Cardiovascular Effects of Incretin-Based Therapies: Integrating Mechanisms With Cardiovascular Outcome Trials

As the worldwide prevalence of diabetes and obesity continues to rise, so does the risk of debilitating cardiovascular complications. Given the significant association between diabetes and cardiovascular risk, the actions of glucose-lowering therapies within the cardiovascular system must be clearly defined. Incretin hormones, including GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide), are gut hormones secreted in response to nutrient intake that maintain glycemic control by regulating insulin and glucagon release. GLP-1 receptor agonists (GLP-1Ras) and dipeptidyl peptidase 4 inhibitors (DPP-4is) represent two drug classes used for the treatment of type 2 diabetes mellitus (T2DM) that improve glucose regulation through stimulating the actions of gut-derived incretin hormones or inhibiting their degradation, respectively. Despite both classes acting to potentiate the incretin response, the potential cardioprotective benefits afforded by GLP-1Ras have not been recapitulated in cardiovascular outcome trials (CVOTs) evaluating DPP-4is. This review provides insights through discussion of clinical and preclinical studies to illuminate the physiological mechanisms that may underlie and reconcile observations from GLP-1Ra and DPP-4i CVOTs. Furthermore, critical knowledge gaps and areas for further investigation will be emphasized to guide future studies and, ultimately, facilitate improved clinical management of cardiovascular disease in T2DM.     

Clinical pharmacology of antidiabetic drugs: What can be expected of their use?

The pharmacotherapy of type 2 diabetes mellitus (T2DM) has markedly evolved in the last two decades. Classical antidiabetic agents (sulphonylureas, metformin, insulin) are now in competition with new glucose-lowering medications. Alpha-glucosidase inhibitors and thiazolidinediones (glitazones) were not able to replace older agents, because of insufficient efficacy and/or poor tolerability/safety. In contrast, incretin-based therapies, both dipeptidyl peptidase-4 inhibitors (DPP-4is or gliptins, oral agents) and glucagon-like peptide-1 receptor agonists (GLP-1RAs, subcutaneous injections) are a major breakthrough in the management of T2DM. Because they are not associated with hypoglycaemia and weight gain, DPP-4is tend to replace sulphonylureas as add-on to metformin while GLP-1RAs tend to replace basal insulin therapy after failure of oral therapies. Furthermore, placebo-controlled cardiovascular outcome trials demonstrated neutrality for DPP-4is, but cardiovascular protection for GLP-1RAs in patients with T2DM at high cardiovascular risk. More recently sodium-glucose cotransporter 2 inhibitors (SGLT2is or gliflozins, oral agents) also showed cardiovascular protection, especially a reduction in hospitalization for heart failure, as well as a renal protection in patients with and without T2DM, at high cardiovascular risk, with established heart failure and/or with chronic kidney disease. Thus, GLP-1RAs and SGLT2is are now considered as preferred drugs in T2DM patients with or at high risk of atherosclerotic cardiovascular disease whereas SGLT2is are more specifically recommended in patients with or at risk of heart failure and renal (albuminuric) disease. The management of T2DM is moving from a glucocentric approach to a broader strategy focusing on all risk factors, including overweight/obesity, and to an organ-disease targeted personalized approach.     

Ilial Transposition and Enteroglucagon/GLP-1 in Obesity (and Diabetic?) Surgery

Background: This is a review of intestinal glucagon, which is released when undigested food is in the terminal ileum. Methods and Results: In the early 1980s, Koopmans and Sclafani showed in fat rats that the transposition of a short segment of ileum to the duodenum would decrease weight just as effectively as intestinal bypass. Sarson and coworkers found elevated enteroglucagon after biliopancreatic diversion (BPD). Scopinaro has observed that patients with diabetes who undergo BPD are cured of diabetes and do not experience a recurrence. N?slund and associates showed recently a high level of plasma glucagon-like peptide (GLP-1) 20 years after jejunoileal bypass. GLP-1 has been shown to be an effective medication for treatment of type 2 diabetes mellitus (DM). It must be given parenterally. It has been used only in short, well-controlled studies. Conclusions: It appears from all that is now known about GLP-1 that ileal transposition would be an ideal operation for treatment of type 2 DM. Release of enteroglucagon from the ileum has probably contributed to weight control in bypass operations for obesity, but the effect has been obscured by the associated malabsorption. The release of GLP-1 after meals has probably been beneficial to patients treated with gastric bypass who had type 2 DM. This is a recommendation for well-planned studies of ileal transposition in the treatment of type 2 DM and obesity. Ileal transposition is not recommended for general use until such studies have shown safety, efficacy, and the requirements for patient selection.     

