Targeting the GPR119/incretin axis: a promising new therapy for metabolic-associated fatty liver disease.

In the past decade, G protein-coupled receptors have emerged as drug targets, and their physiological and pathological effects have been extensively studied. Among these receptors, GPR119 is expressed in multiple organs, including the liver. It can be activated by a variety of endogenous and exogenous ligands. After GPR119 is activated, the cell secretes a variety of incretins, including glucagon-like peptide-1 and glucagon-like peptide-2, which may attenuate the metabolic dysfunction associated with fatty liver disease, including improving glucose and lipid metabolism, inhibiting inflammation, reducing appetite, and regulating the intestinal microbial system. GPR119 has been a potential therapeutic target for diabetes mellitus type 2 for many years, but its role in metabolic dysfunction associated fatty liver disease deserves further attention. In this review, we discuss relevant research and current progress in the physiology and pharmacology of the GPR119/incretin axis and speculate on the potential therapeutic role of this axis in metabolic dysfunction associated with fatty liver disease, which provides guidance for transforming experimental research into clinical applications.

Drug discovery approaches targeting the incretin pathway.

Incretin pathway plays an important role in the development of diabetes medications. Interventions in DPP-4 and GLP-1 receptor have shown remarkable efficacy in experimental and clinical studies and imperatively become one of the most promising therapeutic approaches in the T2DM drug discovery pipeline. Herein, we analyzed the actionmechanismsof DPP-4 and GLP-1 receptor targeting the incretin pathway in T2DM treatment. We gave an insight into the structural requirements for the potent DPP-4 inhibitors and revealed a classification of DPP-4 inhibitors by stressing on the binding modes of these ligands to the enzyme. We then reviewed the drug discovery strategies for the development of peptide and non-peptide GLP-1 receptor agonists (GLP-1 RAs). Furthermore, the drug design strategies for DPP-4 inhibitors and GLP-1R agonists were detailed accurately. This review might provide an efficient evidence for the highly potent and selective DPP-4 inhibitors and the GLP-1 RAs, as novel medicines for patients suffering from T2DM.

Targeting incretin hormones and the ASK-1 pathway as therapeutic options in the treatment of non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is currently one of the leading forms of chronic liver disease, and its rising frequency worldwide has reached epidemic proportions. NAFLD, particularly its progressive variant NASH (non-alcoholic steatohepatitis), can lead to advanced fibrosis, cirrhosis, and HCC. The pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex, and as such myriad therapies are under investigation targeting different pathophysiological mechanisms. Incretin-based therapies, including GLP-1RAs and DPP-4 inhibitors and the inhibition of ASK1 pathway have provided two such novel mechanisms in the management of this disease, and will remain focus of this review.

Effects of flavanols on the enteroendocrine system: Repercussions on food intake.

Flavanols are plant-derived bioactive compounds for which several beneficial effects have been described. When ingested, they reach the gastrointestinal tract, where they can interact with the enteroendocrine cells. In this paper, we consider the possibility that flavanols modulate enterohormone secretion. Because the regulation of food intake is among the principal functions of the hormones that are secreted in the gastrointestinal tract, we also compile the literature that covers how the effects of flavanols on food intake are measured. Although there are some papers showing the effects of flavanols on the regulation of enterohormones, there are very few papers that have addressed the specific effects at the food intake level. Instead, most of the findings are secondary to the study of the action of flavanols on body weight, which makes it difficult to reach a clear conclusion regarding the effects of flavanols on food intake.

Drinks containing anthocyanin-rich blackcurrant extract decrease postprandial blood glucose, insulin and incretin concentrations.

