Insulin associated states

Figure 9.19 Suggested scheme of events after the s.c. administration of soluble human insulin the concentration of hexa-meric zinc-insulin, which is the predominant form of insulin in soluble insulin (40 Unit or 100 Unit - i.e. 0.6 mmol dm ), decreases as diffusion of insulin occurs and os a result the hexamer dissociates into smaller units to achieve monomeric insulin requires a 1000-fold dilution. The importance of the association state is that the larger species have more difficulty dispersing and passing through the capillary membrane.

Some proteins self-associate in aqueous solution to form oligomers. Insulin, for example, exists in several associated states the zinc hexamer of insulin is a complex of insulin and zinc which dissolves slowly into dimers and eventually monomers following its subcutaneous administration, so giving it long-acting properties. In most cases, however, it is desirable to prevent association such that only monomeric or dimeric forms are present in the formulations and a more rapid absorption is achieved. Recent studies have been directed towards engineering insulin molecules which are not prone to association, " or the prevention of association through the addition of surfactants. Protein self-association is a reversible process, i.e. alteration of the solvent properties can lead to the re-formation of the monomeric native protein. There is an important distinction between this association... 

In diabetes mellitus, blood glucose homoeostasis and rate of lipolysis in adipose tissue appear to be associated. This relationship is most apparent in an insulin-deficient state, where glucose homoeostasis is maintained at the expense of other fuel sources, mainly FFA. Insulin deficiency initiates lipolysis. The increase in fatty acid oxidation further favours hepatic gluconeogenesis. 

This ABA-type triblock copolymer was used as a drug release depot for continuous release of hiunan insulin and of glucagons-like peptide-1 (GLP-1). The observation of both reduced initial burst and a constant release of hmnan insulin from ReGel in vitro is due to the domain structure of the gel and to the modification of the association states of insulin by zinc. Animal studies using SD rats were performed to verify the release profile of insuhn from this ABA block copolymer hydrogel. ReGel formrdation maintained insulin release for up to 15 days, which could allow diabetic patients to reduce the number of insulin injections to two per month for basal insulin requirements (31). 

Figure 5. Correlation between time to 50% disappearance from the injection site in pig studies and the mean association state of various insulins at lmmol/1. The association state was deduced from osmometry, and, in the case of hexameric insulins, the tendency to dissociation upon dilution was assessed by size-exclusion chromatography (SEC). Note that T-50% > 100 is log scale. Each figure and letter in the diagram represents the mean results for one insulin or insulin analog H, Human 2Zn-, B, bovine 2Zn-, and P, porcine 2Zn-insulin C, cobalt(III) human insulin Z, human, zinc-free insulin. For other relevant codes, see Table VII. (From Brange ei a/., 1990, with permission.)...

In this study, we designed the sustained release tystem, which provides basal line insulin release for duration of over several weeks by one injectioa Hmnan insulin was entrapped in the hydrogel in order to sustain its release as a subcutaneous insulin delivery system. We tried to modify the association states of insulin by zinc in order to inhibit the initial bmst effect and obtain constant release rate. At otherwise equivalent conditions, insulin associated from monomer and dimer to hexamer with inaeasing zinc concentration [22]. Insulin samples with different zinc contents exhibited different release profiles due to association-state differences within the hydrogel. 

Generally, insulin forms a hexamer with zinc. The insulin association resulted from the zinc content in the insulin [22]. However, without zinc, insulin formed various association states such as monomer, dimer, hexamer, and aggregate. It is thought that insulin without zinc formed the aggregation state inside the gel. The aggregated insulin may not diffuse fast from the ReGel formulation, which presented a slower release (60% after 15 days). Insulin with 0.2 wt% zinc formed the hexameric state. The release profile of the insulin with... 

Metformin. Metformin [657-24-9] (1,1-dimethylbiguanide), mol wt 129.17, forms crystals from propanol, mp 218—220°C, and is soluble in water and 95% ethanol, but practically insoluble in ether and chloroform. Metformin, an investigational dmg in the United States, does not increase basal or meal-stimulated insulin secretion. It lowers blood glucose levels in hyperglycemic patients with Type II diabetes but has no effect on blood glucose levels in normal subjects. It does not cause hypoglycemia. Successful metformin therapy usually is associated with no or some weight loss. 

Insulin is a powerful anabolic hormone but it is unlikely that insulin deficiency causes skeletal muscle atrophy by direct action on muscle fibers (as opposed to neurogenic atrophy) except in chronic untreated cases. There is however a close parallel between the catabolic states induced by glucocorticoid excess and by insulin deficiency. Moreover, impaired insulin action is implicated in other endocrine myopathies as a contributory cause of muscle wasting. Both acromegaly and thyrotoxicosis are associated with insulin resistance due to a postreceptor defect, and secondary hyperparathyroidism due to hypophosphatemia also gives rise to insulin insensitivity. 

Insulin resistance has been associated with a number of other cardiovascular risks, including abdominal obesity, hypertension, dyslipidemia, hypercoagulation, and hyperinsulinemia. The clustering of these risk factors has been termed metabolic syndrome. It is estimated that 50% of the United States population older than 60 years of age have metabolic syndrome. The most widely used criteria to define metabolic syndrome were established by the National Cholesterol Education Program Adult Treatment Panel III Guidelines (summarized in Table 40-2). 

Because of the polyfactorial nature of disease states, such as obesity, type 2 diabetes, and Metabolic Syndrome, it is expected that drugs targeting the lipid synthesis and metabolism pathways will be used in the context of combination therapy [7]. Pre-clinical and clinical results to date indicate that pronounced efficacy could be achieved toward the management of associated lipid levels and insulin resistance, and thus, investigation in these areas provides significant promise. 

It is not clear whether V(V) or V(IV) (or both) is the active insulin-mimetic redox state of vanadium. In the body, endogenous reducing agents such as glutathione and ascorbic acid may inhibit the oxidation of V(IV). The mechanism of action of insulin mimetics is unclear. Insulin receptors are membrane-spanning tyrosine-specific protein kinases activated by insulin on the extracellular side to catalyze intracellular protein tyrosine phosphorylation. Vanadates can act as phosphate analogs, and there is evidence for potent inhibition of phosphotyrosine phosphatases (526). Peroxovanadate complexes, for example, can induce autophosphorylation at tyrosine residues and inhibit the insulin-receptor-associated phosphotyrosine phosphatase, and these in turn activate insulin-receptor kinase. 

Diabetes mellitus is characterized by hypergly-caemia and disturbances of carbohydrate, fat and protein metabolism that are associated with absolute or relative deticiencies in insulin action and/or insulin secretion. Although diabetes is an endocrine deficiency or resistance state its major manifestations are those of metabolic disease with wide ranging tissue effects. Insulin resistance does exist in type 2 diabetes, however it is also exists in many individuals without diabetes. It is difficult to accept insulin resistance is the sole determining pathogenic factor in type 2 diabetes. Therefore, it is more appropriate to describe type 2 diabetes as a condition of /3-cell dysfunction in an insulin resistance background. 

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