New strategy for the treatment of type 2 diabetes mellitus with incretin-based therapy

Incretin-based therapy was first made available for the treatment of type 2 diabetes mellitus (T2DM) in the US in 2006 and in Japan in 2009. Four DPP-4 inhibitors and two GLP-1 analog/receptor agonists are currently available. The effects of incretin-based therapy are assumed to be exerted mainly through the hormonal and neuronal actions of one of the incretins, GLP-1, which is secreted from L cells localized in the small intestine. The benefits of this therapy over conventional sulfonylureas or insulin injections, such as fewer hypoglycemic events and reduced body weight gain, derive from the glucose-dependent insulinotropic effect. The protective effects of this therapy on vulnerable pancreatic β-cells and against micro/macroangiopathy in T2DM are also most welcome. Indications and/or contraindications for incretin-based therapy should be clarified by prospectively studying the experiences of Japanese T2DM patients undergoing this therapy in the clinical setting.     

Incretin manipulation in diabetes management

Incretin-based therapies have revolutionized the medical management of type 2 diabetes mellitus(T2DM) in the 21 st century. Glucagon-like peptide-1(GLP-1) suppresses appetite and gastric motility, and has trophic effects on pancreas, cardio-protective and renal effects. GLP-1 analogues and dipeptidyl peptidase-4 inhibitors form the incretin-based therapies. Significant reduction of hemoglobin A1 c when used as monotherapy and in combination regimens, favorable effects on body weight, and low risk of hypoglycemia are their unique therapeutic benefits. Their safety and tolerability are comparable to other anti-diabetic medications. Concern about elevated risk of pancreatitis has been discarded by two recent meta-analyses. This article discusses the therapeutic manipulation of incretin system for the management of T2 DM.     

Novel pharmacological therapy in type 2 diabetes mellitus with established cardiovascular disease: Current evidence

Cardiovascular diseases(CVDs) remain the leading cause of death in the world and in most developed countries. Patients with type 2 diabetes mellitus(T2DM)suffer from both microvascular and macrovascular diseases and therefore have higher rates of morbidity and mortality compared to those without T2DM. If current trends continue, the Center for Disease Control and Prevention estimates that 1 in 3 Americans will have T2DM by year 2050. As a consequence of the controversy surrounding rosiglitazone and the increasing prevalence of diabetes and CVDs, in 2008 the Food and Drug Administration(FDA) established new expectations for the evaluation of new antidiabetic agents, advising for pre and,in some cases, post-marketing data on major cardiovascular events. As a direct consequence, there has been a paradigm shift in new antidiabetic agents that has given birth to the recently published American Diabetes Association/European Association for the Study of Diabetes consensus statement recommending sodium-glucose cotransporter-2 inhibitors(SGLT2i) and glucagon like peptide-1 receptor agonists(GLP-1RA) in patients with T2DM and established CVD. As a result of over a decade of randomized placebo controlled cardiovascular outcome trials, the aforementioned drugs have received FDA approval for risk reduction of cardiovascular(CV) events in patients with T2DM and established CV disease.SGLT2i have been shown to have a stronger benefit in patients with congestiveheart failure and diabetic kidney disease when compared to their GLP-1RA counterparts. These benefits are not withstanding additional considerations such as cost and the multiple FDA Black Box warnings. This topic is currently an emerging research area and this mini-review paper examines the role of these two novel classes of drugs in patients with T2DM with both confirmed, and at risk for, CVD.     