Blackcurrants are rich in polyphenolic glycosides called anthocyanins, which may inhibit postprandial glycemia. The aim was to determine the dose-dependent effects of blackcurrant extract on postprandial glycemia. Men and postmenopausal women (14M, 9W, mean age 46 years, S.D.=14) were enrolled into a randomized, double-blind, crossover trial. Low sugar fruit drinks containing blackcurrant extract providing 150-mg (L-BE), 300-mg (M-BE) and 600-mg (H-BE) total anthocyanins or no blackcurrant extract (CON) were administered immediately before a high-carbohydrate meal. Plasma glucose, insulin and incretins (GIP and GLP-1) were measured 0-120min, and plasma 8-isoprostane F2α, together with arterial stiffness by digital volume pulse (DVP) was measured at 0 and 120min. Early plasma glucose response was significantly reduced following H-BE (n=22), relative to CON, with a mean difference (95% CI) in area over baseline (AOB) 0-30min of -0.34mmol/l.h (-0.56, -0.11, P<.005); there were no differences between the intermediate doses and placebo. Plasma insulin concentrations (AOB 0-30min) were similarly reduced. Plasma GIP concentrations (AOB 0-120min) were significantly reduced following H-BE, with a mean difference of -46.6ng/l.h (-66.7, -26.5, P<.0001) compared to CON. Plasma GLP-1 concentrations were reduced following H-BE at 90min. There were no effects on 8-isoprostane F2α or vascular function. Consumption of blackcurrant extract in amounts roughly equivalent to 100-g blackcurrants reduced postprandial glycemia, insulinemia and incretin secretion, which suggests that inclusion of blackcurrant polyphenols in foods may provide cardio-metabolic health benefits. This trial was registered at clinicaltrials.gov as NCT01706653.

Gastrointestinal dopamine as an anti-incretin and its possible role in bypass surgery as therapy for type 2 diabetes with associated obesity.

The objective of this review was to summarize and integrate specific clinical observations from the field of gastric bypass surgery and recent findings in beta cell biology. When considered together, these data sets suggest a previously unrecognized physiological mechanism which may explain how Roux-en-Y gastric bypass (RYGB) surgery mediates the early rapid reversal of hyperglycemia, observed before weight loss, in certain type 2 diabetes mellitus (T2DM) patients. The novel mechanism is based on a recently recognized inhibitory circuit of glucose stimulated insulin secretion driven by DA stored in ß-cell vesicles and the gut. We propose that DA and glucagon-like peptide 1 (GLP-1) represent two opposing arms of a glucose stimulated insulin secretion (GSIS) regulatory system and hypothesize that dopamine represents the "anti-incretin" hypothesized to explain the beneficial effects of bariatric surgery on T2DM. These new hypotheses and the research driven by them may directly impact our understanding of: 1) the mechanisms underlying improved glucose homeostasis seen before weight loss following bariatric surgery; and 2) the regulation of glucose stimulated insulin secretion within islets. On a practical level, these studies may result in the development of novels drugs to modulate insulin secretion and/or methods to quantitatively asses in real time beta cell function and mass.

Soluble DPP4 originates in part from bone marrow cells and not from the kidney.

Dipeptidyl peptidase 4 (DPP4) is known to inactivate incretins as well as important chemokines and neuropeptides. DPP4 is expressed as a transmembrane protein but also occurs as a soluble enzyme circulating in the blood. However, the origin of the soluble DPP4 (sDPP4) is still unknown. In this study, DPP4 activity was quantified in plasma and extracted from different rat organs. Then, in order to see if the kidney or the bone marrow was the source of sDPP4, kidney or bone marrow transplantation was performed between wildtype (wt) Dark Agouti (DA) and DPP4 deficient congenic rats (n=6-9). Kidney was verified to have the highest DPP4 activity, followed by spleen and lung. In the following three weeks after successful kidney transplantation only transient trace plasma DPP4 activity was detected in DPP4 deficient rats receiving wt kidneys. In addition, DPP4 activity was not diminished in DA wt rats receiving DPP4 deficient kidneys. Both findings indicated that sDPP4 did not originate from the kidney. In contrast, 43±14% (compared to wt) sDPP4 activity was detected in the plasma of DPP4 deficient DA rats that were reconstituted with wt bone marrow cells. Not only leukocyte but also macrophage subpopulations express DPP4 in bone marrow as well as in blood as assessed by flow cytometry. Thus, bone marrow derived cells but not the kidney represent at least one source of sDPP4. And leukocyte or macrophage subpopulations could be potential candidates.

