Inhibition of phosphatases and increased Ca2+ channel activity by inositol hexakisphosphate.

Inositol hexakisphosphate (InsP6), the dominant inositol phosphate in insulin-secreting pancreatic beta cells, inhibited the serine-threonine protein phosphatases type 1, type 2A, and type 3 in a concentration-dependent manner. The activity of voltage-gated L-type calcium channels is increased in cells treated with inhibitors of serine-threonine protein phosphatases. Thus, the increased calcium channel activity obtained in the presence of InsP6 might result from the inhibition of phosphatase activity. Glucose elicited a transient increase in InsP6 concentration, which indicates that this inositol polyphosphate may modulate calcium influx over the plasma membrane and serve as a signal in the pancreatic beta cell stimulus-secretion coupling.

Deficiency of phosphofructo-1-kinase/muscle subtype in humans is associated with impairment of insulin secretory oscillations.

In healthy humans, insulin is secreted in an oscillatory manner. While the underlying mechanisms generating these oscillations are not fully established, increasing evidence suggests a central role for phosphofructo-1-kinase/muscle subtype (PFK1-M), which also serves as the predominantly active PFK1 subtype in the pancreatic beta-cell. The fact that normal oscillatory secretion is impaired in subjects with impaired glucose tolerance and healthy relatives of patients with type 2 diabetes suggests that this defect may be involved in the secretory dysfunction. To evaluate a possible link between inherited PFK1-M deficiency in humans (Tarui's disease or glycogenosis type VII) and altered insulin oscillations, in vivo studies were performed. We determined basal insulin oscillations during 2 h of frequent plasma sampling in two related teen-aged individuals with homozygous and heterozygous PFK1-M deficiency compared with nondeficient, unrelated control subjects. As predicted by the underlying hypothesis, normal oscillations in insulin secretion were completely abolished in the individual with homozygous deficiency of PFK1-M and significantly impaired in the heterozygous individual, as shown by spectral density and autocorrelation analyses. Thus, deficiency of PFK1-M subtype in humans appears to be associated with an impaired oscillatory insulin secretion pattern and may contribute to the commonly observed secretion defects occurring in type 2 diabetes.

Amplitude and phase relationship between alpha and beta oscillations in the human electroencephalogram.

The relationship between the electro-encephalographic (EEG) alpha and beta oscillations in the resting condition was investigated in the study. EEGs were recorded in 33 subjects, and alpha (7.5-12.5 Hz) and beta (15-25 Hz) oscillations were extracted with the use of a modified wavelet transform. Power, peak frequency and phase synchronisation were evaluated for both types of oscillation. The average beta-alpha peak frequency ratio was about 1.9-2.0 for all electrode derivations. The peak frequency of beta activity was within 70-90 % of the 95 % confidence interval of twice the alpha frequency. A significant (p < 0.05) linear regression was found between beta and alpha power in all derivations in 32 subjects, with the slope of the regression line being approximately 0.3. There was no significant difference in the slope of the line in different electrode locations, although the power correlation was strongest in the occipital locations where alpha and beta oscillations had the largest power. A significant 1:2 phase synchronisation was present between the alpha and beta oscillations, with a phase lag of about pi/2 in all electrode derivations. The strong frequency relationship between the resting beta and alpha oscillations suggests that they are generated by a common mechanism. Power and phase relationships were weaker, suggesting that these properties can be modulated by additional mechanisms as well as be influenced by noise. A careful distinction between alpha-dependent and alpha-independent beta activity should be considered when making statements about the possible significance of genuine beta activity in different neurophysiological mechanisms.

Regular insulin secretory oscillations despite impaired ATP synthesis in Friedreich Ataxia patients.

Friedreich Ataxia is an inherited disorder caused by decreased expression of a mitochondrial protein called frataxin. Deficiency of this protein causes reduced biogenesis of iron-sulfur clusters, and subsequently impaired synthesis and replenishment of ATP IN VIVO. Basal secretion of insulin occurs in an oscillating manner presumably triggered by ATP-dependent feedback inhibition of glycolytic flux. Hence, individuals with reduced ATP synthesis rates should possibly exhibit impaired insulin secretory oscillations if these were solely dependent on ATP. In the present study Friedreich Ataxia patients with a presumptive impairment of ATP synthesis in pancreatic beta-cells were evaluated for regularity of basal secretory oscillations of insulin. Healthy siblings were employed as controls. In conflict with the initial hypothesis, no differences in regards to oscillation patterns were observed between patients and controls. Supported by EX VIVO evidence, these findings tentatively suggest that pulsatile insulin secretion might not be exclusively dependent on ATP feedback inhibition in humans.