Prevention of macrovascular complications in patients with type 2 diabetes mellitus: Review of cardiovascular safety and efficacy of newer diabetes medications

Lack of conclusive beneficial effects of strict glycemic control on macrovascular complications has been very frustrating for clinicians involved in care of patients with diabetes mellitus(DM). Highly publicized controversy surrounding cardiovascular(CV) safety of rosiglitazone resulted in major changes in United States Food and Drug Administration policy in 2008 regarding approval process of new antidiabetic medications, which has resulted in revolutionary data from several large CV outcome trials over the last few years. All drugs in glucagon-like peptide-1 receptor agonist(GLP-1 RA) and sodium-glucose cotransporter-2(SGLT-2) inhibitor classes have shown to be CV safe with heterogeneous results on CV efficacy. Given twofold higher CV disease mortality in patients with DM than without DM, GLP-1 RAs and SGLT-2-inhibitors are important additions to clinician's armamentarium and should be second line-therapy particularly in patients with T2 DM and established atherosclerotic CV disease or high risks for CV disease. Abundance of data and heterogeneity in CV outcome trials results can make it difficult for clinicians, particularly primary care physicians, to stay updated with all the recent evidence. The scope of this comprehensive review will focus on all major CV outcome studies evaluating CV safety and efficacy of GLP-1 RAs and SGLT-2 inhibitors.     

Transient receptor potential vanilloid 1 activation enhances gut glucagon-like peptide-1 secretion and improves glucose homeostasis

Type 2 diabetes mellitus (T2DM) is rapidly prevailing as a serious global health problem. Current treatments for T2DM may cause side effects, thus highlighting the need for newer and safer therapies. We tested the hypothesis that dietary capsaicin regulates glucose homeostasis through the activation of transient receptor potential vanilloid 1 (TRPV1)-mediated glucagon-like peptide-1 (GLP-1) secretion in the intestinal cells and tissues. Wild-type (WT) and TRPV1 knockout (TRPV1(-/-)) mice were fed dietary capsaicin for 24 weeks. TRPV1 was localized in secretin tumor cell-1 (STC-1) cells and ileum. Capsaicin stimulated GLP-1 secretion from STC-1 cells in a calcium-dependent manner through TRPV1 activation. Acute capsaicin administration by gastric gavage increased GLP-1 and insulin secretion in vivo in WT but not in TRPV1(-/-) mice. Furthermore, chronic dietary capsaicin not only improved glucose tolerance and increased insulin levels but also lowered daily blood glucose profiles and increased plasma GLP-1 levels in WT mice. However, this effect was absent in TRPV1(-/-) mice. In db/db mice, TRPV1 activation by dietary capsaicin ameliorated abnormal glucose homeostasis and increased GLP-1 levels in the plasma and ileum. The present findings suggest that TRPV1 activation-stimulated GLP-1 secretion could be a promising approach for the intervention of diabetes.     

Rise in Postprandial GLP-1 Levels After Roux-en-Y Gastric Bypass: Involvement of the Vagus Nerve–Spleen Anti-inflammatory Axis in Type 2 Diabetic Rats

Purpose

The mechanism underlying postprandial glucagon-like peptide-1 (GLP-1) changes after metabolic surgery remains mostly unclarified. This investigation aimed to address whether the vagus nerve–spleen anti-inflammatory axis is involved in the rise in postprandial GLP-1 levels in type 2 diabetes mellitus (T2DM) rats following metabolic surgery.

Materials and Methods

T2DM rat model was established with a high-fat diet and a low dose of streptozotocin and subjected to Roux-en-Y gastric bypass (RYGB) and splenic denervation. A mixed-meal tolerance test for postprandial GLP-1 response was performed. TNF-α in the plasma, spleen, and ileum was measured by ELISA, and alpha 7 nicotinic acetylcholine receptor (α7nAChR) expression in the spleen was analyzed by Western blot.

Results

Postprandial GLP-1 improvement by RYGB was accompanied by the reduction of TNF-α levels in spleen and ileum and up-regulation of splenic α7nAChR in T2DM rats. Splenic denervation abrogates a rise in postprandial GLP-1 levels in response to the mixed-meal challenge, along with higher TNF-α levels in spleen and ileum and down-regulation of splenicα7nAChR, compared with denervated sham rats.

