Insulin stimulators

The absorption of sulfonylureas from the upper gastrointestinal tract is faidy rapid and complete. The agents are transported in the blood as protein-bound complexes. As they are released from protein-binding sites, the free (unbound) form becomes available for diffusion into tissues and to sites of action. Specific receptors are present on pancreatic islet P-ceU surfaces which bind sulfonylureas with high affinity. Binding of sulfonylureas to these receptors appears to be coupled to an ATP-sensitive channel to stimulate insulin secretion. These agents may also potentiate insulin-stimulated glucose transport in adipose tissue and skeletal muscle. 

Metformin restrains hepatic glucose production principally by suppression of gluconeogenesis. The mechanisms involve potentiation of insulin action and decreased hepatic extraction of certain gluconeogenic substrates such as lactate. In addition, metformin reduces the rate of hepatic glycogenolysis and decreases the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake and glycogenesis by skeletal muscle is increased by metformin mainly by increased... 

GLUT 4 Heart and skeletal muscle, adipose tissue Insulin-stimulated uptake of glucose... 

Figure 21-6. Regulation of acetyl-CoA carboxylase by phosphorylation/dephosphorylation.The enzyme is inactivated by phosphorylation by AMP-activated protein kinase (AMPK), which in turn is phosphorylated and activated by AMP-activated protein kinase kinase (AMPKK). Glucagon (and epinephrine), after increasing cAMP, activate this latter enzyme via cAMP-dependent protein kinase. The kinase kinase enzyme is also believed to be activated by acyl-CoA. Insulin activates acetyl-CoA carboxylase, probably through an "activator" protein and an insulin-stimulated protein kinase.

Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity. It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acids, and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue but not in liver. Insulin also—by its ability to depress the level of intracellular cAMP—inhibits lipolysis in adipose tissue and thereby reduces the concentration of... 

Analysis of lipid metabolism in adipocytes (insulin stimulation of lipogenesis) using a 60... 

Boulton, T. G., Yancopoulos, G. D., Gregory, J. S., Slaughter, C., Moomaw, C., Hsu, J., and Cobb, M. H. (1990). An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 249 64-67. 

Nakielny, S., Cohen, P., Wu, J., and Sturgill, T. (1992a). MAP kinase activator from insulin-stimulated skeletal muscle is a protein serine/threonine kinase. EMBO S. 11 2123-2129. 

Sturgill TW, Ray LB, Erikson E, Mailer JL 1988 Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature 334 715-718... 

Insulin also plays a role in fat metabolism. In humans, most fatty acid synthesis takes place in the liver. The mechanism of action of insulin involves directing excess nutrient molecules toward metabolic pathways leading to fat synthesis. These fatty acids are then transported to storage sites, predominantly adipose tissue. Finally, insulin stimulates the uptake of amino acids into cells where they are incorporated into proteins. 

Carayannopoulos, M. O., et al. GLUT8 is a glucose transporter responsible for insulin-stimulated glucose uptake in the blastocyst. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 7313-7318. 

Cheatham, B., Vlahos, C. J., Cheatham, L., Wang, L., Blenis, J., and Kahn, C. R. (1994). Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol. Cell. Biol. 14, 4902-4911. 

Store it while it s here. Insulin binds to a specific receptor on the cell surface and exerts its metabolic effect by a signaling pathway that involves a receptor tyrosine kinase phosphorylation cascade. Note that insulin stimulates storage processes and at the same time inhibits degradative pathways. 

The holochromodulin binds to the insulin-stimulated insulin receptor, helping to maintain its active conformation and increasing insulin signaling. 

It was discovered nearly 20 years ago that V(V) as vanadate and V(IV) as vanadyl can mimic some of the effects of insulin (stimulate glucose uptake and oxidation and glycogen synthesis) (512, 513). Vanadate is an effective insulin mimetic in the diabetic rat (514), but has proved to be too toxic for human use. Vanadyl, as VOS04, is also unsuitable because high doses are needed on account of its poor oral absorption. Vanadium complexes with organic ligands have proved to be less toxic and can have improved aqueous solubility and lipophil-icity. 

Triglyceride and fatty acid synthesis are promoted by insulin stimulation of liver and adipose tissues by causing the phosphorylation of the first and controlling enzyme in the pathway acetyl-CoA carboxylase (see Section 6.3.2). This enzyme catalyses the formation of malonyl-CoA and requires both allosteric activation by citrate and covalent modification for full activity. 

In adipose tissue, insulin stimulation suppresses triglyceride hydrolysis (to free fatty acids and glycerol) by activating cAMP phosphodiesterase (cAMP PDE). Cyclic AMP, (3, 5 cAMP), is required to stimulate hormone sensitive lipase (HSL), the enzyme which hydrolyses triglyceride within adipocytes PDE converts active 3, 5 cAMP to inactive 5 AMP thus preventing the stimulation of HSL. The net effect of insulin on lipid metabolism is to promote storage. 

Activation of protein phosphatases. Paradosically, insulin stimulation via its tyrosine kinase receptor ultimately may lead to dephosphorylating enzymes... 

GLUT 4 Skeletal muscle Adipose tissue 5 mM Insulin-stimulated glucose uptake... 

Insulin stimulates and glucagon inhibits PFK-1 in hepatocytes by an indirect mechanism involving PFK-2 and fructose 2,6-bisphosphate (Figure 1-12-3). 

GLUT 4 Lower K insulin-stimulated adipose and muscle... 

To gain further insight into the mechanisms involved in defective insulin-stimulated glucose uptake in skeletal muscle of insulin-resistant subjects, the possible role of IMCL in the pathogenesis of skeletal muscle insulin resistance and type 2 diabetes mellitus was explored by comparing insulin sensitivity (GIR) and IMCL content of insulin-resistant and insulin-sensitive offsprings of patients with type 2 diabetes. Twenty-six healthy subjects were included in the first study, 13 of them classified as insulin-sensitive and further 13 as insulin-resistant. Metabolic and anthropometric data are given in Table 4. 

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