Liraglutide promotes natriuresis but does not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with type 2 diabetes.

OBJECTIVE: GLP-1 receptor (GLP-1R) agonists induce natriuresis and reduce blood pressure (BP) through incompletely understood mechanisms. We examined the effects of acute and 21-day administration of liraglutide on plasma atrial natriuretic peptide (ANP), urinary sodium excretion, office and 24-h BP, and heart rate (HR). RESEARCH DESIGN AND METHODS: Liraglutide or placebo was administered for 3 weeks to hypertensive subjects with type 2 diabetes in a double-blinded, randomized, placebo-controlled crossover clinical trial in the ambulatory setting. End points included within-subject change from baseline in plasma ANP, Nt-proBNP, office BP, and HR at baseline and over 4 h following a single dose of liraglutide (0.6 mg) and after 21 days of liraglutide (titrated to 1.8 mg) versus placebo administration. Simultaneous 24-h ambulatory BP and HR monitoring and 24-h urine collections were measured at baseline and following 21 days of treatment. RESULTS: Plasma ANP levels did not change significantly after acute (+16.72 pg/mL, P = 0.24, 95% CI [-12.1, +45.5] at 2 h) or chronic (-17.42 pg/mL, 95% CI [-36.0, +1.21] at 2 h) liraglutide administration. Liraglutide significantly increased 24-h and nighttime urinary sodium excretion; however, 24-h systolic BP was not significantly different. Small but significant increases in 24-h and nighttime diastolic BP and HR were observed with liraglutide. Body weight, HbA1c, and cholesterol were lower, and office-measured HR was transiently increased (for up to 4 h) with liraglutide administration. CONCLUSIONS: Sustained liraglutide administration for 3 weeks increases urinary sodium excretion independent of changes in ANP or BP in overweight and obese hypertensive patients with type 2 diabetes.

Managing loss of glycemic control in middle-aged patients with diabetes: the role of GLP-1 receptor agonists in combination-therapy regimens.

Middle-aged patients with type 2 diabetes mellitus may have languished on monotherapy or a stable therapy for a substantial period without reconsideration of comorbidities or current control of glycated hemoglobin A1c (HbA1c). In many patients who lose glycemic control, postprandial hyperglycemia has not been addressed. This is especially true when HbA1c levels are close to--but not at--goal. Glucagon-like peptide-1 receptor agonists are injectable agents that can be added to oral therapy to address postprandial hyperglycemia. These agents may be a useful alternative to insulin therapy as add-on therapy when dual oral therapy is no longer sufficient and additional glucose lowering is required. Compared with insulin, glucagon-like peptide-1 receptor agonists have provided comparable glucose lowering with less hypoglycemia and without weight gain.

Treating patients with diabetes of long duration: GLP-1 receptor agonists and insulin in combination.

Patients with long-standing type 2 diabetes mellitus (T2DM) can be clinically challenging for physicians to treat because these patients often lack sufficient ß-cell function to respond to some oral glucose-lowering agents, may have profound comorbidities, and may have renal impairment that limits the use of traditional agents. These complications, in addition to older age, also increase the risk of hypoglycemia, which can be a major barrier to treatment success. Individualizing treatment targets to balance the benefits of glycemic control with risks of hypoglycemia is the first step to successfully treating these patients. Careful selection of combination therapy strategies to address limited ß-cell function, renal function, and cardiovascular status, along with attention to selection of agents associated with lower risk of hypoglycemia, is important. Basal insulin analogs are often used in patients with long-standing diabetes to address insulinopenic states. Incretin-based therapies, particularly GLP-1 receptor agonists, provide postprandial control with lower risks of hypoglycemia than prandial insulin. The author discusses the management of patients with long-standing diabetes who may have limited ß-cell function and require transition to insulin therapy with gradual intensification.

Initiating a glucagon-like peptide-1 receptor agonist in the management of type 2 diabetes mellitus.

Control of blood glucose levels and restoration of pancreatic islet function are among the goals of physicians seeking to improve outcomes in patients with type 2 diabetes mellitus (T2DM). A growing body of evidence supports the use of incretins to achieve these goals, and current guidelines recommend earlier and more frequent use of these agents. However, in patients with T2DM, treatment paradigms should always be individualized. The author discusses issues for physicians to consider when adjusting T2DM therapy, including patient comorbidities, glucose control patterns, and potential adverse effects. The importance of patient education and practical points for initiating a glucagon-like peptide-1 receptor agonist are also reviewed.

Common patient concerns about the use of glucagon-like peptide-1 receptor agonists in diabetes mellitus management.

