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Interactions of wild-type and Trp120-->Phe glucoamylase with maltooligodextrin (Gx) substrates and the tight-binding inhibitor acarbose (A) were investigated here using stopped-flow fluorescence spectroscopy and steady-state kinetic measurements. All wild-type and Trp120-->Phe glucoamylase reactions followed the three-step model E + Gx(or A) (k1) <==> (k-1) EGx (or A) (k2) <==> (k-2) E*Gx(or A) (k3) --> E + P or E-A, previously shown to account for the glucoamylase-maltose system [Olsen, K., Svensson, B., & Christensen, U. (1992) Eur. J. Biochem. 209, 777-784]. K1 = k-1/k1, k2, and k-2, and the catalytic constant, k3, are determined. Binding of maltooligodextrins in the first reaction step is weak, with little difference between wild-type and Trp120-->Phe glucoamylase. The second step, involving a conformational change, in contrast, is strongly influenced by the mutation and by the substrate length. Here wild-type glucoamylase reacts faster and forms more stable intermediates the longer the substrate. In contrast, Trp120-->Phe reacts slower the longer the substrate. The effect of the mutation is thus smallest on maltose. The Trp120-->Phe substitution reduces the fluorescence signal only by 12-20%, indicating that other tryptophanyl residues are important in reporting the conformational change. Trp120 also strongly influences the actual catalytic step, since the mutation decreases the kc values 30-80-fold. Acarbose behaves similar to maltotetraose in the first and the second steps with wild-type but not the Trp120-->Phe glucoamylase. Also, a third step in the acarbose reaction which parallels the catalytic step is strongly affected by the mutation. The rate constant k3 increases 200-fold.
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This study assessed the effect of postprandial glucose reduction by acarbose on insulin sensitivity and biomarkers of systemic inflammation.
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We have established a new method for the enzymatic diagnosis of glycogen storage disease type II (Pompe disease or acid maltase deficiency) using mixed leukocytes. The method employs glycogen and 4-methylumbelliferyl-alpha-D-glucopyranoside (4MU-alphaGlc) as substrates for measuring the lysosomal acid alpha-glucosidase (acid alphaGlu) activity, and incorporates acarbose to eliminate the interference of unrelated alpha-glucosidases (predominantly maltase-glucoamylase). It is shown that 3.0 micromol/L acarbose completely inhibits the maltase-glucoamylase activity at pH 4.0, but the lysosomal acid alphaGlu activity by less than 5%. With this method, we determined the acid alphaGlu activity in mixed leukocytes from 25 patients with glycogen storage disease type II (2 infantile and 23 late-onset cases), one GAA2/GAA2 homozygote and 30 healthy subjects. In the assay with glycogen as substrate, the addition of acarbose created a clear separation between the patient and the control ranges. In the assay with 4MU-alphaGlc as substrate, the two ranges were fully separated but remained very close despite the use of acarbose. The separation of the patient and normal ranges was improved considerably by taking the ratio of acarbose-inhibited over uninhibited activity. A GAA2/GAA2 homozygote was correctly diagnosed with 4MU-alphaGlc but misdiagnosed as patient when glycogen was used as substrate. We conclude that the inclusion of 3.0 micromol/L acarbose in the assays with glycogen and 4MU-alphaGlc substrates at pH 4.0 allows for the specific measurement of lysosomal acid alphaGlu activity in mixed leukocytes, thus enabling a reliable diagnosis of glycogen storage disease type II in this specimen.
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Besides lifestyle, various pharmacological treatments have proven their efficacy to reduce the incidence of type 2 diabetes in high-risk individuals, especially in those with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG). Major placebo-controlled clinical trials demonstrated favourable effects of various glucose-lowering drugs generally used for the treatment of type 2 diabetes, i.e. metformin, acarbose and thiazolidinediones (glitazones). These trials showed a lower rate of progression to overt diabetes and a higher regression rate to a normal glucose status with active treatment as compared to placebo after a follow up of several years. Ongoing trials should confirm such a favourable effect with those drugs and may demonstrate a similar protective effect with other pharmacological approaches such as glinides or even basal insulin regimen. However, the reported favourable effects were generally observed while the subjects were still on treatment, and partially vanished after a rather short period of wash-out of several weeks. Therefore, the distinction between a true preventing effect and simply a masking effect is difficult with glucose-lowering drugs. In addition, as type 2 diabetes is a progressive disease, it is still questionable whether the effect corresponds to a prevention effect or only to a postponing of the development of the disease. Owing to the pathophysiology of the disease, the only way to block the progression of type 2 diabetes is probably to avoid the progressive loss of beta-cell function and/or mass. Whatsoever, these data obtained in large clinical trials bring further argument to support early treatment of diabetes, even at a prediabetic state, in order to stop the vicious circle leading to an inevitable deterioration of glycaemia in predisposed subjects.
Type 2 diabetes often has an insidious onset with hyperglycaemia being present for many years before diagnosis is made. It is a progressive disease, due in part to loss of beta-cell function, with the reduction in function probably commencing 10-12 years prior to diagnosis and being aggravated by increasing fasting plasma glucose levels. Earlier intervention in those at risk from type 2 diabetes, aimed at minimizing hyperglycaemia, may prevent or delay overt diabetes and the associated development of micro- and macrovascular disease. Six-year follow-up data from the UK Prospective Diabetes Study, confirm that sulphonylurea, metformin and insulin therapy can reduce hyperglycaemia in individuals with type 2 diabetes. Although none of these agents prevent the subsequent progressive increase in fasting glucose levels, preliminary results with acarbose show that fasting plasma glucose levels can be maintained over 1 year of therapy. Three large-scale studies are currently investigating whether treatment with acarbose at an earlier stage of the disease process, in subjects with varying degrees of glucose intolerance, may be beneficial in helping to prevent or delay the onset of diabetes.