Type 2 Diabetes Therapy Research Articles

Glucagon-like peptide-1 and gastric inhibitory polypeptide: new advances.

Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are gastrointestinal peptides that play an important role as incretin hormones in the regulation of plasma glucose and insulin secretion. GLP-1-based therapies have therefore been implemented as treatment for type 2 diabetes (T2D). The purpose of this review is to summarize novel treatment options for T2D with GLP-1-based therapies. In addition, both peptides have relevant extrapancreatic effects that have been further characterized recently and are summarized in this review. Novel findings regarding changes in GLP-1 secretion after bariatric surgery are highlighted, wherein GLP-1 plays a role in promoting body weight loss and diabetes remission. For T2D therapy, novel options with long-acting GLP-1 analogs are summarized that show a good efficacy and safety profile, also in combination with insulin as well as for obesity treatment. As GIP is not suitable for T2D therapy, extrapancreatic effects of GIP, mainly on bone metabolism that have been characterized recently, are described. These show that the activated GIP receptor is important to allow optimal bone mass and structure. This review summarizes new findings on the physiology and pathophysiology of GLP-1 and GIP and novel therapeutic aspects.

Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages.

Glucagon-like peptide 1 (GLP-1), a kind of gut hormone, is used in the treatment of type 2 diabetes (T2D). Emerging evidence indicates that GLP-1 has anti-inflammatory activity. Chronic inflammation in the adipose tissue of obese individuals is a cause of insulin resistance and T2D. We hypothesized that GLP-1 analogue therapy in patients with T2D could suppress the inflammatory response of macrophages, and therefore inhibit insulin resistance. Our results showed that GLP-1 agonist (exendin-4) not only attenuated macrophage infiltration, but also inhibited the macrophage secretion of inflammatory cytokines including TNF-β, IL-6, and IL-1β. Furthermore, we observed that lipopolysaccharide (LPS)-induced macrophage conditioned media could impair insulin-stimulated glucose uptake. This effect was compensated by treatment with the conditioned media from macrophages treated with the combination of LPS and exendin-4. It was also observed that exendin-4 directly inhibited the activation of NF-κB in macrophages. In conclusion, our results indicated that GLP-1 improved inflammatory macrophage-derived insulin resistance by inhibiting NF-κB pathway and secretion of inflammatory cytokines in macrophages. Furthermore, our observations suggested that the anti-inflammatory effect of GLP-1 on macrophages can contribute to GLP-1 analogue therapy of T2D.

The neuroprotective effects of the anti-diabetic drug linagliptin against Aβ-induced neurotoxicity.

The neuroprotective effects of the anti-diabetic drug linagliptin against Aβ-induced neurotoxicity.

Reversibility of β-Cell-Specific Transcript Factors Expression by Long-Term Caloric Restriction in db/db Mouse.

Type 2 diabetes (T2D) is characterized by β-cell dedifferentiation, but underlying mechanisms remain unclear. The purpose of the current study was to explore the mechanisms of β-cell dedifferentiation with and without long-term control of calorie intake. We used a diabetes mouse model (db/db) to analyze the changes in the expression levels of β-cell-specific transcription factors (TFs) and functional factors with long-term caloric restriction (CR). Our results showed that chronic euglycemia was maintained in the db/db mice with long-term CR intervention, and β-cell dedifferentiation was significantly reduced. The expression of Glut2, Pdx1, and Nkx6.1 was reversed, while MafA expression was significantly increased with long-term CR. GLP-1 pathway was reactivated with long-term CR. Our work showed that the course of β-cell dedifferentiation can intervene by long-term control of calorie intake. Key β-cell-specific TFs and functional factors play important roles in maintaining β-cell differentiation. Targeting these factors could optimize T2D therapies.

New Approaches to the Immunotherapy of Type 1 Diabetes Mellitus Using Interleukin-27.