Conclusion

Our results reveal that the vagus nerve–spleen anti-inflammatory axis mediates the rise of postprandial GLP-1 response after RYGB through lowering TNF-α contents in the intestinal tissue in T2DM rats.

     

The role of endogenous incretin secretion as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 diabetes

In order to quantify the role of incretins in first- and second-phase insulin secretion (ISR) in type 2 diabetes mellitus (T2DM), a double-blind, randomized study with 12 T2DM subjects and 12 healthy subjects (HS) was conducted using the hyperglycemic clamp technique together with duodenal nutrition perfusion and intravenous infusion of the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). Intravenous glucose alone resulted in a significantly greater first- and second-phase ISR in HS compared with T2DM subjects. Duodenal nutrition perfusion augmented both first- and second-phase ISR but first-phase ISR more in T2DM subjects (approximately eight- vs. twofold). Glucose-related stimulation of ISR contributed only 20% to overall ISR. Infusion with exendin(9-39) significantly reduced first- and second-phase ISR in both HS and T2DM subjects. Thus, both GLP-1 and non-GLP-1 incretins contribute to the incretin effect. In conclusion, both phases of ISR are impaired in T2DM. In particular, the responsiveness to glucose in first-phase ISR is blunted. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretions are unaltered. The absolute incretin effect is reduced in T2DM; its relative importance, however, appears to be increased, highlighting its role as an important amplifier of first-phase ISR in T2DM.     

Recent advances in new-onset diabetes mellitus after kidney transplantation

A common challenge in managing kidney transplant recipients (KTR) is post-transplant diabetes mellitus (PTDM) or diabetes mellitus (DM) newly diagnosed after transplantation, in addition to known pre-existing DM. PTDM is an important risk factor for post-transplant cardiovascular (CV) disease, which adversely affects patient survival and quality of life. CV disease in KTR may manifest as ischemic heart disease, heart failure, and/or left ventricular hypertrophy. Available therapies for PTDM include most agents currently used to treat type 2 diabetes. More recently, the use of sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and dipeptidyl peptidase 4 inhibitors (DPP4i) has cautiously extended to KTR with PTDM, even though KTR are typically excluded from large general population clinical trials. Initial evidence from observational studies seems to indicate that SGLT2i, GLP-1 RA, and DPP4i may be safe and effective for glycemic control in KTR, but their benefit in reducing CV events in this otherwise high-risk population remains unproven. These newer drugs must still be used with care due to the increased propensity of KTR for intravascular volume depletion and acute kidney injury due to diarrhea and their single-kidney status, pre-existing burden of peripheral vascular disease, urinary tract infections due to immunosuppression and a surgically altered urinary tract, erythrocytosis from calcineurin inhibitors, and reduced kidney function from acute or chronic rejection.     

Mechanisms of type 2 diabetes resolution after Roux-en-Y gastric bypass

BackgroundBariatric surgery is the most effective treatment for the reduction of weight and resolution of type 2 diabetes mellitus (T2 DM). The objective of this study was to longitudinally assess hormonal and tissue responses after RYGB.MethodsEight patients (5 with T2 DM) were studied before and after RYGB. A standardized test meal (STM) was administered before and at 1, 3, 6, 9, 12, and 15 months. Separately, a 2-hour hyperinsulinemic-euglycemic clamp (E-clamp) and a 2-hour hyperglycemic clamp (H-clamp) were performed before and at 1, 3, 6, and 12 months. Glucagon-like peptide-1 (GLP-1) was infused during the last hour of the H-clamp. Body composition was assessed with DXA methodology.ResultsEnrollment body mass index was 49±3 kg/m² (X±SE). STM glucose and insulin responses were normalized by 3 and 6 months. GLP-1 level increased dramatically at 1, 3, and 6 months, normalizing by 12 and 15 months. Insulin sensitivity (M of E-clamp) increased progressively at 3–12 months as fat mass decreased. The insulin response to glucose alone fell progressively over 12 months but the glucose clearance/metabolism (M of H-clamp) did not change significantly until 12 months. In response to GLP-1 infusion, insulin levels fell progressively throughout the 12 months.ConclusionThe early hypersecretion of GLP-1 leads to hyperinsulinemia and early normalization of glucose levels. The GLP-1 response normalizes within 1 year after surgery. Enhanced peripheral tissue sensitivity to insulin starts at 3 months and is associated with fat mass loss. β-cell sensitivity improves at 12 months and after the loss of ≈33% of excess weight. There is a tightly controlled feedback loop between peripheral tissue sensitivity and β-cell and L-cell (GLP-1) responses.     

