**2. Glucose metabolism**

Excessive hepatic glucose output is an important factor in the fasting hyperglycemia of patients with T2DM. Following administration of isotope in healthy subjects and in patients with T2DM, the overall hepatic glucose output was an increase by twofold and the gluconeogenesis more than threefold in patients compare with the controls. This finding demonstrated the increased in gluconeogenesis is the predominant mechanism responsible for increased hepatic glucose output in patients with T2DM and it is correlated with fasting plasma glucose level. [2]. Insulin controls the hepatic glucose production and promotes glucose utilization by the skeletal muscle. There is a correlation between the hepatic glucose production and the fasting glucose, in normal subjects, the postabsorptive hepatic glucose production is increased. But in

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patients with T2DM, the main causes are increased mostly by gluconeogenesis and to less extent by glycogenolysis by the liver. The Increased production of gluconeogenic precursors (lactate, alanine, and glycerol) and hyperglucagonemia with increased hepatic FFA acid oxidation might be responsible for glucogenesis. There is also a reduction in suppression of hepatic glucose production after carbohydrate ingestion which plays a role in the impairment in postprandial glucose homeostasis in T2DM [3].

The increased of the glycogenolysis and the decreased in the hepatic glucose uptake by glucagon will produce hyperglycemic phenotype associated with insulin deficiency and IR. In the overnight fasted, it is essential in countering the suppressive effects of basal insulin to maintain appropriate levels of glycogenolysis, fasting hepatic glucose production and blood glucose. Glycogenolysis is also increased by the counter-regulatory hormones response to hypoglycemia and in exercise [4]. Insulin and glucagon secretion are determined by plasma glucose concentration which is widely fluctuated according to the demand such as exercise and supply as taking high carbohydrate meal. In the resting postabsorptive state, the glyco‐ genolysis and gluconeogenesis are equal or in balance in hepatic glucose release. This is a key regulated process. In the postprandial state, suppression of liver glucose output and stimula‐ tion of skeletal muscle glucose uptake are the most important factors. Under stressful condi‐ tions, the counter-regulatory hormones of the hypoglycemia secretion are increased with increased of the sympathetic nervous system activity. Their actions to increase hepatic glucose output and to suppress tissue glucose uptake are partly mediated by increases in tissue fatty acid oxidation. In T2DM, the fasting hyperglycaemia resulted from increased gluconeogenesis while, the postprandial hyperglycemia occurs due to impaired suppression of glycogenolysis and impaired skeletal muscle glucose uptake [5].

In normal subjects the fasting plasma glucose levels are constant from day to day. This constancy is due to a close co-ordination between glucose production by the liver and glucose uptake in peripheral tissues. In T2DM, fasting hyperglycemia to less extent is correlated with increased hepatic glucose production due to impaired hepatic sensitivity to insulin. But, it is largely due to reduced insulin secretion and increased glucagon secretion. Though the basal immunoreactive insulin and glucagon levels in patients with T2DM may appear normal compared with the normal subjects, the islet function testing at matched glucose levels reveals impairments of the basal, steady-state, and stimulated insulin and glucagon secretion due to a reduction in β- cells secretory capacity and a reduced ability of glucose to suppress glucagon release. Islet α- and β-cells functions are reduced by more than 50% in T2DM by the time that clinical fasting hyperglycemia develops (140 mg/dL) [6]. The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective of the cellular insulin action [6, 7]. The defective in first phase glucose induced insulin secretion is followed by fasting hyperglycemia and the progressive failure in pancreatic β-cells function is matched by rising glucose levels to maintain basal and second-phase insulin output. The glucose is not only directly regulated insulin synthesis and secretion. But, moderated all other islet signals, including other substrates, hormones, and neural factors. In T2DM the defects are in first-phase insulin secretion and in the deficiency of the ability of glucose to potentiate other islet nonglucose β-cell secretagogues. In T2DM patients, the resulting hyperglycemia does not correct the first phase of insulin secretion defect. However, it com‐ pensates for the defective glucose potentiation, maintains nearly normal basal insulin levels and insulin responses to nonglucose secretagogues [8].

patients with T2DM, the main causes are increased mostly by gluconeogenesis and to less extent by glycogenolysis by the liver. The Increased production of gluconeogenic precursors (lactate, alanine, and glycerol) and hyperglucagonemia with increased hepatic FFA acid oxidation might be responsible for glucogenesis. There is also a reduction in suppression of hepatic glucose production after carbohydrate ingestion which plays a role in the impairment

