PMID- 16307847
OWN - NLM
STAT- MEDLINE
DCOM- 20060614
LR  - 20131121
IS  - 0306-9877 (Print)
IS  - 0306-9877 (Linking)
VI  - 66
IP  - 4
DP  - 2006
TI  - PKC-mediated modulation of L-type calcium channels may contribute to fat-induced 
      insulin resistance.
PG  - 824-31
AB  - Increased intracellular free calcium [Ca2+]i has been noted in adipocytes, 
      platelets, and leukocytes of subjects with insulin resistance syndrome or allied 
      disorders. In rodent studies, measures which increase [Ca2+]i in adipocytes and 
      skeletal muscle are associated with impaired insulin signaling, attributable at 
      least in part to diminished ability of insulin to activate phosphoserine 
      phosphatase-1 (PP-1). In fat-fed insulin resistant rats, pre-treatment with a 
      drug that selectively chelates intracellular calcium eliminates about half of the 
      decrement in insulin-stimulated glucose uptake induced by fat feeding; since this 
      chelator does not influence the insulin sensitivity of chow-fed rats, it is 
      reasonable to suspect that fat feeding boosts [Ca2+]i in skeletal muscle, and 
      that this effect is partially responsible for the associated reduction in insulin 
      sensitivity. Clinical insulin resistance is associated with increased levels of 
      triglycerides and other fatty acid metabolites in muscle fibers; this can give 
      rise to diacylglycerol-mediated activation of PKC, which in turn compromises 
      insulin signaling by triggering kinase cascades that phosphorylate IRS-1 on key 
      serine residues. Yet there is also evidence that, in skeletal muscle, PKC 
      activity up-regulates the function of L-type calcium channels, increasing their 
      maximal conductance while left-shifting their voltage dependence. Thus, the PKC 
      activation associated with fat overexposure might be expected to boost basal 
      [Ca2+]i in skeletal muscle, potentially impeding insulin-mediated activation of 
      PP-1. This hypothesis is consistent with several clinical studies demonstrating 
      that long-acting inhibitors of L-type calcium channels can improve insulin 
      sensitivity in overweight hypertensives; it should be readily testable in rodent 
      models of fat-induced insulin resistance. Since parathyroid hormone can act on 
      adipocytes and muscle to boost [Ca2+]i, mild secondary hyperparathyroidism 
      associated with low calcium intakes and poor vitamin D status may contribute to 
      insulin resistance, consistent with certain clinical and epidemiological 
      findings. Magnesium, often thought of as a mild calcium antagonist, appears to 
      have favorable effects on insulin sensitivity and risk for diabetes, and recent 
      evidence indicates that increases of intracellular magnesium within the 
      physiological range can diminish calcium influx through phosphorylated L-type 
      calcium channels. It will be of interest to determine whether calcium antagonism 
      does indeed underlie the favorable influence of good magnesium status on insulin 
      function. A report that chromium picolinate can induce the plasmalemmal 
      Ca2+-ATPase in smooth muscle cells, raises the possibility that modulation of 
      calcium transport might play a role in the insulin-sensitizing efficacy of 
      bioactive chromium.
FAU - McCarty, Mark F
AU  - McCarty MF
AD  - Natural Alternatives International, 1185 Linda Vista Dr., San Marcos, CA 92078, 
      USA. mccarty@pantox.com
LA  - eng
PT  - Journal Article
DEP - 20051122
PL  - United States
TA  - Med Hypotheses
JT  - Medical hypotheses
JID - 7505668
RN  - 0 (Calcium Channels, L-Type)
RN  - 0 (Dietary Fats)
RN  - 0R0008Q3JB (Chromium)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - I38ZP9992A (Magnesium)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Calcium Channels, L-Type/*metabolism
MH  - Chromium/administration & dosage
MH  - Dietary Fats/*administration & dosage
MH  - Hyperparathyroidism/etiology/metabolism
MH  - *Insulin Resistance
MH  - Magnesium/administration & dosage
MH  - Muscle, Skeletal/metabolism
MH  - Protein Kinase C/*metabolism
MH  - Rats
MH  - *Up-Regulation
EDAT- 2005/11/26 09:00
MHDA- 2006/06/15 09:00
CRDT- 2005/11/26 09:00
PHST- 2004/08/09 00:00 [received]
PHST- 2004/08/27 00:00 [accepted]
PHST- 2005/11/26 09:00 [pubmed]
PHST- 2006/06/15 09:00 [medline]
PHST- 2005/11/26 09:00 [entrez]
AID - S0306-9877(05)00488-3 [pii]
AID - 10.1016/j.mehy.2004.08.034 [doi]
PST - ppublish
SO  - Med Hypotheses. 2006;66(4):824-31. doi: 10.1016/j.mehy.2004.08.034. Epub 2005 Nov 
      22.