Minireview: Dopaminergic regulation of insulin secretion from the pancreatic islet.

Exogenous dopamine inhibits insulin secretion from pancreatic ß-cells, but the lack of dopaminergic neurons in pancreatic islets has led to controversy regarding the importance of this effect. Recent data, however, suggest a plausible physiologic role for dopamine in the regulation of insulin secretion. We review the literature underlying our current understanding of dopaminergic signaling that can down-regulate glucose-stimulated insulin secretion from pancreatic islets. In this negative feedback loop, dopamine is synthesized in the ß-cells from circulating L-dopa, serves as an autocrine signal that is cosecreted with insulin, and causes a tonic inhibition on glucose-stimulated insulin secretion. On the whole animal scale, L-dopa is produced by cells in the gastrointestinal tract, and its concentration in the blood plasma increases following a mixed meal. By reviewing the outcome of certain types of bariatric surgery that result in rapid amelioration of glucose tolerance, we hypothesize that dopamine serves as an "antiincretin" signal that counterbalances the stimulatory effect of glucagon-like peptide 1.

Bariatric surgery and T2DM improvement mechanisms: a mathematical model.

BACKGROUND: Consensus exists that several bariatric surgery procedures produce a rapid improvement of glucose homeostasis in obese diabetic patients, improvement apparently uncorrelated with the degree of eventual weight loss after surgery. Several hypotheses have been suggested to account for these results: among these, the anti-incretin, the ghrelin and the lower-intestinal dumping hypotheses have been discussed in the literature. Since no clear-cut experimental results are so far available to confirm or disprove any of these hypotheses, in the present work a mathematical model of the glucose-insulin-incretin system has been built, capable of expressing these three postulated mechanisms. The model has been populated with critically evaluated parameter values from the literature, and simulations under the three scenarios have been compared. RESULTS: The modeling results seem to indicate that the suppression of ghrelin release is unlikely to determine major changes in short-term glucose control. The possible existence of an anti-incretin hormone would be supported if an experimental increase of GIP concentrations were evident post-surgery. Given that, on the contrary, collected evidence suggests that GIP concentrations decrease post-surgery, the lower-intestinal dumping hypothesis would seem to describe the mechanism most likely to produce the observed normalization of Type 2 Diabetes Mellitus (T2DM) after bariatric surgery. CONCLUSIONS: The proposed model can help discriminate among competing hypotheses in a context where definitive data are not available and mechanisms are still not clear.

GLP-1 agonists and dipeptidyl-peptidase IV inhibitors.

Novel therapeutic options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were introduced in 2005. Incretin-based therapies consist of two classes: (1) the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor and (2) dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) as oral medications raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In type 2 diabetes therapy, incretin-based therapies are attractive and more commonly used due to their action and safety profile. Stimulation of insulin secretion and inhibition of glucagon secretion by the above-mentioned agents occur in a glucose-dependent manner. Therefore, incretin-based therapies have no intrinsic risk for hypoglycemias. GLP-1 receptor agonists allow weight loss; DPP-4 inhibitors are weight neutral. This review gives an overview on the mechanism of action and the substances and clinical data available.

Incretin therapies in the management of elderly patients with type 2 diabetes mellitus.

Aging is characterized by a progressive increase in the prevalence of type 2 diabetes mellitus (T2DM), which approaches 20% by age 70 years. Older patients with T2DM are a very heterogeneous group with multiple comorbidities, an increased risk of hypoglycemia, and a greater susceptibility to adverse effects of antihyperglycemic drugs, making treatment of T2DM in this population challenging. The risk of severe hypoglycemia likely represents the greatest barrier to T2DM care in the elderly. Although recent guidelines recommend more flexibility in treating this population with individualized targets, inadequate glycemic control is still closely linked to poor outcome in elderly patients. Incretins (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) are hormones released post-meal from intestinal endocrine cells that stimulate insulin secretion and suppress postprandial glucagon secretion in a glucose-dependent manner. "Incretin therapies," comprising the injectable GLP-1 analogs and oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are promising new therapies for use in older patients because of their consistent efficacy and low risk of hypoglycemia. However, data with these new agents are still scarce in this population, which has not been particularly well represented in clinical trials, highlighting the need for additional specific studies. The objective of this article is to provide an overview of the available data and potential role of these novel incretin therapies in managing T2DM in the elderly. With the exception of the DPP-4 inhibitor vildagliptin, there is no published trial to date dedicated to this population, although a few studies are currently ongoing. Therefore, available data from elderly subgroups of individual studies were also reviewed when available, as well as pooled analyses by age subgroups across clinical programs conducted with incretin therapies.

