Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-06-11
2004-04-06
Nolan, Patrick J. (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S004000
Reexamination Certificate
active
06716592
ABSTRACT:
This application is a 35 USC 371 of PCT/GB97/02440, filed Sep. 11, 1997.
FIELD OF THE INVENTION
The present invention relates to materials and methods for the diagnosis and treatment of diabetes and associated obesity.
BACKGROUND OF THE INVENTION
Diabetes is said to affect about 5% of the world population. The etiology of the two major forms of diabetes, referred to as insulin-dependent diabetes (IDDM) and non-insulin dependent diabetes (NIDDM), is quite different despite similarities in their pathophysiologies. IDDM often arises in early life, and is due to autoimmune destruction of pancreatic &bgr;-cells resulting in partial or complete loss of &bgr;-cell function. NIDDM is more common in later life, typically more than 40 years in age, and about 85% of all diabetics have this form. While the NIDDM group is best regarded as a heterogeneous set of disorders, two major sub-groups are recognised, these are the non-obese, and the obese, with the latter being some 30% of the cases [1].
Some 60 years ago, Himsworth [2] first described the concept of variability in the sensitivity to insulin Insulin resistance, defined as the impaired sensitivity of the effects of insulin on whole body glucose utilization, has, as major components, the suppression of hepatic glucose production and the disposal of glucose loads by muscle via glycogen synthesis and glucose oxidation [3,4]. The importance of insulin resistance in the pathophysiology of NIDDM and the increased risk factors for vascular disease in insulin resistant individuals has been highlighted by Reaven [5,6], who described a cluster of risk factors under the term 'syndrome X′ which included; glucose intolerance, high circulating insulin, disordered lipid metabolism and hypertension. The increased prevalence of NIDDM in developed countries together with its association with heart disease and stroke, makes this one of the most devastating diseases in the Western world.
It is, perhaps, surprising, despite the remarkable increase in our understanding of the complex signalling functions of insulin, of the cellular and molecular mechanisms that underlie the diverse actions of this hormone, and of the role of mutant insulin receptors in insulin resistance, that standard texts and recent review state that “The etiology and pathogenesis of the most frequent types of NIDDM, however, are not well defined” [1]; that “The mechanisms linking obesity and insulin resistance are not known” [7]; and that “. . . the search for the physiological, biochemical and molecular basis for cardiovascular risk factor clustering in syndrome X continues” [8].
SUMMARY OF THE INVENTION
A new insight into the understanding of insulin action and NIDDM has emerged from the identification and partial characterisation of two families of inositol phosphoglycans (IPGs), each exhibiting specific insulin-mimetic properties certain of which are shown in Table 1. The IPG A-type stimulate lipogenesis, inhibit cAMP-dependent protein kinase and modify the activity of adenylate cyclase and cAMP-phosphodiesterase, thus contributing to the control of cAMP and cAMP-regulated intracellular processes which are classically inhibited by insulin. The IPG P-type activate, among other enzymes, pyruvate dehydrogenase phosphatase (PDH P'ase), glycogen synthase phosphatase and glycerol 3-phosphate acyl transferase. The activation of key phosphoprotein phosphatases plays a major role in the regulation of the disposal of glucose by oxidative metabolism via PDH, and by the non-oxidative route of storage by glycogen synthesis, both pathways classically known to be regulated by insulin [see 9-12].
The reported occurrence of inositol phosphoglycans in a wide range of tissues, and the influence of insulin on their release both in vivo and in vitro [10,12,13], has led to an intense interest in the role these compounds might play in the pathogenesis of experimental, genetic and clinical form of diabetes. Evidence that these inositol-containing compounds are important in insulin signalling comes both from in vitro studies on isolated cells and in vivo measurements using animal models of IDDM (type-I) and NIDDM (type-II) diabetes, including the findings that:
(a) Addition of antibody with anti-IPG specificity is able to block both the metabolic and mitogenic actions of insulin [14, Rademacher et al, unpublished observations].
(b) Anti-IPG antiserum inhibits the stimulating effects of insulin and P-type IPG on adipocyte glycerol-3-phosphate acyltransferase in normal Wistar rats [15].
(c) Mutant cells unable to synthesize IPGs respond to insulin as determined by tyrosine phosphorylation, but are not stimulated to elicit at least some of the metabolic effects of the hormone, in particular glycogen synthesis [16].
(d) The glycans promote serine/threonine dephosphorylation in adipocyte extracts via a mechanism requiring protein phosphatase 1, the phosphatase that regulates the activity of both glycogen synthase and phosphorylase [16,17].
(e) Impairment of glycosyl-phosphatidyl inositol-dependent insulin signalling system in isolated rat hepatocytes by strepotozotocin-induced diabetes [18].
(f) Diabetic GK rats, recognised as a model for insulin-resistant type II diabetes [9], have a defect in synthesizing or releasing functional IPGs as shown by the impaired insulin-induced activation of glycerol-3-phosphate acyltransferase by a chiro-inositol-containing insulin mediator [15] and impaired skeletal muscle glycogen synthase activation by insulin [19].
(g) Infusion of chiro-inositol into normal rats given a glucose load, or to streptozotocin-diabetic rats, results in decreased plasma glucose and enhanced activity of glycogen synthase: positive effects of chiro-inositol treatment on insulin-resistant Rhesus monkeys have also been reported [20,21].
Evidence that IPGs are important in the pathogenesis of human insulin-resistant type II diabetes derives largely from studies in which two basic approaches have been used (see Table 2):
(a) Measurements of the free chiro- and myo-inositol content of urine of diabetic subjects using gas chromatography and mass spectrometry.
(b) Measurement of the bioactivity of inositol-phosphoglycan mediators in urine and tissue extracts employing bioassay procedures, e.g. activation of pyruvate dehydrogenase phosphatase, inhibition of cAMP-dependent protein kinase. The main findings from these studies are given in Table 2.
In summary:
(a) Free chiro-inositol. This was shown to be decreased in urine of NIDDM subjects by Kennington et al [22] and by Suzuki et al [23], and to be decreased in urine of spontaneously diabetic rhesus monkeys [24]. The decreased urinary excretion rate has been reported to be directly associated with insulin resistance in a number of studies in human patients [22,25]. In contrast, increased urinary concentrations of chiro-inositol were reported by Ostlune et al [26]. The discrepancies between these reports have not been resolved.
(b) IPG P-type. Decreases in urinary excretion levels, as well as decreased concentration of chiro-inositol-containing IPGs, were found in muscle biopsy samples and haemodialysates of diabetic patients [25].
(c) Free myo-inositol. This was reported to be increased in urine of NIDDM subjects in studies by Kennington et al [22] and by Ostlund et al [26].
(d) IPG A-type. Asplin et al [25] reported unchanged IPG A-Type in urine of NIDDM subjects using the bioassay system of inhibition of cAMP-dependent protein kinase.
Two other lines of work give further support to the concept that IPGs play a significant role in the insulin signal transduction system in diabetic patients.
(a) The report that increased plasma levels of chiro-inositol were found in diabetic patients treated with insulin [Ostlund et al 26].
(b) Studies by Prochazha et al [27&r
McLean Patricia
Rademacher Thomas William
Haliday Emily M.
Nolan Patrick J.
Quine Intellectual Property Law Group P.C.
Rodaris Pharmaceuticals Limited
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