The increased of the glycogenolysis and the decreased in the hepatic glucose uptake by glucagon will produce hyperglycemic phenotype associated with insulin deficiency and IR. In the overnight fasted, it is essential in countering the suppressive effects of basal insulin to maintain appropriate levels of glycogenolysis, fasting hepatic glucose production and blood glucose. Glycogenolysis is also increased by the counter-regulatory hormones response to hypoglycemia and in exercise [4]. Insulin and glucagon secretion are determined by plasma glucose concentration which is widely fluctuated according to the demand such as exercise and supply as taking high carbohydrate meal. In the resting postabsorptive state, the glyco‐ genolysis and gluconeogenesis are equal or in balance in hepatic glucose release. This is a key regulated process. In the postprandial state, suppression of liver glucose output and stimula‐ tion of skeletal muscle glucose uptake are the most important factors. Under stressful condi‐ tions, the counter-regulatory hormones of the hypoglycemia secretion are increased with increased of the sympathetic nervous system activity. Their actions to increase hepatic glucose output and to suppress tissue glucose uptake are partly mediated by increases in tissue fatty acid oxidation. In T2DM, the fasting hyperglycaemia resulted from increased gluconeogenesis while, the postprandial hyperglycemia occurs due to impaired suppression of glycogenolysis

In normal subjects the fasting plasma glucose levels are constant from day to day. This constancy is due to a close co-ordination between glucose production by the liver and glucose uptake in peripheral tissues. In T2DM, fasting hyperglycemia to less extent is correlated with increased hepatic glucose production due to impaired hepatic sensitivity to insulin. But, it is largely due to reduced insulin secretion and increased glucagon secretion. Though the basal immunoreactive insulin and glucagon levels in patients with T2DM may appear normal compared with the normal subjects, the islet function testing at matched glucose levels reveals impairments of the basal, steady-state, and stimulated insulin and glucagon secretion due to a reduction in β- cells secretory capacity and a reduced ability of glucose to suppress glucagon release. Islet α- and β-cells functions are reduced by more than 50% in T2DM by the time that clinical fasting hyperglycemia develops (140 mg/dL) [6]. The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective of the cellular insulin action [6, 7]. The defective in first phase glucose induced insulin secretion is followed by fasting hyperglycemia and the progressive failure in pancreatic β-cells function is matched by rising glucose levels to maintain basal and second-phase insulin output. The glucose is not only directly regulated insulin synthesis and secretion. But, moderated all other islet signals, including other substrates, hormones, and neural factors. In T2DM the defects are in first-phase insulin secretion and in the deficiency of the ability of glucose to

in postprandial glucose homeostasis in T2DM [3].

62 Treatment of Type 2 Diabetes

and impaired skeletal muscle glucose uptake [5].

The major primary reduction of suppression in the output of the endogenous hepatic glucose release and the minor effect of the splanchnic glucose sequestration in these patients are the cause of increasing in systemic glucose delivery which subsequently responsible for the postprandial hyperglycemia [9, 10].

The fasting hyperglycemia is mainly caused by the increased of the released hepatic glucose production. This mechanism is increased in psotabsorptive state and exhibits a positive correlation with fasting glucose level [3, 7 11].

The increase of the glucogenesis in the postprandial state represents the primary mechanism responsible for impaired suppression of hepatic glucose production [3]. The increased in the rate of glucose release by the liver results in part from impaired hepatic sensitivity to insulin, but it is largely due to reduced insulin secretion and increased glucagon secretion [6]. The degree of fasting hyperglycemia in a given patient with T2DM is closely related to the degree of impaired pancreatic β-cells responsiveness to glucose.

The fasting insulin secretion in normal subject and in patients with T2DM is comparable. But, there is a marked impairment of insulin secretion in patients with DM in relation to the degree of hyperglycemia. This is demonstrating the closed feedback loop operating between glucose levels and pancreatic β-cells which regulates the relationship of insulin secretion and hepatic glucose production [11]. The glucose uptake by peripheral tissue is impaired due to a combi‐ nation of decreased insulin secretion and defective in cellular insulin action [6, 7].

The amyloid deposition process is associated with disproportionate hyperproinsulinemia. The amylin in transgenic mice develops islet amyloid deposits and hyperglycemia. This is sug‐ gestive the process of amyloid fibril formation impairs the function of the β-cells and eventual death. The progressive loss of β-cell function in T2DM, initially reflected by the loss in firstphase insulin secretion, followed by a decrease in the maximal capacity of glucose to potentiate all non-glucose signals. Finally, a defective steady-state and basal insulin secretion develops, leading to complete β-cells failure requiring insulin therapy [12].

The conclusion is, T2DM is characterized by a steady-state re-regulation of plasma glucose concentration at an elevated level in which islet cells dysfunction play a necessary role [7].
