**2. Structure of insulin**

The monomeric structure of insulin is made up of "A" chain with 21 amino acids and "B" chain with 30 amino acids, which are bound by disulfide bonds. Actually three disulfide bonds are present in the structure of insulin monomer, two in between the A and B chains (A7–B7, A20–B19) and one within the A chain (A7–A11) [10]. The secondary structure of the A chain is made up of two antiparallel α-helices in between A2–A8 and A13–A19 residues. Also the helices are connected by residues at A9–A12. As a result of this particular arrangement the two ends remains in close proximity to each other and side by side [11].

The B chain is made up of α-helices and β-pleated sheets [11] and in the T state it exists in two different conformations in crystallized form [12]. The α-helix exists between B9 and B19, a β-turn between B20 and B23 and the chain folds in a "V" due to Gly20 and Gly23. An extended β-strand structure in between residues B24 and B30 which allows the chain to be in close proximity to form a β-sheet with PheB24 and TyrB26 which are in close contact with B11 and B15 leucine residues of α-helix. There is a continuous α-helix from B1 to B19 in the R state. The stability of the native insulin structure is due to the disulfide bonds in between Cys residues A7–B7 and A20–B19. The affinity of insulin towards the insulin receptor is determined by the side chain interactions in between A chain and B chain. These disulfide bonds between the A and B chain provide the tertiary structure of insulin monomer which is very highly organized. The various amino acid interactions in the side chain also contribute to the stable tertiary structure of the insulin monomer molecule. These interactions are also responsible for the interaction or affinity of insulin towards its receptor [11].

The hydrophobic inner core of the insulin monomer is composed of the following amino acids residues: A6–A11 and Leu A11, B1 and B15, Ile A2, Phe B24, Val A3, Ile A13, Val B18 and Val B12. The amino acid residues from B20 to B23 are necessary for stabilizing the β-turn thereby leading to the folding of the β-sheet in between B23 and B30 towards the α-helix and hydrophobic inner core. In the dimeric form of insulin these non-polar amino acids remain in the inner side. The insulin subunits

**5**

critical [20].

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

generally remain as dimers [12]. The dimeric form of insulin is stabilized by the antiparallel β-sheets at the carboxy terminals of the B chains which remain expose on the surface of the dimeric structure. The hydrophobic core of the insulin dimer is

There are three dimers made up of six molecules of insulin peptide to make a hexamer. Some differences in the side chain like in the 25th residue (Phe) in the B chain, which is arranged to be inside the hydrophobic core of the peptide chain on one side of the dimer, deforms the perfect two-fold symmetry [11]. Also there are two zinc atoms with the imidazole groups in three histidine residues in the B chain

The knowledge about the structure of insulin is necessary to understand its interaction with insulin receptor. The amino acids in the specific regions of the insulin molecule that facilitate its binding with the receptor are located at the amino terminal of the A chain: GlyA1, IleA2, ValA3, GluA4: carboxy terminal of the A chain: TyrA19, CysA20, AsnA21; and carboxy terminal of the B chain: GlyB23, PheB24, PheB25, TyrB26. These residues have are denoted as the "cooperative site"

• Out of the two chains in the structure of insulin, the A chain has more significant role for binding to the receptor. Acetylation of the amino terminal reduces binding to receptor by 30% which makes a free amino terminus necessary for

• Gly1 deletion reduces binding to receptor by 15% which may be due to some salt bridge formation between Gly1 and B chain carboxy terminus [16].

• Also TyrA19, CysA20 and AsnA21 in the carboxy terminus of the A chain are

• The carboxy terminal of the B chain has also a significant role in the receptor binding activity, specially the first four residues, whose deletion reduces recep-

• Fifteen percent of the receptor binding activity is detained when HisB5 is deleted and 1% of binding activity is reduced when LeuB6 is deleted [19].

• For the maintenance of disulfide bonds between A and B chain, CysB7 is

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

composed of non-polar residues [11].

*Structure of insulin [10, 11, 12, 20].*

**Figure 1.**

binding to receptor [15].

along with two water molecules in the insulin hexamer [12].

of the insulin due to their negative cooperativity [13, 14].

also necessary for insulin receptor activity [16].

tor binding activity by 30% [17, 18].

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

**Figure 1.** *Structure of insulin [10, 11, 12, 20].*

*Type 2 Diabetes - From Pathophysiology to Modern Management*

proliferation and increased apoptosis [1, 8].

glucagon like peptide-1 [9].

