Exendin-4 Uses Irs2 Signaling to Mediate Pancreatic β Cell Growth and Function

Abstract

The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes ␤ cell replication, function, and survival, especially during metabolic stress. Because exendin-4 (Ex4), a long acting glucagon-like peptide 1 receptor agonist, has similar effects upon ␤ cells in rodents and humans, we investigated whether Irs2 signaling was required for Ex4 action in isolated ␤ cells and in Irs2 ؊/؊ mice. Ex4 increased cAMP levels in human islets and Min6 cells, which promoted Irs2 expression and stimulated Akt phosphorylation. In wild type mice Ex4 administered continuously for 28 days increased ␤ cell mass 2-fold. By contrast, Ex4 failed to arrest the progressive ␤ cell loss in Irs2 ؊/؊ mice, which culminated in fatal diabetes; however, Ex4 delayed the progression of diabetes by 3 weeks by promoting insulin secretion from the remaining islets. We conclude that some short term therapeutic effects of glucagon-like peptide 1 receptor agonists can be independent of Irs2, but its long term effects upon ␤ cell growth and survival are mediated by the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.Diabetes mellitus is a complex disorder that arises from various causes, including dysregulated glucose sensing and impaired insulin secretion (maturity-onset diabetes of youth, MODY), autoimmune-mediated ␤ cell destruction (type 1), or insufficient compensation for peripheral insulin resistance (type 2) (1). Type 2 diabetes is the most prevalent form. It usually occurs at middle age and afflicts more than 30 million people over the age of 65 but is appearing with greater frequency in children and adolescents (2). Dysregulated insulin signaling exacerbated by chronic hyperglycemia promotes a cohort of systemic disorders, including dyslipidemia, hypertension, cardiovascular disease, and female infertility (3, 4). The search for strategies to promote ␤ cell function and regeneration has lead to the discovery that glucagon-like peptide-1 (GLP1) 2 receptor agonists increase insulin biosynthesis and secretion from ␤ cells, inhibit glucagon secretion from ␣-cells, and promote peripheral insulin sensitivity and satiety in type 2 diabetics (5-9). During a meal, GLP1 is secreted into the circulation from L cells located in the intestine (10); however, GLP1 is quickly inactivated by circulating dipeptidyl-peptidase IV, which diminishing its usefulness as an injectable therapeutic. Compounds that inhibit dipeptidyl-peptidase IV or GLP1 homologs like exendin-4 (Ex4) that are not degraded by dipeptidyl-peptidase IV display improved therapeutic efficacy (11-16). Administration of Ex4 to rodents or humans with type 2 diabetes increases first-phase insulin secretion and increases ␤ cell mass, which can compensate for peripheral insulin resistance (8,9,17,18). Recently, a synthetic Ex4 called Exenatide (Byetta, Amylin/Lily) has gained Food and Drug Administration approval as an injectable treatment for type 2 diabetes (15). Because Exenatide is the...

Extracts of Rehmanniae radix, Ginseng radix and Scutellariae radix improve glucose-stimulated insulin secretion and β-cell proliferation through IRS2 induction

“…2). Previous studies had revealed that induction of IRS2 results in improved glucose sensing and b-cell proliferation through enhancing insulin/IGF-1 signaling in islets [8,15]. Expression of PDX-1 and glucokinase was associated with glucose sensing and b-cell proliferation, respectively [7,11,12].…”

“…Pancreatic islets from male rats were isolated by collagenase digestion as previously described [8,15], and then incubated for 24 h in high glucose Dulbecco's modified Eagles medium (DMEM) containing 10% (v/v) heatinactivated fetal bovine serum, 50 lM b-mercaptoethanol, penicillin and streptomycin at 37°C in a humidified atmosphere with 5% CO 2 to allow recovery from the isolation process and to eliminate acinar cells. Twenty islets were pre-incubated with low glucose DMEM containing 5 mg/ml bovine serum albumin (BSA) for 16 h in order to recover condition following the digestion process.…”

“…The question was raised whether IRS2 induction occurs under physiological conditions. White [17] found evidence that a cAMP responding element (CRE) site exits upstream of the IRS2 coding region in humans and mice [15]. Several studies have shown that CRE binding protein (CREB) activation increases IRS2 expression [10,15].…”

“…White [17] found evidence that a cAMP responding element (CRE) site exits upstream of the IRS2 coding region in humans and mice [15]. Several studies have shown that CRE binding protein (CREB) activation increases IRS2 expression [10,15]. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist originally extracted from lizard venom, increased IRS2 levels in islets through elevated intracellular cAMP levels [15].…”

“…Several studies have shown that CRE binding protein (CREB) activation increases IRS2 expression [10,15]. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist originally extracted from lizard venom, increased IRS2 levels in islets through elevated intracellular cAMP levels [15]. GLP-1/exendin-4 is known to enhance glucose-stimulated insulin secretion and to increase b-cell transcription factors, such as pancreas duodenum homeobox-1 (PDX-1), to promote b-cell growth and survival [4,15].…”