The authors present a case of a 46-year-old woman with type 2 diabetes mellitus who has been on a treatment regimen involving diet, exercise, and metformin. After 2 years of treatment, she has a body mass index of 35 and a glycosylated hemoglobin level of 8.0%, and this level is increasing. Her physician recommends adding a glucagon-like peptide-1 (GLP-1) receptor agonist to her treatment regimen, prompting her to ask several questions. The authors present these questions along with proposed answers, highlighting the practical application of GLP-1 receptor agonists in the context of common patient concerns.

Incorporating glucagon-like peptide-1 receptor agonists into clinical practice.

Two glucagon-like peptide-1 (GLP-1) receptor agonists are currently approved for use in patients with type 2 diabetes mellitus: exenatide and liraglutide. Both of these injectable agents improve glycemic control as monotherapy or as combination therapy with oral agents. Overall, GLP-1 receptor agonists provide additive effects in dual and triple therapy regimens. In a clinical trial, the use of liraglutide resulted in greater improvements in glycosylated hemoglobin and fasting plasma glucose levels compared to exenatide, although the effects of exenatide on postprandial plasma glucose levels were greater. Clinical trials have also demonstrated statistically significant weight reduction, small beneficial effects on blood pressure, and unchanged lipid profiles with GLP-1 receptor agonists. The author reviews clinical trial data on the use of GLP-1 receptor agonists for patients with type 2 diabetes mellitus, outlines potential contraindications of these agents, and discusses the role of GLP-1 receptor agonists in algorithms for the initiation and advancement of treatment.

Jejunal linoleic acid infusions require GLP-1 receptor signaling to inhibit food intake: implications for the effectiveness of Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass surgery results in sustained decreases in food intake and weight loss. A key component is likely the direct delivery of nutrients to the jejunum and resulting changes in levels of gut peptide secretion. Prior work modeling this aspect of the surgery has shown that small-volume, prolonged jejunal infusions of linoleic acid (LA) produce sustained decreases in food intake and weight loss. LA infusions also significantly elevate plasma glucagon-like peptide-1 (GLP-1) levels. To assess a role for the increased circulating GLP-1 in the feeding suppression, we examined the effect of prolonged peripheral minipump administration of the GLP-1 receptor antagonist exendin 9-39 (Ex 9) on the feeding suppression produced by jejunal LA. Using a 2 × 2 design, we infused either saline or LA in the jejunum (7 h/day, 11.4 kcal) for 5 days with a subset of animals from each group receiving either saline or Ex 9 (25 pmol·kg(-1)·min(-1)) continuously via a minipump. The antagonist alone had no effect on food intake. LA reduced daily food intake greatly in excess of the kilocalories infused. Ex 9 completely blocked the feeding suppression produced by the jejunal LA infusion. Ex 9 also attenuated the increase in plasma GLP-1 induced by jejunal LA infusions. These data demonstrate that endogenous GLP-1 receptor signaling is necessary for the reduction in food intake produced by jejunal LA infusions. Whether increased secretion of additional gut peptides is also necessary for such suppressions remains to be determined.

GLP-1 receptor agonists and HBA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) receptor agonists are available for the treatment of type 2 diabetes. We assessed the efficacy of exenatide and liraglutide to reach the HbA(1c) target of <7% in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted an electronic search for randomized controlled trials (RCTs) involving GLP-1 agonists through September 2010. RCTs were included if they lasted at least 12 weeks, included 30 patients or more, and reported the proportion of patients reaching the HbA(1c) target of <7%. RESULTS: A total of 25 RCTs reporting 28 comparisons met the selection criteria, which included 9771 study participants evaluated for the primary endpoint, 5083 treated with a GLP-1 agonist and 4688 treated with placebo or a comparator drug. GLP-1 agonists showed a statistically significant reduction in HbA(1c) compared to placebo and the proportion of participants achieving the HbA(1c) goal <7% was 46% for exenatide, 47% for liraglutide, and 63% for exenatide LAR (long-acting release). Moreover, the reduction of the HbA(1c) level and the rate of HbA(1c) goal attainment were higher for both exenatide LAR and liraglutide, as compared to comparator drugs. Higher rates of hypoglycemia with exenatide b.i.d. and liraglutide compared to placebo were associated with the concomitant use of a sulfonylurea. Exenatide b.i.d. and liraglutide were associated with weight loss compared to placebo or other antidiabetic drugs. Baseline HbA(1c) was the best predictor for achievement of A1c target (overall weighted R(2) value = 0.513, p < 0.001). CONCLUSIONS: A greater proportion of patients with type 2 diabetes can achieve the HbA(1c) goal <7% with GLP-1 agonists compared to placebo or other antidiabetic drugs; in absolute terms, exenatide LAR was best for the attainment of the HbA(1c) goal.