**2. Structure of insulin**

Increasing of β-cells in a compensatory mechanism to avoid the complications caused due to insulin resistance and henceforth prevents diabetes [4]. This unique mechanism of β-cell mass expansion has been observed in normal individuals during physiological growth [5] as well as in insulin resistant patients, especially pregnant women [6] and obese people [7]. In patients having T2D the initial stage of β-cell compensation is followed by dysfunction or failure of β-cells due to less

Pancreatic β-cell dysfunction plays a critical role in progression of T2D. Insulin is produced as preproinsulin and then processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretory granules. Synthesis of insulin is regulated at both transcription and translational level. Several transcription factors in the cis-acting sequences within the 5′ region and trans-activators regulate insulin gene transcription. These transcription factors are paired homeobox gene 6 (PAX6), pancreatic and duodenal homeobox-1 (Pdx-1), MafA and B-2/ Neurogenic differentiation 1 (NeuroD1). Insulin secretion from β-cells contains a series of events and is controlled by variety of factors and signaling pathways that ultimately leads to the fusion of secretory granules with the plasma membrane. The various stimulants that regulate insulin secretion are glucose, free fatty acids, amino acids, also various hormones like melatonin, estrogen, leptin, growth hormone and

The monomeric structure of insulin is made up of "A" chain with 21 amino acids and "B" chain with 30 amino acids, which are bound by disulfide bonds. Actually three disulfide bonds are present in the structure of insulin monomer, two in between the A and B chains (A7–B7, A20–B19) and one within the A chain (A7–A11) [10]. The secondary structure of the A chain is made up of two antiparallel α-helices in between A2–A8 and A13–A19 residues. Also the helices are connected by residues at A9–A12. As a result of this particular arrangement the two

The B chain is made up of α-helices and β-pleated sheets [11] and in the T state it exists in two different conformations in crystallized form [12]. The α-helix exists between B9 and B19, a β-turn between B20 and B23 and the chain folds in a "V" due to Gly20 and Gly23. An extended β-strand structure in between residues B24 and B30 which allows the chain to be in close proximity to form a β-sheet with PheB24 and TyrB26 which are in close contact with B11 and B15 leucine residues of α-helix. There is a continuous α-helix from B1 to B19 in the R state. The stability of the native insulin structure is due to the disulfide bonds in between Cys residues A7–B7 and A20–B19. The affinity of insulin towards the insulin receptor is determined by the side chain interactions in between A chain and B chain. These disulfide bonds between the A and B chain provide the tertiary structure of insulin monomer which is very highly organized. The various amino acid interactions in the side chain also contribute to the stable tertiary structure of the insulin monomer molecule. These interactions are also responsible for the interaction or affinity of insulin towards its

The hydrophobic inner core of the insulin monomer is composed of the following amino acids residues: A6–A11 and Leu A11, B1 and B15, Ile A2, Phe B24, Val A3, Ile A13, Val B18 and Val B12. The amino acid residues from B20 to B23 are necessary for stabilizing the β-turn thereby leading to the folding of the β-sheet in between B23 and B30 towards the α-helix and hydrophobic inner core. In the dimeric form of insulin these non-polar amino acids remain in the inner side. The insulin subunits

ends remains in close proximity to each other and side by side [11].

**4**

receptor [11].

generally remain as dimers [12]. The dimeric form of insulin is stabilized by the antiparallel β-sheets at the carboxy terminals of the B chains which remain expose on the surface of the dimeric structure. The hydrophobic core of the insulin dimer is composed of non-polar residues [11].

There are three dimers made up of six molecules of insulin peptide to make a hexamer. Some differences in the side chain like in the 25th residue (Phe) in the B chain, which is arranged to be inside the hydrophobic core of the peptide chain on one side of the dimer, deforms the perfect two-fold symmetry [11]. Also there are two zinc atoms with the imidazole groups in three histidine residues in the B chain along with two water molecules in the insulin hexamer [12].

The knowledge about the structure of insulin is necessary to understand its interaction with insulin receptor. The amino acids in the specific regions of the insulin molecule that facilitate its binding with the receptor are located at the amino terminal of the A chain: GlyA1, IleA2, ValA3, GluA4: carboxy terminal of the A chain: TyrA19, CysA20, AsnA21; and carboxy terminal of the B chain: GlyB23, PheB24, PheB25, TyrB26. These residues have are denoted as the "cooperative site" of the insulin due to their negative cooperativity [13, 14].

