**3. Insulin synthesis**

The various stimulants in blood that lead to insulin secretion are glucose, monosaccharide, amino acid and fatty acid.

### **3.1 Glucose stimulated insulin secretion**

Glucose acts as the main stimulus for insulin secretion in rodents as well as human beings because it is one of the major constituents of their diet and enters the circulation immediately after digestion of food. Glucose transporter 2, i.e., GLUT2 is the main glucose sensor found in the plasma membrane of β-cells. Translocation of GLUT2 to plasma membrane is dependent on insulin and it bears low substrate affinity, hence leading to high uptake of glucose. Upon entry into β-cell glucose is phosphorylated to glucose-6-phosphate by glucokinase, a type of hexokinase. Glucokinase is the rate-limiting step in the glucose metabolism in β-cells [23]. Since pyruvate dehydrogenase is not found in β-cells, pyruvate is metabolized to produce metabolic coupling factors via two pathways: (a) pyruvate is metabolized to acetyl-coA and thereby it enters glucose oxidation: the main signaling pathway couple to pyruvate oxidation through the tricarboxylic acid cycle (TCA) by mitochondria "ATP-sensitive potassium (KATP) channel-dependent insulin release." The other pathway is anaplerosis where pyruvate, like other TCA cycle intermediates is replenished. However, some of the products of these processes can act as signals stimulating release of insulin, like malonyl-CoA, NADPH, and glutamate. These products are known to amplify KATP channel-dependent insulin secretion [24, 25].

Formation of glycerol-3-phosphate (Gly3P) is the third glucose signal. Glucokinase phosphorylates glucose into glucose-6-phosphate (G6P), G6P then enters glycolysis to produce pyruvate. Gly3P can also be produced by G6P via dihydroxyacetone phosphate (DHAP) pathway. These compounds stimulate insulin secretion. Gly3P also promotes β-cell glycolysis via the mitochondrial Gly3P NADH shuttle process, which activates mitochondrial energy metabolism and augments insulin secretion [26, 27]. Dysfunction of β-cells after prolonged exposure to elevated levels of glucose has been linked to changes in glucose detection and metabolism, apoptosis, and calcium handling. Now it has already been reported that glucotoxicity impedes final steps in insulin secretion, i.e., exocytosis [28].

#### **3.2 Fatty acids and insulin secretion**

Free fatty acids (FFAs) exert both positive and negative effects on β-cell survival and insulin secretory function, depending on concentration, duration, and glucose abundance. Insulin secretion from β-cell is also stimulated by free fatty acids (FFAs).

**7**

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

The FFAs can also upregulate glucose stimulated insulin secretion (GSIS) from β-cells. In total absence of FFAs the β-cells lose their insulin secreting capability which can again be restored when exogenous fatty acids are added [29–31]. The FFAs act upon β-cells through free fatty acid receptor (FFAR)-1, hence controlling β-cell function [32, 33]. The intracellular metabolism of FFA leads to the production of lipid signal molecules like long-chain acyl-CoA and DAG [34]. DAG in turn activates protein kinase C (PKC), which in turn tales part in insulin secretion [35]. The effect of fatty acids on pancreatic islet insulin release depends mainly on degree and time of exposure. Circulating low levels of free fatty acids in the range of physiologic postprandial values actually aids in enhancing glucose-induced insulin secretion. However, excessive accumulation of lipids within islets impairs insulin secretion [36].

At individual concentrations amino acids found in physiological concentrations are poor insulin secretagogues. Some combinations of amino acids at physiological concentrations are capable of enhancing GSIS [37], like that of, glutamine cannot stimulate insulin secretion or enhance GSIS alone, but in combination with leucine, glutamine is capable of stimulating insulin secretion from β-cells and enhancing GSIS [38]. Leucine activates glutamate dehydrogenase, and glutamate dehydrogenase can convert glutamate to α-ketoglutarate, leading to production of ATP and stimulating insulin secretion [37]. Two important incretin hormones secreted from K-cells and L-cells in the gastrointestinal tract, Glucose dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), are stimulated to be secreted after ingestion of nutrients like glucose and amino acids. These hormone levels rise in the circulation after feeding food rich in protein and carbohydrates. Then they directly trigger insulin secretion from β-cells by binding to their specific cell-surface

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

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

GLP-1 secretion is dependent on high blood glucose levels [45, 46].

