*4.1.1 GLP-1*

GLP-1 is an incretin hormone secreted from small intestinal L-cells along with GIP when the nutrient content in blood is high generally after ingestion [42, 43]. Nutrient load from oral route triggers more insulin secretion than intravenous nutrient load [44]. GLP1-agonists and analogues are already used as an effective therapy for type 2 diabetes that are safe due to the glucose dependent effect on the insulin secretion and large randomized clinical trials proved their additional cardiovascular benefits [45]. GLP-1 acts upon β-cells due to the presence of GLP-1 receptor (GLP-1R). Activation of GLP-1R leads to activation of adenylyl cyclase, which in turn generates cAMP. Elevated level of cAMP in the cytosol enhances GSIS. Hence GLP-1 secretion is dependent on high blood glucose levels [45, 46].

### *4.1.2 Leptin*

Leptin, secreted from adipocytes, regulates function of insulin upon the glucose storing fat and liver cells [47, 48]. However, in absence of leptin, hyperinsulinemia leads to drop in blood glucose levels [47, 49]. The inhibitory action of leptin has been well known in clonal β-cells [50], cultured rodent islets [51], perfused rodent

pancreas [50, 52], human islets [51, 53, 54] and mice islets [51]. Leptin inhibits insulin secretion by antagonizing the action of elevated intracellular cAMP [55]. 3-isobutyl-1-methylxanthine (IBMX) induces leptin, elevating cAMP content by inhibiting phosphodiesterases (PDEs) [56], the enzymes which catalyze hydrolysis of cAMP. GLP-1-induced insulin secretion is also inhibited by leptin, and GLP-1 which augments insulin secretion by activation of the cAMP signaling pathways [52].

### *4.1.3 Estrogen*

In the "classical" mechanism of action of estrogen, the estrogen molecules diffuse into cell and bind to the estrogen receptor ER located in the nucleus. Rapid or "nongenomic" effects of estrogen are thought to occur through the ER located in or adjacent to the plasma membrane and may require presence of "adaptor" proteins, which target the ER to the membrane. Activation of the membrane ER leads to a rapid change in cellular signaling molecules and stimulation of kinase activity, which in turn may affect transcription [57].

β-cells are not general estrogen targets but the presence of estrogen receptor in islets makes the effect of 17β-estradiol on β-cells noteworthy [58, 59]. 17β-estradiol enhances insulin secretion from β-cells [60] and in humans, it is known to increase insulin secretion in postmenopausal women [61, 62], thus it augments glucosestimulated insulin secretion (GSIS) [63]. Two types of are present in β-cells: (1) the estrogen receptors in the nucleus, i.e., nuclear ERs (ERα and ERβ) and (2) the estrogen receptors in the membrane, i.e., the membrane ER (ERγ) [64]. 17β-estradiol significantly decreases activity of KATP channel [60], causing membrane depolarization and opening of voltage-gated Ca2+ channels, thereby potentiating glucoseinduced intracellular [Ca2+] oscillations, in a reversible manner.

### *4.1.4 Melatonin*

Melatonin, a hormone secreted by pineal gland, helps in maintaining circadian rhythm and biological clock [65]. However, melatonin receptors are found on clonal β-cells [66, 67] and human islets [68]. Melatonin shows both stimulatory [69] and inhibitory effects [70, 71], as well as neutral effects [72] on insulin section. However a decent number of reports have been found in literature about the inhibitory effect of melatonin in clonal β-cells [66, 68, 69, 73]. Melatonin inhibits glucose- and KClstimulated insulin secretion in rat islets [74]. Long term melatonin administration enhances hyperinsulinemia in vivo [75]. The signaling pathway of melatonin shows that melatonin receptor is coupled to Gi, which inhibits G protein [76]. Melatonin mediates stimulatory effect on insulin secretion through its receptor MTNR1A, by activation of Gq/11 which provokes release of IP3 by activating PLC-ε to augment insulin secretion [69, 77, 78].

#### *4.1.5 Growth hormone*

Growth hormone (GH) stimulates production of insulin-like growth factor-I (IGF-I) and its binding proteins [79]. Human IGF1 and IGF2 show high sequence similarity with insulin. Insulin receptor (IR) has two isoforms, IRA and IRB. IRB only binds insulin with high affinity while IRA binds both insulin and IGF2 with equal affinity. The IGF1 receptor (IGF1R) has high affinity towards both IGF1 and IGF2 but it binds insulin with very low affinity. According to the conventional view regarding the actions of insulin and IGF-1 in mammals, insulin mediates mainly a metabolic response, and IGF-1 mediates growth promoting effects in vivo [80]. Recombinant human IGF-I decreases serum levels of insulin and C-peptide in

**9**

**Figure 2.**

*Emerging Role of Pancreatic β-Cells during Insulin Resistance*

which is responsible for breaking down cAMP in β-cells.

human [81]. IGF-1 also suppresses insulin secretion in isolated rat islets [82]. This inhibitory activity of growth hormone is mediated through PDE3B activation [83],

Adrenergic drugs (epinephrine, norepinephrine and isoproterenol) are known to inhibit insulin secretion by binding to alpha receptors present in rat pancreas. On the other hand cholinergic drugs (acetylcholine and carbamylcholine) stimulate insulin secretion but this effect is suppressed by simultaneous addition of atropine. Thus the autonomic nervous system regulates insulin secretion under physiological

SIRT1, mammalian sirtuin homolog, plays a key role in energy homeostasis and

extends a cell lifespan by calorie restriction [85]. Glucose metabolism is tightly coupled to the regulation of insulin secretion and β-cell function [86]. Till now there are two reports showing SIRT1 positively regulates glucose-stimulated insulin secretion in pancreatic β-cells [87, 88]. In β-cells, FoxO1 is constitutively phosphorylated in cytoplasm, and activates insulin receptor signaling [89]. Accumulation of FoxO1 in the nucleus of insulin-secreting cells is triggered by palmitate during induction of lipotoxicity and impairs insulin secretion [90, 91]. Increased expression of SIRT1 in pancreatic β cells in mice improves glucose tolerance by enhancing insulin secretion [87]; deletion of SIRT1 can impair glucose-stimulated insulin secretion [88]. In both these reports, SIRT1 enhances insulin secretion by transcriptional repression of uncoupling protein 2 (UCP2) [92]. Activation of SIRT1 gives

*Hormonal and nutrient regulation of insulin secretion [23, 26, 27, 32–35, 45, 46, 55, 57, 60, 64, 72].*

*DOI: http://dx.doi.org/10.5772/intechopen.83350*

*4.1.6 Adrenergic and cholinergic agents*

**4.2 Regulation by signaling pathways**

conditions [84] (**Figure 2**).

*4.2.1 SIRT1*

*Emerging Role of Pancreatic β-Cells during Insulin Resistance DOI: http://dx.doi.org/10.5772/intechopen.83350*

human [81]. IGF-1 also suppresses insulin secretion in isolated rat islets [82]. This inhibitory activity of growth hormone is mediated through PDE3B activation [83], which is responsible for breaking down cAMP in β-cells.
