Is non-insulin dependent glucose uptake a therapeutic alternative? Part 1: physiology, mechanisms and role of non insulin-dependent glucose uptake in type 2 diabetes

• Published in: Diabetes & metabolism 2005-11, Vol.31 (5), p.415-426
• Main Author: Wiernsperger, NF
• Format: Article
• Language: English
• Subjects: AMPK; Biological and medical sciences; Biological Transport; Blood Glucose - metabolism; Cell Membrane - metabolism; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Diabète de type 2; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucokinase; Glucose Transport Proteins, Facilitative - metabolism; Glucose transporter; Glycogène; Humans; Insulin - physiology; Medical sciences; Nitric oxide; Non-insulin dependent glucose transport; Oxide nitrique; Transport du glucose non dépendant de l'insuline; Transporteurs du glucose; Type 2 diabetes
• ISSN: 1262-3636; 1878-1780
• DOI: 10.1016/S1262-3636(07)70212-4

Several decades of research for treating type 2 diabetes have yielded new drugs but the actual experience with the available oral antidiabetic compounds clearly shows that therapeutic needs are not matched. This highlights the urgent need for exploring other pathways. All cell types have the capacity to take up glucose independently of insulin, whereby basal but also hyperglycaemia-promoted glucose supply is ensured. Although poorly explored, insulin-independent glucose uptake might nevertheless represent a therapeutic target, as an alternative to the clear limits of actual drug treatments. This review not only critically examines some major pathways not requiring insulin (although they may be influenced by the hormone) but importantly, this analysis extends to the clinical applicability of these potential therapeutic principles by also considering their predictable tolerability for long-term therapy. In particular vascular safety (the ultimate problem linked with diabetes) will be envisaged because of the ubiquitous distribution of glucose transporters and some linked mechanisms. Several mechanisms can be identified which do not require insulin for their functioning. The first part of this review deals with the description, the regulation and the limits of some mechanisms representing potential pharmacological targets capable of having a highly significant impact on glucose uptake. These selected topics are: a) unmasking and/or activation of glucose transporters in cell plasma membranes, b) insulin mimetics acting at postreceptor level, c) activation of AMPK, d) increasing nitric oxide and e) increasing glucose-6P and glycogen stores. Le captage du glucose non insulinodépendant représente-il une nouvelle voie thérapeutique? 1 re partie. Physiologie, mécanisme et rôle du captage du glucose non insulinodépendant dans le diabète de type 2 Malgré plusieurs décennies de recherche intensive et l'apparition de molécules nouvelles, l'expérience clinique montre clairement leur insuffisance à combattre l'évolution du diabète de type 2 sur le long terme. Le besoin de molécules plus puissantes est aujourd'hui une évidence, ce qui implique d'envisager des voies nouvelles de recherche pharmacologique. L'une d'elles, très peu abordée jusqu'ici, pourrait être l'augmentation du transport du glucose par l'activation de voies non dépendantes de l'insuline. Cet article examine de façon critique plusieurs mécanismes susceptibles de répondre à cette attente mais l'analyse intè