Pathogenesis of hyperglycemia in type diabetes

Type 2 diabetes is a heterogeneous disease manifested by hyperglycemia that results from multiple dysregulated biologic pathways. Each of these pathways represents a potential target for therapy (see Figure 3.2). The two major metabolic abnormalities are: 1) insulin resistance in skeletal muscle, liver, and adipocytes, and 2) a progressive decline in insulin production by

Figure 3.2 Effect of agents on the biologic pathways in patients with type 2 diabetes

Class

Primary mechanism of action

Biguanides

Decrease glucose production (liver)

Sulfonylureas

Increase insulin secretion (pancreas)

Glinides

Increase insulin secretion (pancreas)

Thiazolidinediones

Increase glucose uptake (muscle, fat)

a-Glucosidase inhibitors

Delay carbohydrate absorption (gut)

Gliptins

Prolong effects of GLP-1 (Î insulin,vl/ glucagon)

GLP-1 analogs

Similar effects as GLP-1 (Î insulin,vP glucagon,^ satiety, delays gastric emptying)

Amylin analogs

Similar effects as amylin (J- glucagon,^ satiety, delays gastric emptying)

GLP-1, glucagon-like peptide 1; T, increased; ^ decreased.

GLP-1, glucagon-like peptide 1; T, increased; ^ decreased.

pancreatic p-cells [6]. Insulin resistance results from both environmental factors (predominantly obesity and physical inactivity) and genetic factors that have yet to be fully identified. Early in the natural history of type 2 diabetes, insulin-resistant individuals who are prediabetic compensate by secreting increased amounts of insulin. Hyperglycemia results as the capacity of the pancreas to secrete insulin deteriorates and endogenous insulin production is insufficient to overcome insulin resistance. Because p-cell failure is progressive, treatment interventions must be continuously monitored and advanced. The progressive p-cell deterioration of type 2 diabetes mandates the stepwise addition of non-insulin agents and/or insulin over time. An agent that could halt the decline in p-cell function, therefore, would be of tremendous benefit. To date, no agent has been definitively shown to do this.

There is increasing evidence that the incretin system may also play a role in glucose homeostasis [7]. The incretin hormone most strongly implicated is glucagon-like peptide 1 (GLP-1). GLP-1 is a naturally occurring peptide produced by the L-cells of the small intestine. Although GLP-1 secretion is reduced in patients with type 2 diabetes, its action is preserved. GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon secretion, slows gastric emptying, and increases satiety. In normal conditions, GLP-1 is very rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV), which makes native GLP-1 impractical for use as a diabetes treatment. However, other strategies to prolong GLP-1 action, including GLP-1 analogs resistant to DPP-IV

inactivation and inhibitors of DPP-IV (see below), have been developed as antihyperglycemic agents.

Finally, there is some evidence that amylin, a pancreatic hormone that is normally co-secreted with insulin, may contribute to glucose homeostasis, particularly in advanced type 2 diabetes [8]. Its secretion appears to be diminished in advanced type 2 diabetes, but its action is preserved. Amylin has been found to slow gastric emptying, suppress postprandial glucagon secretion, and increase satiety.

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