Inhibition Insulin

Raz I> Katz A, Spencer MK Epinephrine inhibits insulin-mediated glycogenesis but enhances glycolysis in human skeletal muscle. Am J Physiol 1991 260 E430. 

Karas, M., M. Danilenko, D. Fishman et al. 1997. Membrane-associated insulin-like growth factor-binding protein-3 inhibits insulin-like growth factor-I-induced insulin-like growth factor-I receptor signaling in ishikawa endometrial cancer cells. J Biol Chem 272(26) 16514—16520. 

Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW and Shulman GI. 2002. Mechanism by which fatty acids inhibit insulin activation ofinsuhn receptor substrate-1 (IRS-l)-associatedphosphatidylinositol 3-kinase activity in muscle. J Biol Chem 27 277(52) 50230-50236. 

Design concepts are now being applied more effectively to mineral supplements. For example, by controlling the redox potential of iron, toxic effects associated with excess Fe(II) during parental supplementation can be avoided. Peroxovanadate complexes can inhibit insulin-receptor-associated phosphotyrosine phosphatase and activate insulin receptor kinase, and both V(IV) and V(V) offer promise as potential insulin mimics. 

Jordan SD, Kruger M, Willmes DM et al (2011) Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nat CeU Biol 13 434-446... 

These compounds include NE, which acts on both a and P receptors, and epinephrine, which is more active on p receptors. As mentioned previously, catecholamines lacking a 4-OH group, such as phenylephrine (4.47) and methoxamine (4.48), show almost pure a, activity. They are both vasoconstrictors, used in treating hypotension (low blood pressure) and nasal congestion. These drugs may also inhibit insulin release. 

The time- and concentration-dependent inhibitory and stimulatory effects of IL-1 on insulin secretion by islets are paralleled by similar changes in preproinsulin mRNA levels. Treatment of rat islets with concentrations of IL-1 that inhibit insulin sectetion reduce preproinsulin mRNA content. Conditions of IL-1 treatment which stimulate insulin secretion increase preproinsulin mRNA content of islets (Spinas et al., 1987 Eizirilc, et al., 1990). Islet-cell replication is also inhibited by exposure to IL-1. The importance of these findings are unknown, although increases in preproinsulin mRNA levels have been suggested to participate in lL-1-induced stimulation of glucose-induced insulin secretion (Spinas et al., 1987). The reduction of preproinsulin mRNA levels by lL-1 treatment on the other hand does not appear to participate in IL-1-induced inhibition of glucose-stimulated insulin secretion (see below). 

IL-1 also appears to inhibit insulin secretion by modulating the mitochondrial oxidative metabolism of purified P cells. Treatment of purified P cells for 18 hr with IL-1 results in nearly complete inhibition of the oxidation of [ CJ-D-glucose to C02 (Fig. 10). This inhibition is completely prevented by NMMA (Corbett et al., 1992b). Treatment of purified a cells with lL-1 has no effect on glucose oxidation, suggesting that the effects of IL-1 are specific to the endocrine P cell (Fig. 10). These findings are further supported by the observation that lL-1 induces iron-nitrosyl complex formation and the accumulation of cGMP in the... 

If jS-cell production of nitric oxide participates in IDDM, human islets must produce nitric oxide in response to cytokines. We have shown that a combination of cytokines (lL-1, IFN, and TNF) induce the formation of nitric oxide by isolated human islets (Corbett et al., 1993b). The formation of nitric oxide has been demonstrated by cytokine-induced cGMP accumulation, nitrite formation, and EPR-detectable iron-nitrosyl complex formation (Fig. 12), all of which were prevented by NMMA. The cytokine combination of IFN and lL-1 are required for nitrite production, while TTSIF potentiates IL-1 and IFN-induced nitrite formation by human islets. The cytokine combination of lL-1, TNF, and IFN also influences the physiological function of insulin secretion by human islets. Low concentrations of this cytokine combination slightly stimulate insulin secretion, while high concentrations inhibit insulin secretion, similar to the concentration-dependent effects of lL-1 on rat islet function. NMMA partially prevents the inhibitory effects of this cytokine combination on insulin secretion from human islets, suggesting that nitric oxide may participate in )3-cell dysfunction associated with IDDM. 

Corbett, J. A., Sweetland, M. A., Lancaster, J. R., Jr., and McDaniel, M. L. (1993a). A 1 hour pulse with IL-lb induces the formation of nitric oxide and inhibits insulin secretion by rat islets of Langerhans Evidence for a tyrosine kinase signaling mechanism. FASEBJ. 7, 369-374. 

Hughes, J. H., Colca, J. R., Easom, R. A., Turk, J., and McDaniel, M. L. (1990a). Interleukin 1 inhibits insulin secretion from isolated rat pancreatic islets by a process that requires gene transcription and mRNA translation. J. Clin. Invest. 86, 856-863. 

Diazoxide inhibits insulin release from the pancreas (probably by opening potassium channels in the beta cell membrane) and is used to treat hypoglycemia secondary to insulinoma. Occasionally, hyperglycemia complicates diazoxide use, particularly in persons with renal insufficiency. 

Calcium channel blockers minimally interfere with stimulus-secretion coupling in glands and nerve endings because of differences between calcium channel type and sensitivity in different tissues. Verapamil has been shown to inhibit insulin release in humans, but the dosages required are greater than those used in management of angina. 

Nickel also may act to stimulate or inhibit the release of various hormones (Nielsen, 1971. 1972 Dormer et al., 1973 Clay, 1975 Harak-Sunderman, 1975). Nickel has been found to inhibit insulin release from the pancreas (Dormer et al.. 1973 Clay, 1975). and stimulates glucagon secretion (Horak-S underman, 1975). 

Pancreatic beta cells in rats express NMDA receptors, stimulation of which leads to insulin secretion (325). The authors postulated that dextromethorphan inhibits insulin secretion by blocking NMDA receptors and thus impairs glucose tolerance. Both patients had reduced insulin... 

Adhami VM, Siddiqui IA, Ahmad N, Gupta S, Mukhtar H. 2004. Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer. Cancer Res 64 8715-8722. 

Alpha2 antagonists have relatively little clinical usefulness. There has been experimental interest in the development of highly selective antagonists for use in Raynaud s phenomenon to inhibit smooth muscle contraction and in the treatment of type 2 diabetes (n2 receptors inhibit insulin secretion) and psychiatric depression. It is not known to what extent the recognition of multiple subtypes of a2 receptors will lead to development of clinically useful subtype-selective new drugs. 

Howard BD, Gundersen CBJ (1980) Effects and mechanisms of polypeptide neurotoxins that act presynaptically. Annu Rev Pharmacol Toxicol 20 307-36 Huang X, Wheeler MB, Kang YH, Sheu L, Lukacs GL et al. (1998) Truncated SNAP-25 (1-197), like botulinum neurotoxin A, can inhibit insulin secretion from HIT-T15 insulinoma cells. Mol Endocrinol 12 1060-70... 

Activation of a2-adrenoceptors in pancreatic p-cells inhibits insulin release, and this effect is blocked by 0C2 adrenoceptor antagonists (Angel and Langer. 1988 Lorrain et al. 1992). A peripherally active 0C2 adrenoceptor antagonist, SL 84.0148, was developed for the treatment of type 11 diabetes (Angel et al. 1992 1996) but was abandoned in Phase 11 (S.Z. Langer, unpublished). 

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