Association, of insulin

Self-association of Insulin A Protein-Protein Interaction... 

Lawlor DA, Smith GD, Ebrahim S. British Women s Heart and Health Study. Association of insulin resistance with depression Cross sectional findings from the British Women s Heart and Health Study. BMJ 2003 327 1383-1384. 

The association of insulin resistance with a clustering of cardiovascular risk factors including hyperinsuhnemia, hypertension, abdominal obesity, dyslipidemia, and coagulation abnormahties has been referred to by a variety of names including the insuhn resistance syndrome, the metabolic syndrome, the dysmetabolic syndrome, and the deadly quartet, to name a few. Since the description of the insulin resistance syndrome by Reaven in 1988, the number of associated factors has continued to grow. 

Fig. 13. Association of insulin molecules. At left two monomers are represented with their disulfide linkages. The histidyl residues can form a complex with zinc, thereby stabilizing the dimer. In the further associations the dimers are drawn schematically as columns.

Insulin is composed of two peptide chains covalently linked by disulfide bonds (Figures 5.17 and 6.35). This monomer of insulin is the active form that binds to receptors in target cells. However, in solution, insulin spontaneously forms dimers, which themselves aggregate to form hexamers. The surface of the insulin molecule that self-associates to form hexamers is also the surface that binds to insulin receptors in target cells. Thus, hexamers of insulin are inactive. 

Type 2 diabetes is a heterogeneous and progressive endocrine disorder associated with insulin resistance (impaired insulin action) and defective function of the insulin-secreting (3-cells in the pancreatic islets of Langerhans. These endocrine disorders give rise to widespread metabolic disturbances epitomised by hyperglycaemia. The present classes of antidiabetic agents other than insulin act to either increase insulin secretion, improve insulin action, slow the rate of intestinal... 

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

METHODS OF ADMINISTERING INSULIN. Several methods can be used to administer insulin. The most common method is the use of a needle and syringe Use of microfine needles has reduced the discomfort associated with an injection. Another method is the jet injection system, which uses pressure to deliver a fine stream of insulin below the skin. Another method uses a disposable needle and special syringe The syringe uses a cartridge that is prefilled with a specific type of insulin (eg, regular human insulin, isophane [NPH] insulin, or a mixture of isophane and regular insulin). 

Figure 2. Mechanism of PDH. The three different subunits of the PDH complex in the mitochondrial matrix (E, pyruvate decarboxylase E2, dihydrolipoamide acyltrans-ferase Ej, dihydrolipoamide dehydrogenase) catalyze the oxidative decarboxylation of pyruvate to acetyl-CoA and CO2. E, decarboxylates pyruvate and transfers the acetyl-group to lipoamide. Lipoamide is linked to the group of a lysine residue to E2 to form a flexible chain which rotates between the active sites of E, E2, and E3. E2 then transfers the acetyl-group from lipoamide to CoASH leaving the lipoamide in the reduced form. This in turn is oxidized by E3, which is an NAD-dependent (low potential) flavoprotein, completing the catalytic cycle. PDH activity is controlled in two ways by product inhibition by NADH and acetyl-CoA formed from pyruvate (or by P-oxidation), and by inactivation by phosphorylation of Ej by a specific ATP-de-pendent protein kinase associated with the complex, or activation by dephosphorylation by a specific phosphoprotein phosphatase. The phosphatase is activated by increases in the concentration of Ca in the matrix. The combination of insulin with its cell surface receptor activates PDH by activating the phosphatase by an unknown mechanism.

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. 

Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary disease)... 

Acanthosis nigricans A skin condition characterized by dark, thickened velvety patches, especially in the folds of skin in the armpits, groin, and back of the neck that is often associated with insulin resistance. Also may be associated with internal malignancy, endocrine disorders, and obesity. 

R16. Ross, R., Miell, J., Freeman, E Jonest, J., Matthews, D., Preece, M and Buchanan, C, Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin-like growth factor-I. Clin. Endocrinol. 35,47-54 (1991). 

Petrik J, Pell JM, Arany E et al 1999 Overexpression of insulin-like growth factor-II in transgenic mice is associated with pancreatic islet cell hyperplasia. Endocrinology 140 2353-2363... 

---