Type 1 diabetes (T1D) is a pancreatic beta cell specific autoimmune disease. One of the most significant current discussions in T1D studies is therapy. Since the conventional therapy, islet transplantation and external insulin, e.g., cannot prevent the destructive autoimmune process against original beta cells and persistent hyperglycemia remains, so recent developments in the field of T1D therapy paved the way to a renewed interest in immunotherapy based on the disease process, especially monoclonal antibody therapy. Due to encouraging laboratory results, cytokine antibody-based drugs could be effective in the clinical direction of the T1D disease process. Hence, implementation of this approach can be useful to improve clinical and laboratory manifestations of T1D.

Type 2 Diabetes and ADP Receptor Blocker Therapy.

Type 2 diabetes (T2D) is associated with several abnormalities in haemostasis predisposing to thrombosis. Moreover, T2D was recently connected with a failure in antiplatelet response to clopidogrel, the most commonly used ADP receptor blocker in clinical practice. Clopidogrel high on-treatment platelet reactivity (HTPR) was repeatedly associated with the risk of ischemic adverse events. Patients with T2D show significantly higher residual platelet reactivity on ADP receptor blocker therapy and are more frequently represented in the group of patients with HTPR. This paper reviews the current knowledge about possible interactions between T2D and ADP receptor blocker therapy.

Retinoic acid receptor β2 agonists restore glycaemic control in diabetes and reduce steatosis.

To investigate the effects of specific retinoic acid receptor (RAR) agonists in diabetes and fatty liver disease. Synthetic agonists for RARβ2 were administered to wild-type (wt) mice in a model of high-fat-diet (HFD)-induced type 2 diabetes (T2D) and to ob/ob and db/db mice (genetic models of obesity-associated T2D). We show that administration of synthetic agonists for RARβ2 to either wt mice in a model of HFD-induced T2D or to ob/ob and db/db mice reduces hyperglycaemia, peripheral insulin resistance and body weight. Furthermore, RARβ2 agonists dramatically reduce steatosis, lipid peroxidation and oxidative stress in the liver, pancreas and kidneys of obese, diabetic mice. RARβ2 agonists also lower levels of mRNAs involved in lipogenesis, such as sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase, and increase mRNAs that mediate mitochondrial fatty acid β-oxidation, such as CPT1α, in these organs. RARβ2 agonists lower triglyceride levels in these organs, and in muscle. Collectively, our data show that orally active, rapid-acting, high-affinity pharmacological agonists for RARβ2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RARβ2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis.

Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus — A randomized clinical trial

It is unknown if cholecalciferol is able to modify defects in regulatory T cells (Tregs) in type 1 diabetes (T1D). In this randomized, double-blind, placebo controlled trial 30 young patients with new-onset T1D were assigned to cholecalciferol (70IU/kgbodyweight/day) or placebo for 12months. Tregs were determined by FACS-analysis and functional tests were assessed with ex vivo suppression co-cultures at months 0, 3, 6 and 12. Suppressive capacity of Tregs increased (p<0.001) with cholecalciferol from baseline (−1.59±25.6%) to 3 (30.5±39.4%), 6 (44.6±23.8%) and 12months (37.2±25.0%) and change of suppression capacity from baseline to 12months was significantly higher (p<0.05) with cholecalciferol (22.2±47.2%) than placebo (−16.6±21.1%). Serum calcium and parathormone stayed within normal range.This is the first study, which showed that cholecalciferol improved suppressor function of Tregs in patients with T1D and vitamin D could serve as one possible agent in the development of immunomodulatory combination therapies for T1D.

A Mendelian randomization study of the effect of type-2 diabetes on coronary heart disease.

