellular membrane compartments and does not display any significant insulin responsiveness until 6-9 h. Surprisingly, the acquisition of insulin responsiveness did not require plasma membrane endocytosis, as expression of a dominant-interfering dynamin mutant (Dyn/K44A) had no effect on the insulin-stimulated GLUT4 translocation. Furthermore, expression of endocytosis-defective GLUT4 mutants or continuous surface labeling with an exofacial specific antibody demonstrated that GLUT4 did not transit the cell surface prior to the acquisition of insulin responsiveness. The expression of a dominant-interfering GGA mutant (VHS-GAT) had no effect on the trafficking of newly synthesized GLUT1 or VSV-G protein to the plasma membrane, but completely blocked the insulin-stimulated translocation of newly synthesized GLUT4. Furthermore, in vitro budding of GLUT4 vesicles but not GLUT1 or the transferrin receptor was inhibited by VHS-GAT. Together, these data demonstrate that following biosynthesis, GLUT4 directly sorts and traffics to the insulin-responsive storage compartment through a specific GGA-sensitive process.

PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance.

Protein targeting to glycogen (PTG) is a scaffolding protein that targets protein phosphatase 1alpha (PP1alpha) to glycogen, and links it to enzymes involved in glycogen synthesis and degradation. We generated mice that possess a heterozygous deletion of the PTG gene. These mice have reduced glycogen stores in adipose tissue, liver, heart, and skeletal muscle, corresponding with decreased glycogen synthase activity and glycogen synthesis rate. Although young PTG heterozygous mice initially demonstrate normal glucose tolerance, progressive glucose intolerance, hyperinsulinemia, and insulin resistance develop with aging. Insulin resistance in older PTG heterozygous mice correlates with a significant increase in muscle triglyceride content, with a corresponding attenuation of insulin receptor signaling. These data suggest that PTG plays a critical role in glycogen synthesis and is necessary to maintain the appropriate metabolic balance for the partitioning of fuel substrates between glycogen and lipid.

The adipocyte plasma membrane caveolin functional/structural organization is necessary for the efficient endocytosis of GLUT4.

It is well established that insulin stimulation of glucose uptake requires the translocation of intracellular localized GLUT4 protein to the cell surface membrane. This plasma membrane-redistributed GLUT4 protein was partially co-localized with caveolin as determined by confocal fluorescent microscopy but was fully excluded from lipid rafts based upon Triton X-100 extractability. Cholesterol depletion with methyl-beta-cyclodextrin, filipin, or cholesterol oxidase resulted in an insulin-independent increase in the amount of plasma membrane-localized GLUT4 that was fully reversible by cholesterol replenishment. This basal accumulation of cell surface GLUT4 occurred due to an inhibition of GLUT4 endocytosis. However, this effect was not specific since cholesterol extraction also resulted in a dramatic inhibition of clathrin-mediated endocytosis as assessed by transferrin receptor internalization. To functionally distinguish between caveolin- and clathrin-dependent endocytic processes, we took advantage of a dominant-interfering caveolin 1 mutant (Cav1/S80E) that specifically disrupts caveolae organization. Expression of Cav1/S80E, but not the wild type (Cav1/WT) or Cav1/S80A mutant, inhibited cholera toxin B internalization without any significant effect on transferrin receptor endocytosis. In parallel, Cav1/S80E expression increased the amount of plasma membrane-localized GLUT4 protein in an insulin-independent manner. Although Cav1/S80E also decreased GLUT4 endocytosis, the extent of GLUT4 internalization was only partially reduced ( approximately 40%). In addition, expression of Cav1/WT and Cav1/S80A enhanced GLUT4 endocytosis by approximately 20%. Together, these data indicate that the endocytosis of GLUT4 requires clathrin-mediated endocytosis but that the higher order structural organization of plasma membrane caveolin has a significant influence on this process.

Intracellular insulin-responsive glucose transporter (GLUT4) distribution but not insulin-stimulated GLUT4 exocytosis and recycling are microtubule dependent.

To investigate the potential role of microtubules in the regulation of insulin-responsive glucose transporter (GLUT4) trafficking in adipocytes, we examined the effects of microtubule depolymerizing and stabilizing agents. In contrast to previous reports, disruption or stabilization of microtubule structures had no significant effect on insulin-stimulated GLUT4 translocation. However, consistent with a more recent study (Molero, J. C., J. P. Whitehead, T. Meerloo, and D. E. James, 2001, J Biol Chem 276:43829-43835) nocodazole did inhibit glucose uptake through a direct interaction with the transporter itself independent of the translocation process. In addition, the initial rate of GLUT4 endocytosis was not significantly affected by microtubule depolymerization. However, these internalized GLUT4 compartments are confined to regions just beneath the plasma membrane and were not exposed to the extracellular space. Furthermore, they were unable to undergo further sorting steps and trafficking to the perinuclear region. Nevertheless, these apparent early endocytic GLUT4 compartments fully responded to a second insulin stimulation with an identical extent of plasma membrane translocation. Together, these data demonstrate that although microtubular organization may play a role in the trafficking of GLUT4 early endocytic vesicles back to the perinuclear region, they do not have a significant role in insulin-stimulated GLUT4 exocytosis, initial endocytosis from the plasma membrane and/or recycling back to the plasma membrane.