The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects

The intestinally derived hormone glucagon-like peptide 1 (GLP-1) (7-36 amide) has potent effects on glucose-mediated insulin secretion, insulin gene expression, and beta-cell growth and differentiation. It is, therefore, considered a potential therapeutic agent for the treatment of type 2 diabetes. However, the dose-response relationship between GLP-1 and basal and glucose-stimulated prehepatic insulin secretion rate (ISR) is currently not known. Seven patients with type 2 diabetes and seven matched nondiabetic control subjects were studied. ISR was determined during a graded glucose infusion of 2, 4, 6, 8, and 12 mg x kg(-1) x min(-1) over 150 min on four occasions with infusion of saline or GLP-1 at 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1). GLP-1 enhanced ISR in a dose-dependent manner during the graded glucose infusion from 332 +/- 51 to 975 +/- 198 pmol/kg in the patients with type 2 diabetes and from 711 +/- 123 to 2,415 +/- 243 pmol/kg in the control subjects. The beta-cell responsiveness to glucose, expressed as the slope of the linear relation between ISR and the glucose concentration, increased in proportion to the GLP-1 dose to 6 times relative to saline at the highest GLP-1 dose in the patients and 11 times in the control subjects, but it was 3 to 5 times lower in the patients with type 2 diabetes compared with healthy subjects at the same GLP-1 dose. During infusion of GLP-1 at 0.5 pmol x kg(-1) x min(-1) in the patients, the slope of ISR versus glucose became indistinguishable from that of the control subjects without GLP-1. Our results show that GLP-1 increases insulin secretion in patients with type 2 diabetes and control subjects in a dose-dependent manner and that the beta-cell responsiveness to glucose may be increased to normal levels with a low dose of GLP-1 infusion. Nevertheless, the results also indicate that the dose-response relation between beta-cell responsiveness to glucose and GLP-1 is severely impaired in patients with type 2 diabetes.     

Fatty liver disease in diabetes mellitus

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus (T2DM), likely reflecting the frequent occurrence of obesity and insulin resistance in T2DM. NAFLD also can occur in type 1 DM (T1DM), but must be distinguished from the more common glycogen hepatopathy as a cause of hepatomegaly and liver function abnormalities in T1DM. Weight reduction achieved by diet and exercise is effective in preventing and treating NAFLD in obese diabetic subjects. Bariatric surgery also has been shown to reverse NAFLD in T2DM, and recently approved weight loss medications should be evaluated for their impact on the development and progression of NAFLD. There is limited evidence suggesting that specific drugs used for blood glucose control in T2DM [thiazolidinediones (TZDs), glucagon-like peptide-1 (GLP-1) analogs, and dipeptidyl peptidase-4 (DPP-4) inhibitors] and also statins may have a role in preventing or treating NAFLD in patients with diabetes.     

