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Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies

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Considering insulin resistance and pancreatic β-cell dysfunction in our 3 cases

  • Newly diagnosed with T2DM, the patient in Case 1 probably has 20% to 50% of his β-cell function remaining; preservation of β-cell function would be desirable, especially before he reaches the second phase of decline in β-cell function, about 3 years after diagnosis
  • Diagnosed with T2DM about 2.5 years ago and not previously treated with a secretagogue, the patient in Case 2 has some β-cell function remaining; however, he is likely close to entering the second phase of steep decline in β-cell function observed in the Belfast Diet Study; in addition, insulin resistance related to his obesity must be addressed, as his obesity serves to stimulate pancreatic β-cells to secrete more insulin
  • The Case 3 patient, diagnosed with T2DM about 5 years ago, is probably in the second phase of steep decline in β-cell function and has limited β-cell function remaining; furthermore, she has failed dual oral therapy that included almost 2 years of treatment with glyburide

The incretin system and GLP-1

As discussed in greater detail in a previous Journal of Family Practice supplement,1 the incretin system is integrally involved in glucose homeostasis. Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are the 2 most important incretin hormones secreted in response to food ingestion. Patients with T2DM are resistant to GIP, which contributes to the impaired incretin response. In animal models and humans, GLP-1, the most clinically important incretin hormone, has been shown to:

  • Increase insulin biosynthesis in a glucose-dependent manner through direct activation of receptors on islet β-cells and via the vagus nerve11-13
  • Inhibit glucagon secretion in a glucose-dependent manner through direct activation of receptors on islet α-cells12,14,15
  • Slow gastric emptying16
  • Promote satiety17,18
  • Promote proliferation, increase differentiation, and prolong survival of β-cells19-21
  • Improve myocardial function22

The actions of endogenous GLP-1 are short-lived, as GLP-1 undergoes rapid degradation by the enzyme DPP-4. To overcome this rapid degradation, 2 treatment approaches have been taken. Injectable GLP-1 agonists, which are resistant to the enzymatic action of DPP-4, have been developed. Oral DPP-4 inhibitors, which allow for prolonged physiologic actions of endogenous GLP-1, also have been developed. Because of the pharmacologic levels of GLP-1 activity achieved, GLP-1 agonists have better glucose-lowering efficacy and also promote weight loss compared with DPP-4 inhibitors.23-26

Impaired incretin effect in T2DM

Until recently, it was thought that secretion of GLP-1 in response to ingestion of a meal in people with T2DM was significantly impaired compared with that in healthy controls (P<.001).27,28 Recent investigation, however, found that the GLP-1 levels in patients with T2DM did not decrease after oral ingestion of glucose or a mixed meal. The secretion of GIP, on the other hand, increased following oral ingestion of a mixed meal but not of glucose.29 These observations suggest that the unaltered secretion of GLP-1 in people with T2DM may be insufficient to make up for the diminished insulinotropic activity of GIP in people with T2DM. Consequently, pharmacologic levels of GLP-1 would be necessary to restore the insulinotropic actions of the incretin system.30

Incretin effects on the pancreatic β-cell and insulin resistance

Animal studies have indicated that GLP-1 has the ability to preserve β-cell function by suppressing β-cell apoptosis and stimulating neogenesis and proliferation.31,32 Several trials in people with T2DM have shown that administration of a GLP-1 agonist (exenatide or liraglutide) for up to 52 weeks either as monotherapy or added on to existing therapy results in significant improvement in pancreatic β-cell function.33-39 One trial involving patients whose treatment with metformin had not provided glycemic control showed a significant increase in first- and second-phase glucose-stimulated C-peptide secretion, both markers of β-cell function, with exenatide (1.53- and 2.85-fold, respectively; P<.0001) compared with insulin glargine.34 A 26-week trial found that the addition of exenatide or liraglutide to metformin, a sulfonylurea, or both resulted in improvement in β-cell function, as determined by the homeostasis model of assessment– β-cell function (HOMA-B); the improvement was significantly greater with liraglutide than with exenatide (32% vs 3%; P<.0001).37 The greater improvement in β-cell function may be a reflection of the greater lowering of fasting plasma glucose with liraglutide than with exenatide.

Clinical trials with DPP-4 inhibitors (saxagliptin or sitagliptin) also have shown significant improvement in β-cell function (up to 16%; P<.05) over 24 weeks.40-43 Generally, however, there are fewer data regarding effects on pancreatic β-cell function for the DPP-4 inhibitors than for the GLP-1 agonists.44

Treatment with a GLP-1 agonist or DPP-4 inhibitor also appears to improve insulin resistance and sensitivity.34,41,42,45 A 52-week trial found a significant reduction in insulin resistance with liraglutide 1.2 mg or 1.8 mg once daily (–0.65% and –1.35%, respectively) compared with a 0.85% increase with glimepiride (P=.0249 and P=.0011 vs liraglutide 1.2 mg and 1.8 mg, respectively).45 Another trial found comparable improvement in insulin sensitivity following 52 weeks of treatment with exenatide or insulin glargine (0.9 vs 1.1 mg/min-1/kg-1, respectively; P=.49).34

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