Posts Tagged ‘Impaired glucose tolerance’


Pathophysiology of GLP-1 in Type 2 Diabetes

Reporter: Aviva Lev-Ari, PhD, RN

By Mark Abrahams, MD

Reviewed by Loren Wissner Greene, MD, MA (Bioethics), Clinical Associate Professor of Medicine, NYU School of Medicine, New York, NY

Published: 05/23/2012




For many years, it has been well known that causes of type 2 diabetes include: decreased ability of pancreatic beta cells to produce insulin, insulin resistance, and increased production of glucose by the liver.1,2 More recently, the role of the incretin hormones, GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide) has been elucidated. This article reviews the pathophysiology of GLP-1 and the impaired incretin effect observed in type 2 diabetes.

The significant reduction in the “incretin effect” observed in patients with type 2 diabetes offers strong evidence as to the importance of GLP-1. The incretin effect refers to the observation that, when challenged by glucose delivered via an oral route (as would occur with ingestion of a meal), the resulting increase in insulin levels is higher than that seen when glucose is delivered intravenously.3 The impaired ability of patients with type 2 diabetes to mount such a postprandial incretin effect appears to be due primarily to decreased circulating levels of GLP-1. This may be secondary to either decreased secretion by the gut or increased elimination of GLP-1 (elimination occurs most notably via enzymatic degradation by DPP-4 [dipeptidyl peptidase-4]).4

Despite the impaired incretin effect seen in patients with type 2 diabetes, the ability of GLP-1, when present, to elicit the secretion of insulin by pancreatic beta cells appears to be preserved.4Furthermore, it has also been shown that the ability of GLP-1 to slow gastric emptying and decrease glucagon secretion remains intact in these patients.4 This implies that the impaired incretin effect appears to be largely a function of decreased circulating levels of incretin hormones, rather than a decreased ability of target tissues to respond appropriately.

At present, it is not known if the decreased incretin effect seen in patients with type 2 diabetes is a cause or effect of the disease. While it may be intuitive to think about pathophysiology as preceding clinical disease, at least two studies suggest otherwise. In one study in patients with chronic pancreatitis, the investigators leveraged the assumption that these patients eventually develop diabetes.5 This study compared patients with chronic pancreatitis and secondary diabetes to patients with chronic pancreatitis and normal glucose tolerance. In the patients with secondary diabetes, the incretin effect was significantly impaired—but not so in patients with normal glucose tolerance. The authors concluded that clinical diabetes is more likely a cause of an impaired incretin effect rather than a consequence. In another study comparing identical twins, one with type 2 diabetes and one without, impaired secretion of GLP-1 was seen only in the siblings with diabetes—also suggesting that clinical disease may precede deficits in GLP-1 secretion.6Regardless, this subject remains controversial.

The relationship between obesity and the incretin effect is an area of active exploration as well. In one study investigating the impact of obesity on the incretin effect, a proportional relationship was observed between severity of obesity and degree of impairment of incretin effect. The authors concluded that obesity was an independent cause of diminished incretin effect.7

In summary, decreased levels of circulating GLP-1 and GIP appear to be primarily responsible for the impaired ability of the type 2 diabetes patient to mount an effective postprandial insulin response—while tissue sensitivity to hormone, when present, remains intact. Obesity is believed to contribute to the development of such an impaired incretin effect, and the question of incretin effect as either causing, or resulting from, clinical disease remains controversial.



  1. Boyle PJ, et al. Application of Incretin Mimetics and Dipeptidyl Peptidase IV Inhibitors in Managing Type 2 Diabetes Mellitus. J Am Osteopath Assoc. 2007;107(suppl):S10-S16.
  2. Freeman JS. The Pathophysiologic Role of IncretinsJ Am Osteopath Assoc. 2007;107(suppl):S6-S9.
  3. Phillips WT, et al. Rapid Gastric Emptying of an Oral Glucose Solution in Type 2 Diabetic Patients. J Nucl Med. 1992;33:1496-1500.
  4. Freeman JS. Role of the Incretin Pathway in the Pathogenesis of Type 2 Diabetes Mellitus. Cleve Clin J Med. 2009;76(suppl 5):S12-S19.
  5. Knop FK, et al. Reduced Incretin Effect in Type 2 Diabetes: Cause or Consequence of the Diabetic State?Diabetes. 2007;56:1951-1959.
  6. Vaag AA, et al. Gut Incretin Hormones in Identical Twins Discordant for Non-Insulin-Dependent Diabetes Mellitus (NIDDM)-Evidence for Decreased Glucagon-Like Peptide 1 Secretion During Oral Glucose Ingestion in NIDDM Twins. Eur J Endocrinol. 1996;135:425-432.
  7. Muscelli E, et al. Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients. Diabetes. 2008;57:1340-1348.


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