Biochemical and Biophysical Research Communications
Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents
Introduction
The pancreatic beta-cell mass and the capacity of beta-cells to secrete insulin are controlled under physiological conditions to the metabolic demand of the body. Failure of the pancreas to provide appropriate insulin secreting capacity due to decreased beta-cell mass and function is one of the underlying mechanisms of the onset and deterioration of type 2 diabetes [1], [2]. Thus, finding means to preserve beta-cell mass and function may be useful for the treatment of diabetes. In this regard, agonists of glucagon-like peptide-1 receptor (GLP-1R) are promising anti-diabetic agents, since activation of GLP-1R has been reported to preserve beta-cell mass by stimulating beta-cell proliferation, inhibiting beta-cell apoptosis in addition to enhancing glucose-induced insulin secretion [3], [4], [5].
In beta-cells, increased cAMP levels by activation of GLP-1R provoke the MAP kinase cascade, leading to rapid phosphorylation of Erk1/2 [6], [7]. The PI3 kinase/Akt pathway may be activated via transactivation of the EGF receptor by betacellulin, which is released from the beta-cell surface by c-Src dependent signaling [8]. The PI3 kinase/Akt pathway is also regulated by transcriptional induction of IRS-2 through the PKA/CREB pathway [9]. The IRS-2/PI3 kinase/Akt pathway appears to be central to the growth-promoting and anti-apoptotic effects of GLP-1R activation in beta-cells [10], [11], [12].
Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia [2], [13], [14]. Accumulating evidence suggests that in addition to the direct effects on beta-cells, GLP-1 exerts its anti-diabetic actions through various other pathways, acting on the brain to induce satiety, inhibiting gastric emptying, and stimulating glucose uptake by the liver, all together leading to improvement in glucose homeostasis [15], [16], [17], [18], [19]. Stimulation of GLP-1R does not necessarily result in increased beta-cell proliferation and mass, since it could reduce peripheral insulin resistance, a major stimulant for beta-cell proliferation. While many studies assessing beta-cell proliferation by GLP-1 and agonists for GLP-1R have been conducted, the dose, treatment period for GLP-1, and animal model used varied depending among the studies [4], [5], [20], [21], and results obtained from these studies were inconsistent. To obtain a comprehensive understanding of the gluco-regulatory actions induced by transient versus sustained activation of GLP-1R, we assessed in the present study the effects of short-term and long-term administration of exendin-4 on beta-cell proliferation and mass, and other metabolic parameters of non-diabetic C57BL/6J mice under various doses and duration of treatment and diet conditions.
Section snippets
Materials and methods
Animals. The study protocol was reviewed and approved by the Animal Care and Use Committee at Juntendo University. Male C57BL/6J mice were purchased from CLEA Japan, Inc. at 4 weeks of age. Mice were maintained under 12-h light/dark cycle, fed a standard rodent diet (Oriental Yeast Co.) for standard fed (STD) study or rodent diet containing 60% fat (Research Diet Co.) for 8-week high-fat fed (HF) study from 4 to 12 weeks of age, and provided with water ad libitum, except where noted.
Acute and
Acute effects of exendin-4 on glucose metabolism and beta-cell function
To examine the acute effects of the GLP-1R agonist exendin-4 on glucose tolerance and insulin secretion, exendin-4 was injected intraperitoneally 30 min before glucose challenge. A single pre-administration of high-dose exendin-4 markedly suppressed glycemic excursions after intraperitoneal glucose challenge, by enhancing postprandial insulin secretion, which has been well characterized as the incretin effect (Fig. 1A and B). On the other hand, pre-administration of low-dose exendin-4 resulted
Acknowledgments
We thank Mr. S. Ichinose and R. Kosuge from the Institute for Environmental and Gender-Specific Medicine at Juntendo University for animal care. This work was supported by grants from the Takeda Science Foundation (to H.W.).
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