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser.

The two major deficits in type 2 diabetes, insulin resistance and impaired beta cell function, are often treated with metformin and incretin-based drugs, respectively. However, there may be unappreciated benefits of this combination of therapies. In this issue of Diabetologia, Maida et al. (doi: 10.1007/s00125-010-1937-z) report that metformin acutely increases plasma levels of glucagon-like peptide 1 (GLP-1) in mice. Moreover, they show that metformin enhances the expression of the genes encoding the receptors for both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in mouse islets and also increases the effects of GIP and GLP-1 on insulin secretion from beta cells. Interestingly, these incretin-sensitising effects of metformin appear to be mediated by a peroxisome proliferator-activated receptor α-dependent pathway, as opposed to the more commonly ascribed pathway of metformin action involving AMP-activated protein kinase. These provocative findings by Maida et al. extend our understanding of the mechanism of action of metformin and provide further insights into the benefits of combining metformin with incretin-based drugs to combat diabetes.

Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice.

AIMS/HYPOTHESIS: Metformin is widely used for the treatment of type 2 diabetes. Although it reduces hepatic glucose production, clinical studies show that metformin may reduce plasma dipeptidyl peptidase-4 activity and increase circulating levels of glucagon-like peptide 1 (GLP-1). We examined whether metformin exerts glucoregulatory actions via modulation of the incretin axis. METHODS: Metformin action was assessed in Glp1r(-/-), Gipr(-/-), Glp1r:Gipr(-/-), Pparα (also known as Ppara)(-/-) and hyperglycaemic obese wild-type mice with or without the GLP-1 receptor (GLP1R) antagonist exendin(9-39). Experimental endpoints included glucose tolerance, plasma insulin levels, gastric emptying and food intake. Incretin receptor expression was assessed in isolated islets from metformin-treated wild-type and Pparα(-/-) mice, and in INS-1 832/3 beta cells with or without peroxisome proliferator-activated receptor (PPAR)-α or AMP-activated protein kinase (AMPK) antagonists. RESULTS: In wild-type mice, metformin acutely increased plasma levels of GLP-1, but not those of gastric inhibitory polypeptide or peptide YY; it also improved oral glucose tolerance and reduced gastric emptying. Metformin significantly improved oral glucose tolerance despite loss of incretin action in Glp1r(-/-), Gipr(-/-) and Glp1r(-/-) :Gipr(-/-) mice, and in wild-type mice fed a high-fat diet and treated with exendin(9-39). Levels of mRNA transcripts for Glp1r, Gipr and Pparα were significantly increased in islets from metformin-treated mice. Metformin directly increased Glp1r expression in INS-1 beta cells via a PPAR-α-dependent, AMPK-independent mechanism. Metformin failed to induce incretin receptor gene expression in islets from Pparα(-/-) mice. CONCLUSIONS/INTERPRETATION: As metformin modulates multiple components of the incretin axis, and enhances expression of the Glp1r and related insulinotropic islet receptors through a mechanism requiring PPAR-α, metformin may be mechanistically well suited for combination with incretin-based therapies.

Glucagon receptor antagonist-mediated improvements in glycemic control are dependent on functional pancreatic GLP-1 receptor.

Antagonism of the glucagon receptor (GCGR) is associated with increased circulating levels of glucagon-like peptide-1 (GLP-1). To investigate the contribution of GLP-1 to the antidiabetic actions of GCGR antagonism, we administered an anti-GCGR monoclonal antibody (mAb B) to wild-type mice and GLP-1 receptor knockout (GLP-1R KO) mice. Treatment of wild-type mice with mAb B lowered fasting blood glucose, improved glucose tolerance, and enhanced glucose-stimulated insulin secretion during an intraperitoneal glucose tolerance test (ipGTT). In contrast, treatment of GLP-1R KO mice with mAb B had little efficacy during an ipGTT. Furthermore, pretreatment with the GLP-1R antagonist exendin-(9-39) diminished the antihyperglycemic effects of mAb B in wild-type mice. To determine the mechanism whereby mAb B improves glucose tolerance, we generated a monoclonal antibody that specifically antagonizes the human GLP-1R. Using a human islet transplanted mouse model, we demonstrated that pancreatic islet GLP-1R signaling is required for the full efficacy of the GCGR antagonist. To identify the source of the elevated GLP-1 observed in GCGR mAb-treated mice, we measured active GLP-1 content in pancreas and intestine from db/db mice treated with anti-GCGR mAb for 8 wk. Elevated GLP-1 in GCGR mAb-treated mice was predominantly derived from increased pancreatic GLP-1 synthesis and processing. All together, these data show that pancreatic GLP-1 is a significant contributor to the glucose-lowering effects observed in response to GCGR antagonist treatment.

