**3. Insulin secretion, function and impairment**

Insulin is synthesized and produced by β- cells in the pancreas. It is a peptide hormone regulates the metabolism of fat and carbohydrate in the body. It helps glucose absorption from the circulation by fat tissue and skeletal muscles. Figures 1 [13] and 2 [14].

**Figure 1.** Insulin secretion [13].

**Figure 2.** Insulin functions [14].

Pancreatic β-cells secrete insulin in two phases, first and second phase (biphasic manner). The loss of first phase is an independent predictor of T2DM onset. In patients with T2DM, the restoration of this phase suppresses the hepatic glucose output and improves the blood glucose concentration [15]. There are many metabolic abnormalities precede the clinical picture of T2DM as demonstrated in a study of normal first- degree subjects who had relatives with T2DM. Following intravenous glucose infusion, these subjects showed a reduced first phase insulin secretion with decreased ability of the β-cells to respond to successive increase or decrease in glucose with mild elevation in 2hours post challenge glucose level [16]. In patients with T2DM, the earliest detectable defect and exhaustion of β- cells function appeared in the reduction of the first-phase insulin secretion. This phase is brief burst and spike lasting for about 10 minutes followed by plateau second phase lasted for 2-3 hours. The reductions in both phases occur equally early and precede development of IR [17]. The fasting plasma insulin concentration is often a marker of insulin sensitivity (IS) and the changing in acute insulin secretion following glucose challenge is an early observation of progressive pancreatic defect. Glucotoxicity and lipototoxicity are contributor factors in progressive and the continuous decline in pancreatic function [1, 18].

Insulin is secreted from the secretory cells by priming reaction. Each cell contains thousands of secretory vesicles/granules. Less than <5% of these cells exist to release the readily pool insulin by exocytosis followed by minimal latency of immediate releasable pool of insulin. The bulk of granules in the cell (>95%) exist in a non-releasable reserve pool of insulin, which must undergo a series of ATP-, Ca2+-, and temperature-dependent reactions to release insulin [19].

**Figure 1.** Insulin secretion [13].

64 Treatment of Type 2 Diabetes

**Figure 2.** Insulin functions [14].

Pancreatic β-cells secrete insulin in two phases, first and second phase (biphasic manner). The loss of first phase is an independent predictor of T2DM onset. In patients with T2DM, the restoration of this phase suppresses the hepatic glucose output and improves the blood glucose concentration [15]. There are many metabolic abnormalities precede the clinical picture of The prevalence of Gestational diabetes (GDM) is 2-3% of all pregnant women. GDM women have the same second –phase insulin response as women with normal oral GTT. But, the first phase-insulin secretion is reduced with intravenous glucose and has a later peak rise with OGTT. Both groups showed a decreased in IS by 50-70%, this is back to normal in postpartum period in women with normal OGTT but this is not in women with GDM. In the same period, the latter group also demonstrated a persistent and excessive proinsulin secretion. Women with GDM have also a substantial increase in insulin secretion with OGTT or a meal compared to the same women in postpartum period. But this rise is less in women with GDM compared with pregnant women who retain normal OGTT [20].

The glycemic progression from normal to IGT mainly due to IR and from this state to overt DM depends primarily on β-cells failure in addition to progression to severe IR. Two studies, San Antonio and Hoorn Study showed the high fasting proinsulin reflects the β-cells dysfunc‐ tion and the progression to DM. IR is determined by fasting hyperinsulinemia and lower glucose removal. Therefore, the 2 hours blood glucose level following oral glucose load is the most powerful in prediction of development of T2DM. IR and progressive β-cells dysfunction are the two important defects in development of the disease [21]. IFG and IGT are intermediate states in glucose metabolism that exist between normal GT and overt diabetes are related to these defects in addition to the reduction in early-phase insulin secretion. But, subjects with IGT also have impaired late-phase insulin secretion. The latter group also demonstrated a significant higher muscle IR and low hepatic IR while subjects with IFG have severe hepatic IR with normal or near-normal muscle IS [22]. The insulin secretion and glucose homeostasis in the first phaase insulin secretion is determined by a complex pathawy of multiple signals including hypoxia inducible factor 1α, von Hippel-Lindau, factor inhibiting HIF, nicotinamide phospho-ribosyl-transferase, and the sirtuin family in addition to many other novel regulatory factors are crucial [15].