In observational studies, type-2 diabetes (T2D) is associated with an increased risk of coronary heart disease (CHD), yet interventional trials have shown no clear effect of glucose-lowering on CHD. Confounding may have therefore influenced these observational estimates. Here we use Mendelian randomization to obtain unconfounded estimates of the influence of T2D and fasting glucose (FG) on CHD risk. Using multiple genetic variants associated with T2D and FG, we find that risk of T2D increases CHD risk (odds ratio (OR)=1.11 (1.05–1.17), per unit increase in odds of T2D, P=8.8 × 10−5; using data from 34,840/114,981 T2D cases/controls and 63,746/130,681 CHD cases/controls). FG in non-diabetic individuals tends to increase CHD risk (OR=1.15 (1.00–1.32), per mmol·per l, P=0.05; 133,010 non-diabetic individuals and 63,746/130,681 CHD cases/controls). These findings provide evidence supporting a causal relationship between T2D and CHD and suggest that long-term trials may be required to discern the effects of T2D therapies on CHD risk.

PDB89 - A Multivariate analysis of Prescribing Information for Next Generation type 2 Diabetes treatments

To compare the pivotal clinical endpoints on the prescribing information labels of next generation treatments for type 2 diabetes (T2D) and to identify the most clinically-relevant antidiabetic outcomes. This multivariate analysis was designed to identify the appropriate treatment paradigm for the management of patients with T2D, based on symptomatology and relative efficacy. A multivariate analysis of clinical efficacy endpoints from product information labels of 10 recently approved next generation treatments for adult T2D was undertaken, with 26-week, placebo-controlled endpoint data for utilized all compounds, including change from baseline in hemoglobin A1c (%), body weight (kg), fasting plasma glucose (mg/dL), post-prandial plasma glucose (mg/dL), and the incidence of hypoglycemic events (%). Clinical relevance for this analysis was defined as 1% reduction in HbA1c, 5kg reduction in mean body weight from baseline, and an incidence of hypoglycemia <1%. Data with metformin in combination therapy was included where available, based on current therapeutic guidelines. The multivariate analysis highlighted that no single compound met the predefined hypothesis of clinical relevance after 26-weeks of treatment. Canagliflozin 300mg / metformin (-1.06%) and liraglutide (-1.00%) reported the greatest reduction in HbA1c. Canagliflozin 300mg / metformin (-4.07kg) and dapaglaflozin 10mg / metformin (-2.86kg) had the greatest mean reduction in body weight from baseline. Linagliptin 5mg / metformin (0.60%) and dapaglaflozin 10mg / metformin (1.10%) had the lowest incidence of hypoglycemia. Physicians should consider all clinically-relevant outcomes of available T2D therapies with individual patient needs before initiating treatment. Clinicians must be aware of the various clinical outcomes for available therapies to ensure a safe and effective treatment regimen based on the symptomatic profile of individual patients. A triple-goal targeted approach to the management of T2D may reduce healthcare costs and treatment augmentation while improving quality of life for patients.

Molecular tweezers inhibit islet amyloid polypeptide assembly and toxicity by a new mechanism.

In type-2 diabetes (T2D), islet amyloid polypeptide (IAPP) self-associates into toxic assemblies causing islet β-cell death. Therefore, preventing IAPP toxicity is a promising therapeutic strategy for T2D. The molecular tweezer CLR01 is a supramolecular tool for selective complexation of K residues in (poly)peptides. Surprisingly, it inhibits IAPP aggregation at substoichiometric concentrations even though IAPP has only one K residue at position 1, whereas efficient inhibition of IAPP toxicity requires excess CLR01. The basis for this peculiar behavior is not clear. Here, a combination of biochemical, biophysical, spectroscopic, and computational methods reveals a detailed mechanistic picture of the unique dual inhibition mechanism for CLR01. At low concentrations, CLR01 binds to K1, presumably nucleating nonamyloidogenic, yet toxic, structures, whereas excess CLR01 binds also to R11, leading to nontoxic structures. Encouragingly, the CLR01 concentrations needed for inhibition of IAPP toxicity are safe in vivo, supporting its development toward disease-modifying therapy for T2D.