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

**3.3 Amino acid stimulated insulin secretion**

receptors, hence enhancing GSIS [39–41].

**4. Regulation of insulin secretion**

**4.1 Neural and hormone regulation**

*4.1.1 GLP-1*

*4.1.2 Leptin*

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

*Type 2 Diabetes - From Pathophysiology to Modern Management*

sulin is not converted to insulin [21].

ity than normal insulin [22].

saccharide, amino acid and fatty acid.

**3.2 Fatty acids and insulin secretion**

**3.1 Glucose stimulated insulin secretion**

**3. Insulin synthesis**

• HisB10 is necessary for activity because when substituted with AspB10, proin-

• However, synthetic insulin containing AspB10 has 500% greater binding affin-

• PheB24 forms hydrogen bonds important for dimer formation and PheB25 is

The various stimulants in blood that lead to insulin secretion are glucose, mono-

Glucose acts as the main stimulus for insulin secretion in rodents as well as human beings because it is one of the major constituents of their diet and enters the circulation immediately after digestion of food. Glucose transporter 2, i.e., GLUT2 is the main glucose sensor found in the plasma membrane of β-cells. Translocation of GLUT2 to plasma membrane is dependent on insulin and it bears low substrate affinity, hence leading to high uptake of glucose. Upon entry into β-cell glucose is phosphorylated to glucose-6-phosphate by glucokinase, a type of hexokinase. Glucokinase is the rate-limiting step in the glucose metabolism in β-cells [23]. Since pyruvate dehydrogenase is not found in β-cells, pyruvate is metabolized to produce metabolic coupling factors via two pathways: (a) pyruvate is metabolized to acetyl-coA and thereby it enters glucose oxidation: the main signaling pathway couple to pyruvate oxidation through the tricarboxylic acid cycle (TCA) by mitochondria "ATP-sensitive potassium (KATP) channel-dependent insulin release." The other pathway is anaplerosis where pyruvate, like other TCA cycle intermediates is replenished. However, some of the products of these processes can act as signals stimulating release of insulin, like malonyl-CoA, NADPH, and glutamate. These products are known to amplify KATP channel-dependent insulin secretion [24, 25]. Formation of glycerol-3-phosphate (Gly3P) is the third glucose signal. Glucokinase phosphorylates glucose into glucose-6-phosphate (G6P), G6P then enters glycolysis to produce pyruvate. Gly3P can also be produced by G6P via dihydroxyacetone phosphate (DHAP) pathway. These compounds stimulate insulin secretion. Gly3P also promotes β-cell glycolysis via the mitochondrial Gly3P NADH shuttle process, which activates mitochondrial energy metabolism and augments insulin secretion [26, 27]. Dysfunction of β-cells after prolonged exposure to elevated levels of glucose has been linked to changes in glucose detection and metabolism, apoptosis, and calcium handling. Now it has already been reported that glucotoxicity impedes final steps in insulin secretion, i.e., exocytosis [28].

Free fatty acids (FFAs) exert both positive and negative effects on β-cell survival and insulin secretory function, depending on concentration, duration, and glucose abundance. Insulin secretion from β-cell is also stimulated by free fatty acids (FFAs).

• GlyB23, PheB24, PheB25 and TyrB26 in the B chain carboxy terminus are evolutionarily conserved residues needed for receptor binding [16] (**Figure 1**).

important for conformation of the native insulin structure [16].

**6**

The FFAs can also upregulate glucose stimulated insulin secretion (GSIS) from β-cells. In total absence of FFAs the β-cells lose their insulin secreting capability which can again be restored when exogenous fatty acids are added [29–31]. The FFAs act upon β-cells through free fatty acid receptor (FFAR)-1, hence controlling β-cell function [32, 33]. The intracellular metabolism of FFA leads to the production of lipid signal molecules like long-chain acyl-CoA and DAG [34]. DAG in turn activates protein kinase C (PKC), which in turn tales part in insulin secretion [35]. The effect of fatty acids on pancreatic islet insulin release depends mainly on degree and time of exposure. Circulating low levels of free fatty acids in the range of physiologic postprandial values actually aids in enhancing glucose-induced insulin secretion. However, excessive accumulation of lipids within islets impairs insulin secretion [36].
