Dominic wrote:
>Thanks for the responses, even the couple of
>very rude and unprofessional ones I got from
>poorly informed would-be scientists who spend
>more time discrediting good scientists than
>doing real science.
>It appears the reason for the confusion about
>whether PFK is rate limiting depends on the
>cell type. The nay sayers are citing yeast
>and trypanosomes, while I am focused on mammalian
>PFK studies, largely in skeletal muscle and
>pancreatic beta cells. In the latter case, it
>appears to remain valid that PFK is effectively
>rate limiting.
I find it surprising that pancreatic beta cells are singled out as a mammmalian cell where PFK is rate-limiting. A lot of the literature that I read on the metabolic signalling method that converts blood glucose into insulin secretion says that Glucokinase is the "rate-limiting step" or "glucose sensor" of glucose utilisation in beta cells.
The arguments usuallly focus on its Km being similar to that of glucose usage by the cell as a whole or it being the first commited step etc... At least one paper where they've made an attempt of measuring the flux control coefficient of glucokinase over glucose utilisation in beta-cells (Wang & Iyendjian, PNAS 1997, 94, 4372-4377) found that graded over-expression of glucokinase of up to ~8 fold caused a proportional increase in glucose consumption so long as glucose was low (2.5mM) meaning that glucokinase has a flux control coefficient of effectively 1. Unsurprisingly, raising the glucose to 24mM lead to a drop in the control coefficient to 0.3 (but still not 0).
While I'm not arguing for Glucokinase in beta-cells to be 'the rate limiting step' in all conditions (otherwise I'd have to hand back all that grant money) the diabetes research community, including some of 'the great and the good' scientists, do hold it in high esteem.
Ed Ainscow
(A poorly informed would-be scientist).
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