Clinical efficacy of autologous stem cell transplantation for the treatment of patients with type 2 diabetes mellitus: a meta-analysis

Background aimsIn this study, we investigate whether bone marrow mononuclear cells (BM-MNC) or peripheral blood mononuclear cells (PB-MNC) have therapeutic efficacy in type 2 diabetes (T2D). MethodsSearch terms included stem cell, bone marrow cell, peripheral blood cell, umbilical cord blood and T2D in MEDLINE, the Cochrane Controlled Trials Register, EMBASE, the Wanfang Database, the China Science and Technology Periodical Database and China Journal Net. ResultsFifteen trials met our inclusion criteria (n = 497). One group included 266 cases with BM-MNC therapy and the other group contained 231 cases with PB-MNC treatment. Glycosylated hemoglobin was decreased after BM-MNC or PB-MNC therapy compared with that before (12 months: P < 0.001; 6 months: P < 0.001; 3 months: P < 0.05). Fasting plasma glucose was reduced in BM-MNC therapy group compared with control after 12-month follow-up (P < 0.001) and after BM-MNC therapy compared with that before (9 months: P < 0.001) but was not obvious in other stages. Meanwhile, the analysis showed that C-peptide level increased after BM-MNC and PB-MNC therapy compared with the control therapy (12 months: P < 0.001) and with that before therapy (6 months: P < 0.05). Insulin requirement reduction was also observed in patients receiving BM-MNC therapy (3, 6, 9 and 12 months: P < 0.05). ConclusionsTo a certain extent, BM-MNC or PB-MNC therapy for T2D demonstrated superiority of glycemic control, increased insulin biosynthesis and elevated insulin secretion from existing β-cells and might prevent islet cell loss.

Generation of β cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice.

Several β cell antigens recognized by T cells in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D) are also T cell targets in the human disease. While numerous antigen-specific therapies prevent diabetes in NOD mice, successful translation of rodent findings to patients has been difficult. A human leucocyte antigen (HLA)-transgenic mouse model incorporating human β cell-specific T cells might provide a better platform for evaluating antigen-specific therapies. The ability to study such T cells is limited by their low frequency in peripheral blood and the difficulty in obtaining islet-infiltrating T cells from patients. We have worked to overcome this limitation by using lentiviral transduction to 'reprogram' primary human CD8 T cells to express three T cell receptors (TCRs) specific for a peptide derived from the β cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP265-273 ) and recognized in the context of the human class I major histocompatibility complex (MHC) molecule HLA-A2. The TCRs bound peptide/MHC multimers with a range of avidities, but all bound with at least 10-fold lower avidity than the anti-viral TCR used for comparison. One exhibited antigenic recognition promiscuity. The β cell-specific human CD8 T cells generated by lentiviral transduction with one of the TCRs released interferon (IFN)-γ in response to antigen and exhibited cytotoxic activity against peptide-pulsed target cells. The cells engrafted in HLA-A2-transgenic NOD-scid IL2rγ(null) mice and could be detected in the blood, spleen and pancreas up to 5 weeks post-transfer, suggesting the utility of this approach for the evaluation of T cell-modulatory therapies for T1D and other T cell-mediated autoimmune diseases.

Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients

Most autoimmune diseases (AID) are linked to an imbalance between autoreactive effector T cells (Teffs) and regulatory T cells (Tregs). While blocking Teffs with immunosuppression has long been the only therapeutic option, activating/expanding Tregs may achieve the same objective without the toxicity of immunosuppression. We showed that low-dose interleukin-2 (ld-IL-2) safely expands/activates Tregs in patients with AID, such HCV-induced vasculitis and Type 1 Diabetes (T1D). Here we analyzed the kinetics and dose-relationship of IL-2 effects on immune responses in T1D patients. Ld-IL-2 therapy induced a dose-dependent increase in CD4+Foxp3+ and CD8+Foxp3+ Treg numbers and proportions, the duration of which was markedly dose-dependent. Tregs expressed enhanced levels of activation markers, including CD25, GITR, CTLA-4 and basal pSTAT5, and retained a 20-fold higher sensitivity to IL-2 than Teff and NK cells. Plasma levels of regulatory cytokines were increased in a dose-dependent manner, while cytokines linked to Teff and Th17 inflammatory cells were mostly unchanged. Global transcriptome analyses showed a dose-dependent decrease in immune response signatures. At the highest dose, Teff responses against beta-cell antigens were suppressed in all 4 patients tested. These results inform of broader changes induced by ld-IL-2 beyond direct effects on Tregs, and relevant for further development of ld-IL-2 for therapy and prevention of T1D, and other autoimmune and inflammatory diseases.