Diabetes mellitus: new drugs for a new epidemic

The prevalence of diabetes mellitus (DM) is increasing rapidly in the 21st century as a result of obesity, an ageing population, lack of exercise, and increased migration of susceptible patients. This costly and chronic disease has been likened recently to the 'Black Death' of the 14th century. Type 2 DM is the more common form and the primary aim of management is to delay the micro- and macrovascular complications by achieving good glycaemic control. This involves changes in lifestyle, such as weight loss and exercise, and drug therapy. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments: glucagon-like peptide-1 (GLP-1) mimetics, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and insulin analogues. GLP-1 agonists mimic the effect of this incretin, whereas DPP-4 inhibitors prevent the inactivation of the endogenously released hormone. Both agents offer an effective alternative to the currently available hypoglycaemic drugs but further evaluation is needed to confirm their safety and clinical role. The past decade has seen the rise and fall in the use of the TZDs (glitazones), such that the only glitazone recommended is pioglitazone as a third-line treatment. The association between the use of rosiglitazone and adverse cardiac outcomes is still disputed by some authorities. The advent of new insulin analogues, fast-acting, and basal release formulations, has enabled the adoption of a basal-bolus regimen for the management of blood glucose. This regimen aims to provide a continuous, low basal insulin release between meals with bolus fast-acting insulin to limit hyperglycaemia after meals. Insulin therapy is increasingly used in type 2 DM to enhance glycaemic control. Recently, it has been suggested that the use of the basal-release insulins, particularly insulin glargine may be associated with an increased risk of cancer. Although attention is focused increasingly on newer agents in the treatment of diabetes, metformin and the sulphonylureas are still used in many patients. Metformin, in particular, remains of great value and may have novel anti-cancer properties.     

Genetics of macrovascular complications in type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that currently affects more than 400 million worldwide and is projected to cause 552 million cases by the year 2030. Long-term vascular complications, such as coronary artery disease, myocardial infarction, stroke, are the leading causes of morbidity and mortality among diabetic patients. The recent advances in genome-wide technologies have given a powerful impetus to the study of risk markers for multifactorial diseases. To date, the role of genetic and epigenetic factors in modulating susceptibility to T2DM and its vascular complications is being successfully studied that provides the accumulation of genomic knowledge. In the future, this will provide an opportunity to reveal the pathogenetic pathways in the development of the disease and allow to predict the macrovascular complications in T2DM patients. This review is focused on the evidence of the role of genetic variants and epigenetic changes in the development of macrovascular pathology in diabetic patients.     

Pharmacogenetic studies update in type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment.     

Hepatitis C virus infection and type 1 and type 2 diabetes mellitus

Hepatitis C virus(HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus(T1DM) and T2 DM. T2 DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1 DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2 DM and chronic hepatitis C(CHC) infection. The processes through which CHC is associated with T2 DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immunemediated mechanisms. Few data have been reported on the association of CHC and T1 DM and reports on the potential association between T1 DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoim-munity and in certain cases lead to the development of T1 DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with nondiabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effec-tive programmes for the surveillance and treatment of diabetic CHC patients.     

The evolving place of incretin-based therapies in type 2 diabetes

Treatment options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were first introduced in 2005. These comprise the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor on the one hand and orally active dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In adult medicine, both treatment options are attractive and more commonly used because of their action and safety profile. The incretin-based therapies stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner and carry no intrinsic risk of hypoglycaemia. GLP-1 receptor agonists allow weight loss, whereas DPP-4 inhibitors are weight neutral. This review gives an overview of the mechanism of action and the substances and clinical data available.     

Diabetic nephropathy in children and adolescents

Type 1 diabetes mellitus (T1DM) commonly occurs in childhood or adolescence, although the rising prevalence of type 2 diabetes mellitus (T2DM) in these age groups is now being seen worldwide. Diabetic nephropathy (DN) develops in 15–20% of subjects with T1DM and in similar or higher percentage of T2DM patients, causing increased morbidity and premature mortality. Although overt DN or kidney failure caused by either type of diabetes are very uncommon during childhood or adolescence, diabetic kidney disease in susceptible patients almost certainly begins soon after disease onset and may accelerate during adolescence, leading to microalbuminuria or incipient DN. Therefore, all diabetics warrant ongoing assessment of kidney function and screening for the earliest manifestations of renal injury. Pediatric health care professionals ought to understand about risk factors, strategy for prevention, method for screening, and treatment of early DN. This review considers each form of diabetes separately, including natural history, risk factors for development, screening for early manifestations, and strategy recommended for prevention and treatment of DN in children and adolescents.