Incretin-based therapies: review of current clinical trial data.

Incretin hormones are secreted in response to food ingestion and help manage glycemic control by regulating insulin and glucagon release, slowing gastric emptying, and reducing caloric intake. Glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, secreted from the L-cells of the lower gut and K-cells of the intestines, respectively, are responsible for these incretin effects, which are reduced in patients with type 2 diabetes mellitus. Initially, the rapid degradation of either incretin by dipeptidyl peptidase-4 (DPP-4) complicated the development of viable therapeutics based on either hormone. However, the US Food and Drug Administration (FDA) has approved 2 incretin-based therapies in which their mechanisms of action augment or amplify the effects of naturally occurring GLP-1. Exenatide, a first-in-class GLP-1 receptor agonist, exhibits the same mechanisms of action as native GLP-1. Sitagliptin inhibits the DPP-4 enzyme, thus increasing the half-life of endogenous GLP-1. This review examines data from recent GLP-1 receptor agonist and DPP-4 inhibitor studies in patients with type 2 diabetes, as well as data on other incretin-based therapies in clinical development.

Recent advances in the management of type 2 diabetes mellitus: a review.

Type 2 diabetes mellitus (T2DM) is a progressive disorder caused by a combination of insulin resistance and beta cell dysfunction. It is associated with an increased and premature risk of cardiovascular disease as well as specific microvascular complications such as retinopathy, nephropathy and neuropathy. In the last 5 years new glucose lowering drugs acting on novel pathways have been developed, licensed and launched, such as the glucagon-like peptide (GLP-1) agonists (exenatide) and dipeptidyl peptidase (DPP-IV) inhibitors such as sitagliptin and vildagliptin. This review looks at these new agents in terms of their mode of action, pharmacokinetics and use in clinical practice. This review also includes new agents in the area of weight loss that may have a positive effect for glucose management-for example, rimonabant.

New approaches to treating type 2 diabetes mellitus in the elderly: role of incretin therapies.

The increasing proportion of elderly persons in the global population, and the implications of this trend in terms of increasing rates of chronic diseases such as type 2 diabetes mellitus, continue to be a cause for concern for clinicians and healthcare policy makers. The diagnosis and treatment of type 2 diabetes in the elderly is challenging, as age-related changes alter the clinical presentation of diabetic symptoms. Once type 2 diabetes is diagnosed, the principles of its management are similar to those in younger patients, but with special considerations linked to the increased prevalence of co-morbidities and relative inability to tolerate the adverse effects of medication and hypoglycaemia. In addition, there are many underappreciated factors complicating diabetes care in the elderly, including cognitive disorders, physical disability and geriatric syndromes, such as frailty, urinary incontinence and pain. Available oral antihyperglycaemic drugs include insulin secretagogues (meglitinides and sulfonylureas), biguanides (metformin), alpha-glucosidase inhibitors and thiazolidinediones. Unfortunately, as type 2 diabetes progresses in older persons, polypharmacy intensification is required to achieve adequate glycaemic control with the attendant increased risk of adverse effects as a result of age-related changes in drug metabolism. The recent introduction of the incretins, a group of intestinal peptides that enhance insulin secretion after ingestion of food, as novel oral antihyperglycaemic treatments may prove significant in older persons. The two main categories of incretin therapy currently available are: glucagon-like peptide-1 (GLP-1) analogues and inhibitors of GLP-1 degrading enzyme dipeptidyl peptidase-4 (DPP-4). The present review discusses the effect of aging on metabolic control in elderly patients with type 2 diabetes, the current treatments used to treat this population and some of the more recent advances in the field of geriatric type 2 diabetes. In particular, we highlight the efficacy and safety of GLP-1 and DPP-4 inhibitors, administered as monotherapy or in combination with other oral antihyperglycaemic agents, especially when the relevant clinical trials included older persons. There is strong evidence that use of incretin therapy, in particular, the DPP-4 inhibitors, could offer significant advantages in older persons. Clinical evidence suggests that the DPP-4 inhibitors vildagliptin and sitagliptin are particularly suitable for frail and debilitated elderly patients because of their excellent tolerability profiles. Importantly, these agents lack the gastrointestinal effects seen with metformin and alpha-glucosidase inhibitors taken alone, and have a low risk of the hypoglycaemic events commonly seen with agents that directly lower blood glucose levels.