Anti-CD44 antibody treatment lowers hyperglycemia and improves insulin resistance, adipose inflammation, and hepatic steatosis in diet-induced obese mice.

Type 2 diabetes (T2D) is a metabolic disease affecting >370 million people worldwide. It is characterized by obesity-induced insulin resistance, and growing evidence has indicated that this causative link between obesity and insulin resistance is associated with visceral adipose tissue inflammation. However, using anti-inflammatory drugs to treat insulin resistance and T2D is not a common practice. We recently applied a bioinformatics methodology to open public data and found that CD44 plays a critical role in the development of adipose tissue inflammation and insulin resistance. In this report, we examined the role of CD44 in T2D by administering daily injections of anti-CD44 monoclonal antibody (mAb) in a high-fat-diet mouse model. Four weeks of therapy with CD44 mAb suppressed visceral adipose tissue inflammation compared with controls and reduced fasting blood glucose levels, weight gain, liver steatosis, and insulin resistance to levels comparable to or better than therapy with the drugs metformin and pioglitazone. These findings suggest that CD44 mAb may be useful as a prototype drug for therapy of T2D by breaking the links between obesity and insulin resistance.

A second look at the ancient drug: new insights into metformin.

Metformin, a biguanide derived from Galega officinalis (French lilac), has been used for the treatment of type 2 diabetes (T2D) for over half century. It is now the most widely prescribed anti-diabetic drug and recommended as the first line oral therapy for T2D. Metformin is generally considered as a very safe drug with favorable cost-efficacy-ratio. With regard to the safety concern of its use in gestational diabetes, Bertoldo et al. provided us an excellent summary of the current knowledge on the role of metformin in pregnant women as well as in fetal development. In addition to its use in T2D, metformin has also been prescribed for polycystic ovary syndrome (PCOS). In this issue, Neil P. Johnson reviewed the best available evidence for the use of metformin in women with PCOS and discussed its position among other options used to treat various problems faced by women with PCOS. In recent years, metformin has gained a lot of attention for its potential application in the prevention and treatment of cancer. The idea of cancer preventive and therapeutic effect of metformin originates from a serious of observational studies in populations with or without metformin consumption. Compared to its definitive performance in diabetic patients, the exact mechanism(s) of action and the direct molecular target(s) of metformin are less conclusive. In this special issue, Kasznicki et al. provided us an overview of proposed mechanism(s) of action of metformin in cancer prevention and therapy, along with preclinical and clinical data suggesting its favorable effect against cancer in different populations. The role of metformin on selective modulation of microRNAs to reprogram altered metabolism of a cancer cell toward that of untransformed cell was extensively reviewed by Pulito et al. Considering the crucial role of microRNAs in cancer stem cells (CSCs) or stem cell-like cancer cells, which are believed to be difficult to eradicate by various treatments, Bao et al. further discussed the potential role of metformin in modulaing CSC-associated microRNAs as part of the novel mechanism of action of metformin in the development and progression of breast and pancreatic cancers. Aside from the anti-tumor effect of metformin, Dr. Vladimir N. Anisimov presented a critical review regarding the capacity of metformin to prevent spontaneous and induced tumorigenesis based on published data derived from animal studies in an attempt to address the question “do metformin a real anticarcinogen”. Despite the popularity of metformin in the field of cancer research, it is not negligible that concerns have been raised towards various observational studies indicating that metformin use may reduce the incidence and/or mortality of different types of cancer. In order to help us uncover the veil of mysterious biases occured during these cohort studies, which have been mostly critized, Yang and Chan reviewed and discussed in detail the methodologies employed in metformin-related observational studies. Another paradox that metformin is facing is whether it acts against or towards cognitive impairment and Alzheimer disease in patients with T2D. In two separate editorials, European scientists Ilker Tasci and Paula I. Moreira presented their own opinion towards this controversy. Herein, I would like to acknowledge each and every one who has devoted their time and efforts to this special issue. We believe this issue has included most up-to-date information regarding the conventional use of metformin as well as the potential expansion of its applications. Hopefully our readers will enjoy and benefit from reading this special issue.

