Glucose-stimulated insulin secretion

Incretins gut hormones that increase glucose-stimulated insulin secretion GLP-1 glucagon-like peptide-1 GDP Gastric inhibitory peptide or glucose-dependent insulino-tropic peptide... 

GDP) was isolated. It was characterized as being released by the duodenum following an oral glucose load and increasing glucose-stimulated insulin secretion. However, this pqDtide was not able to account fully for the... 

Moynihan, K.A., Grimm, A.A., Plueger, M.M., Bernal-Mizrachi, E., Ford, F., Cras-Meneur, C., Permutt, M.A. and Imai, S. (2005) Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metabolism, 2, 105-117. 

Brixel, L. R., Monteilh-Zoller, M. K., Ingenbrandt, C. S., Fleig, A., Penner, R., Enklaar, T., Zabel, B. U., and Prawitt, D. (2010). TRPM5 regulates glucose-stimulated insulin secretion. Pflugers Arch, doi 10.1007/s00424-010-0835-z. 

In 1985 Nerup and co-workers demonstrated that treatment of isolated rat and human islets with conditioned media derived from activated mononuclear cells resulted in the inhibition of glucose-stimulated insulin secretion (Mandrup-Poulsen et cd., 1985). The cytokine IL-1/3 was found to be the active component of the conditioned media (Bendtzen etal., 1986). Mandrup-Poulsen et al. (1986) further showed that continuous exposure of islets to IL-1 is toxic. 

The pioneering work of Nerup and co-workers provided the initial evidence suggesting that local fluctuations of cytokine concentrations may influence insulin secretion by islets. The effects of IL-1)8 on insulin secretion have been confirmed and extended to show that lL-l/3-induced inhibition of glucose stimulated insulin secretion by isolated islets is both time- and concentration-depen-dent as shown in Fig. 1 (Spinas et al., 1986 Comens et al., 1987 McDaniel et al., 1988a Palmer etal., 1989). Treatment of islets for short periods of time with high concentrations of IL-lj8 (1-10 U/ml) or for longer periods of time with... 

Effects of IL-1 on glucose-stimulated insulin secretion Concentration and time dependence. The ability of IL-1 to modulate insulin secretion by isolated rat islets is illustrated. Short exposures of islets to high concentrations of lL-1 [2 nM as shown here, or 5 U/ml (5 pM) as used in other studies], or prolonged exposure to low concentrations of lL-1 (0.5 pM or 0.5 U/ml) result in a stimulation of glucose-induced insulin secretion. Incubation of islets for 18 hr with 2 nM (or 5 U/ml) IL-1 results in a potent and reversible inhibition of glucose stimulated insulin secretion. Islet destruction is observed when islets are treated for 4 to 6 days with 2 nM (or 5 U/ml) lL-1. Reproduced with permission from Diabetes (McDaniel et al, 1988), by the American Diabetes Association, Inc. 

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). 

Effects of lL 1/3 on glucose-stimulated insulin secretion by jS cells purified by FACS. Islets were isolated, dispersed into single cells, and p cells were then purified by FACS. Purified p cells were incubated for 18 hr with 5 U/ml lL-1/3, 0.5 mM NMMA, or lL-10 and NMMA and then insulin secretion was examined as described previously (Corbett etal., 1992b). The lL-1 pretreatment results in a potent inhibition of glucose-stimulated insulin secretion which is significantly attenuated by treatment of purified p cells with NMMA in addition to IL-1. Reproduced wirh permission from/. Clin. Invest. (Corbett et al., 1992b), by the American StKiety for Clinical Invesrigation. 

Proposed model of IL-l-induced inhibition of glucose-stimulated insulin secretion and islet destruc-... 

Glucose Tolerance, Insulin Tolerance, and Glucose-Stimulated Insulin Secretion Tests... 

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key factor in beta-cell failure in T2DM. Some targets may show a phenotype only with GSIS and not in a GTT (11). 

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