An overview of incretin clinical trials.

This article reviews many of the key incretin clinical trials, with a focus on the efficacy and safety of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors compared with placebo and other glucose-lowering agents used as comparators. These agents have been tested either as monotherapy or in combination with one or more oral antidiabetic drugs (OADs). The article also discusses some of the important clinical differences between GLP-1 receptor agonists and DPP-4 inhibitors.

How to implement incretin therapy.

The roles of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are rapidly evolving, despite limited recommendations on their use in current guidelines. This evolution is based on data from the large number of clinical trials demonstrating the clinical efficacy and favorable safety profile of these agents in individuals with type 2 diabetes mellitus (T2DM). This article focuses on factors to consider when implementing the GLP-1 receptor agonists and DPP-4 inhibitors as monotherapy or in combination with other agents in the treatment of T2DM.

New treatments for type 2 diabetes mellitus: combined therapy with sitagliptin.

BACKGROUND: Sitagliptin is a highly selective oral dipeptidyl peptidase-4 inhibitor. This drug increases the plasma concentration of active glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide. These two hormones then simulate the secretion of insulin in a glucose-dependent manner and inhibit glucagon secretion, thus reducing circulating glucose levels. In animal models, GLP-1 increases beta-cell mass. OBJECTIVE: To review the efficacy and safety of sitagliptin in combined therapies (as add on or initial combination treatment) in type 2 diabetes. METHODS: A Medline search on published clinical trials involving sitagliptin in combined therapies was performed; additional information from published papers and abstracts to congresses on preclinical and basic science issues was also included to support the mechanistic rationale of combinations. RESULTS/CONCLUSION: In humans sitagliptin administration reduces fasting and postprandial glucose and A1c levels. Sitagliptin is as effective as glipizide (close to 0.7% mean A1c reduction), but has fewer hypoglycemic events than other oral insulin secretagogues. Since metformin reduces hepatic glucose production and increases GLP-1 release, combined therapy with sitagliptin becomes complementary and has been shown to have important additive effects. Sitagliptin combined with pioglitazone resulted in improved metabolic control when compared with pioglitazone plus placebo. Combined administration with insulin requires further studies. The weight neutral effect of sitagliptin, its glucose-dependent action (lower risk of hypoglycemia), the beneficial effects on beta-cell function and its eventual protective action on beta-cell mass makes it an excellent option for monotherapy or combined with metformin, glitazones or even sulfonylurea.

Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes.

Dipeptidyl peptidase IV (DPP IV) is a widely distributed physiological enzyme that can be found solubilized in blood, or membrane-anchored in tissues. DPP IV and related dipeptidase enzymes cleave a wide range of physiological peptides and have been associated with several disease processes including Crohn's disease, chronic liver disease, osteoporosis, multiple sclerosis, eating disorders, rheumatoid arthritis, cancer, and of direct relevance to this review, type 2 diabetes. Here, we place particular emphasis on two peptide substrates of DPP IV with insulin-releasing and antidiabetic actions namely, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The rationale for inhibiting DPP IV activity in type 2 diabetes is that it decreases peptide cleavage and thereby enhances endogenous incretin hormone activity. A multitude of novel DPP IV inhibitor compounds have now been developed and tested. Here we examine the information available on DPP IV and related enzymes, review recent preclinical and clinical data for DPP IV inhibitors, and assess their clinical significance.