Impact of information technology on the therapy of type-1 diabetes: a case study of children and adolescents in Germany.

Being able to manage and adjust insulin doses is a key part of managing type-1 diabetes. Children and adolescents with type-1 diabetes mellitus often have serious difficulties with this dosage adjustment. Therefore, this paper aims to investigate the impact of using novel mobile, web and communication technologies in assisting their therapy and treatment. A trial was conducted in the north-eastern part of Germany to evaluate the impact of the “Mobil Diab”, a mobile diabetes management system, on the clinical outcome. 68 subjects aged between 8 and 18 years, divided randomly into control and intervention groups, were included into the study. Metrics such as changes in the quality of metabolic control, changes in psychological parameters, usability and acceptance of the technology were used for evaluation purpose. Metabolic control was mainly assessed by the mean HbAlc. Analysis showed a good acceptance of the proposed system. An overall improvement in mean levels of HbA1c was observed, however further studies will be conducted to prove evidence of the weight and BMI improvements. Moreover, initial indications of positive impact on the improvement in psychological parameters were presumed based on the result of the conducted study. The system appeared to be an efficient and time saving tool in diabetes management.

GLP-1: The Oracle for Gastric Bypass?

Despite enormous efforts to find effective pharmacological targets, bariatric surgery is still the most effective treatment for morbid obesity. Beyond weight loss, this procedure often results in remarkable improvements in type 2 diabetes (T2D). However, several clinical trials have shown that between 22 and 28% of patients with T2D did not experience improvements in their diabetes after surgery (1). Personalized medicine seeks to identify the best possible therapeutic outcome with minimal adverse events. However, it requires an understanding of the molecular underpinnings of disease as well as signaling pathways triggered by both pharmacological and surgical treatments that predict an individual’s likelihood of responding favorably to treatment. Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released into the bloodstream postprandially from the ileum and colon. Among its multiple biological actions (2), GLP-1 stimulates insulin secretion in a glucose-dependent manner (3,4) and decreases appetite (5). GLP-1–based T2D therapies are now commonly used in combination with other drugs with the added weight-loss effect broadening its therapeutic application in human obesity (6,7). Since bariatric surgery causes weight loss and T2D remission with enhanced postprandial GLP-1 secretion, the role of GLP-1 as a mediator of surgery-associated benefits has been investigated (8,9). However, to date, this hypothesis remains inconclusive because mice lacking GLP-1 receptors (GLP-1Rs) responded similarly to controls after vertical sleeve gastrectomy (10). In this issue, Habegger et al. …

Insulin Micro-secretionin Patients with Long Duration Type 1 Diabetes: Implications of Interferon-γ?

Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by the destruction of pancreatic β-cells leading to absolute insulin deficiency [1]. Exogenous insulin represents the core of therapy for T1D that is fatal unless treated[2]. Several years of progressive autoimmune β-cells damage generally precede the clinical onset of diabetes [2]. Moreover, it has been found that the decline in insulin production in patients with T1D is variable [2]. The majority of patients with long-duration T1D has been demonstrated to be insulin microsecretors and to have residual functioning β-cells [2,3]. On this regard, it has been speculated that the small still functional β-cells could have escaped immune attack or have undergone a regeneration process known to be so far extremely limited in human adult [2,4]. Multiple immunological mechanisms have been proposed to contribute to β-cell destruction[5]. Although cytotoxic T lymphocytes directly attack β-cell in T1D, cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet β-cell dysfunction and death [2-7]. Apoptosis represents the main form of cytokine-induced pancreatic β-cell death [5]. Different proinflammatory cytokines, such as Tumor necrosis factor-α (TNF-α), Interleukin-1 (IL-1) and Interferon-γ (IFN-γ), have been involved in T1D pathogenesis [1]. Among these cytokines, IFN-γ has been conventionally described as responsible for driving pancreatic islets autoimmune damage, leading to β-cell apoptosis and the initial destruction of pancreatic β-cells in the onset of diabetes [1,2,4-8]. IFNγ has been reported to influence immune and autoimmune responses by supporting the homing of diabetogenic activated T cells [8]. The development of diabetes has been linked to the accumulation of IFN-γ producing T-cells in the islets [6]. Furthermore, an association between IFN-γ polymorphism and T1D onset has been corroborated [7]. On the contrary, it has been provided evidence that IFN-γ receptor deficiency prevents diabetes [9]. What is more, reduced diabetes incidence was observed by neutralizing endogenous IFN-γ with anti IFN-γ antibodies [9,10]. Interestingly, IFN-γ has also been shown to play a major role in β-cell dysfunction associated with chronic pancreatitis [11]. The different biological effects of IFN-γ have been connected with its action in regulating gene transcription [5,7,12].

Abstract 18968: Bromocriptine-QR: A Potential Novel Strategy for Cardiovascular Risk Reduction in Type 2 Diabetes

Type 2 diabetes (T2D) is associated with a substantially increased risk of cardiovascular disease (CVD). Of the available therapies for T2D, none have been conclusively shown to reduce CVD risk. Metformin has long been considered the only agent with some evidence, albeit limited, of a potential CVD benefit. Bromocriptine-QR (BQR), a quick release sympatholytic dopamine agonist, is a newer FDA-approved therapy for T2D. Based on preclinical and clinical study findings, it is postulated that BQR restores the normal circadian peak in central dopaminergic tone diminished in insulin resistant states, which in turn reduces hyperactive sympathetic tone and improves central fuel sensing thereby reducing postprandial hepatic glucose and lipid output as well as reduces vascular resistance, oxidative stress, and inflammation. In a one-year randomized trial of BQR vs. placebo added to standard therapy (diet and/or ≤ 2 diabetes medications including sulfonylureas, TZD, metformin, or insulin) in 3070 T2D subjects (average duration of T2D: 7.9 years), including individuals with pre-existing CVD, BQR therapy resulted in a 40% hazard rate reduction (HRR) in major CVD events, pre-specified as a composite of time to first myocardial infarction, stroke, coronary revascularization, hospitalization for angina or congestive heart failure. In the present study, this CVD effect of BQR was evaluated in a subset of this original study population on metformin +/- another anti-diabetes therapy at baseline (N = 1791). The composite CVD end point occurred in 16/1208 BQR-treated (1.3%) and 18/583 placebo-treated (3.1%) subjects resulting in a 53% CVD HRR (ITT group, Cox regression analysis; HR 0.47, 95% CI 0.24, 0.92, P = 0.028) adjusted by age (HR 1.08, 95% C.I. 1.04, 1.12, P = 0.0003) and pre-existing CVD (HR 2.27, 95% C.I. 1.02, 5.07, P = 0.041). Kaplan-Meier Curves of the cumulative incidence rate yielded a CVD HRR of 58% (HR 0.42, 95% C.I. 0.21, 0.85, Log-Rank = 0.017). These findings reaffirm prior observations of CVD risk reduction with BQR therapy and further demonstrate the potential for a marked additive effect of BQR above any derived from metformin, suggesting a potential novel strategy for CVD risk reduction in T2D.