Mechanisms of tolbutamide-stimulation of pancreatic B cells — A reply
Dear Sir
Letters to the E d i t o r M e c h a n i s m s o f T o l b u t a m i d e - S t i m u l a t i o n o f P a n c r e a t i c B Cells - A
-
There is no doubt that the mechanisms of action
of sulphonylureas on pancreatic B cells are still
incompletely understood. The letter by Dr. Malaisse
and his colleagues reinforces one conclusion of my
article [
1
]: "The basis of the interaction between
glucose and tolbutamide, not investigated here, remains
to be clarified".
The following points in their letter deserve some
comments:
1) The proposal that tolbutamide directly
interferes with Ca 2+ transport in B cells is interesting, but
difficult to evaluate adequately since the reference
paper is not available yet [
2
]. From abstract reports
[
3, 4
], it can be appreciated, however, that Malaisse
et al. ascribe the insulinotropic activity of
sulphonylureas to a Ca2+-ionophoretic capacity, similar to that
of the classical Ca2+-ionophore A23187. Such an
interpretation does not seem compatible with the
evidence that tolbutamide does not penetrate B cells [5].
2) In the absence of glucose stimulation,
tolbutamide decreases Rb § effiux from islet cells [
6
].
This original report has been confirmed [
7
] and
extended [
1
]. Furthermore, recent
electrophysiological evidence [
8
] strongly suggests that the reduction
in K § permeability is involved in the depolarization
of B cells by tolbutamide. It also shows that
increasing the concentration of extracellular Ca 2+ during
tolbutamide stimulation tends to repolarize B cells and
replaces the continuous electrical activity by regular
bursts. These observations [
8
] and the measurements
of insulin release, Ca 2§ uptake and Rb + effiux [
1
]
would be difficult to explain, if tolbutamide were
acting simply as a Ca2+-ionophore.
3) In the presence of a stimulatory concentration
of glucose (8.3mmol/1), tolbutamide surprisingly
produces a short-lived increase in Rb § effiux. Such
an effect, however, is not specific to sulphonylureas.
Potentiation of glucose-stimulated (7 mmol/1) insulin
release by 2 mmol/1 theophylline is also attended by
an initial and transient rise in the rate of Rb + effiux
[
9
]. If. one a priori rules out that such a brief event
might occur in non-B cells, the most plausible
explanation is that it reflects activation of the K +
permeability of B cells by a rise in intracellular Ca2+ [
10
]. By
no means, however, is it sufficient to exclude
activation of voltage-dependent Ca channels, the
permeability of which depends on the membrane potential
and not on the K + permeability per se. Although the
electrical effects of tolbutamide on B cells stimulated
by glucose have been paid little attention, so far,
preliminary data [
11
] suggest that the drug increases
the duration of the phases of depolarization induced
by 11 mmol/1 glucose.
No explanation is completely satisfactory for all
effects of tolbutamide on B cells; their understanding
obviously requires further investigation. I suggest,
however, that to avoid unnecessary controversies,
more attention be paid to the relevant concentrations
of the drug. Thus, it has become clear now [
1, 8
], that
concentrations of tolbutamide similar to those found
in vivo produce, in B cells, ionic, electrical and
secretory effects, different from the supposedly
"classical" effects described with the high concentrations
(>50 ~tg/ml) commonly used in vitro.
Yours sincerely,
J. C. Henquin
Letters to the Editor
Diabetologia
9 by Springer-Verlag 1980
Haematocrit, Glycosylated Haemoglobin and Diabetic Microangiopathy
Poorly controlled diabetics tend to have higher
HbA1 values than well-controlled diabetics and
nondiabetics [
1
]. It has been suggested that glycosylated
haemoglobin, by causing a shift in the oxygen
dissociation curve [
2
], may lead to local tissue hypoxia and
so stimulate erythropoietin production. Ditzel and
Standl [
3
] have suggested a role for tissue hypoxia in
the evolution of microvascular diabetic
complications. Not only could local hypoxia be damaging by
itself, it could also, by the mechanism outlined
induce polycythaemia, increase blood viscosity and
so impair flow in the microcirculation.
In a recent paper Graham et al. (Diabetologia 18:
205, 1980) claimed that diabetics tend to have a
relative polycythaemia which correlates with their HbA1
values when compared with non-diabetics. We would
like to raise several points. First, although
retinopathy and nephropathy often occur together
and are therefore both considered to be examples of
microangiopathy, it is not yet proven that they have
an identical aetiopathogenesis. Secondly, when
severe nephropathy coexists with retinopathy blood
analysis may reveal a normocytic normochromic
anaemia. When assessing the degree of
polycythaemia we agree that red cell mass is the most
accurate method currently available but we feel that
as a simpler method the packed cell volume (PCV) or
haematocrit is a more useful index of (...truncated)