Colonic GLP-2 is not sufficient to promote jejunal adaptation in a PN-dependent rat model of human short bowel syndrome.

BACKGROUND: Bowel resection may lead to short bowel syndrome (SBS), which often requires parenteral nutrition (PN) due to inadequate intestinal adaptation. The objective of this study was to determine the time course of adaptation and proglucagon system responses after bowel resection in a PN-dependent rat model of SBS. METHODS: Rats underwent jugular catheter placement and a 60% jejunoileal resection + cecectomy with jejunoileal anastomosis or transection control surgery. Rats were maintained exclusively with PN and killed at 4 hours to 12 days. A nonsurgical group served as baseline. Bowel growth and digestive capacity were assessed by mucosal mass, protein, DNA, histology, and sucrase activity. Plasma insulin-like growth factor I (IGF-I) and bioactive glucagon-like peptide 2 (GLP-2) were measured by radioimmunoassay. RESULTS: Jejunum cellularity changed significantly over time with resection but not transection, peaking at days 3-4 and declining by day 12. Jejunum sucrase-specific activity decreased significantly with time after resection and transection. Colon crypt depth increased over time with resection but not transection, peaking at days 7-12. Plasma bioactive GLP-2 and colon proglucagon levels peaked from days 4-7 after resection and then approached baseline. Plasma IGF-I increased with resection through day 12. Jejunum and colon GLP-2 receptor RNAs peaked by day 1 and then declined below baseline. CONCLUSIONS: After bowel resection resulting in SBS in the rat, peak proglucagon, plasma GLP-2, and GLP-2 receptor levels are insufficient to promote jejunal adaptation. The colon adapts with resection, expresses proglucagon, and should be preserved when possible in massive intestinal resection.

Unraveling the science of incretin biology.

Type 2 diabetes mellitus has become an enormous and worldwide healthcare problem that is almost certain to worsen. Current therapies, which address glycemia and insulin resistance, have not adequately addressed the complications and treatment failures associated with this disease. New treatments based on the incretin hormones provide a novel approach to address some components of the complex pathophysiology of type 2 diabetes. The purpose of this review is to elucidate the science of the incretin hormones and describe the incretin effect and its regulatory role in beta-cell function, insulin secretion, and glucose metabolism. The key endogenous hormones of incretin system are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1); a key enzymatic regulator of these hormones is dipeptidyl peptidase-4, which rapidly inactivates/degrades the incretin hormones. The roles of the incretin hormones in the regulation of glucose metabolism and other related physiologic processes such as gut motility and food intake are disturbed in type 2 diabetes. These disturbances--defects in the incretin system--contribute to the pathophysiology of type 2 diabetes in manifold ways. Consequently, therapies designed to address impairments to the effects of the incretin hormones have the potential to improve glucose regulation and other abnormalities (e.g., weight gain, loss of beta-cell function) associated with type 2 diabetes.

Unraveling the science of incretin biology.

Type 2 diabetes mellitus has become an enormous and worldwide healthcare problem that is almost certain to worsen. Current therapies, which address glycemia and insulin resistance, have not adequately addressed the complications and treatment failures associated with this disease. New treatments based on the incretin hormones provide a novel approach to address some components of the complex pathophysiology of type 2 diabetes. The purpose of this review is to elucidate the science of the incretin hormones and describe the incretin effect and its regulatory role in beta-cell function, insulin secretion, and glucose metabolism. The key endogenous hormones of incretin system are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1); a key enzymatic regulator of these hormones is dipeptidyl peptidase-4, which rapidly inactivates/degrades the incretin hormones. The roles of the incretin hormones in the regulation of glucose metabolism and other related physiologic processes such as gut motility and food intake are disturbed in type 2 diabetes. These disturbances--defects in the incretin system--contribute to the pathophysiology of type 2 diabetes in manifold ways. Consequently, therapies designed to address impairments to the effects of the incretin hormones have the potential to improve glucose regulation and other abnormalities (e.g., weight gain, loss of beta-cell function) associated with type 2 diabetes.