SetD7 (Set7/9) is a novel target of PPARγ that promotes the adaptive pancreatic ß-cell glycemic response.

Loss of functional pancreatic ß-cell mass leads to type 2 diabetes (T2D), attributable to modified ß-cell-dependent adaptive gene expression patterns. SetD7 is a histone methyltransferase enriched in pancreatic islets that mono- and dimethylates histone-3-lysine-4 (H3K4), promoting euchromatin modifications, and also maintains the regulation of key ß-cell function and survival genes. However, the transcriptional regulation of this important epigenetic modifier is unresolved. Here we identified the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARγ) as a major transcriptional regulator of SetD7 and provide evidence for direct binding and functionality of PPARγ in the SetD7 promoter region. Furthermore, constitutive shRNA-mediated PPARγ knockdown in INS-1 ß-cells or pancreas-specific PPARγ deletion in mice led to downregulation of SetD7 expression as well as its nuclear enrichment. The relevance of the SetD7-PPARγ interaction in ß-cell adaptation was tested in normoglycemic 60% partial pancreatectomy (Px) and hyperglycemic 90% Px rat models. Whereas a synergistic increase in islet PPARγ and SetD7 expression was observed upon glycemic adaptation post-60% Px, in hyperglycemic 90% Px rats, islet PPARγ, and PPARγ targets SetD7 and Pdx1 were downregulated. PPARγ agonist pioglitazone treatment in 90% Px rats partially restored glucose homeostasis and ß-cell mass and enhanced expression of SetD7 and Pdx1. Collectively, these data provide evidence that the SetD7-PPARγ interaction serves as an important element of the adaptive ß-cell response.

Optimizing Postprandial Glucose Management in Adults With Insulin-Requiring Diabetes: Report and Recommendations.

Faster-acting insulins, new noninsulin drug classes, more flexible insulin-delivery systems, and improved continuous glucose monitoring devices offer unprecedented opportunities to improve postprandial glucose (PPG) management and overall care for adults with insulin-treated diabetes. These developments led the Endocrine Society to convene a working panel of diabetes experts in December 2018 to assess the current state of PPG management, identify innovative ways to improve self-management and quality of life, and align best practices to current and emerging treatment and monitoring options. Drawing on current research and collective clinical experience, we considered the following issues for the ∼200 million adults worldwide with type 1 and insulin-requiring type 2 diabetes: (i) the role of PPG management in reducing the risk of diabetes complications; (ii) barriers preventing effective PPG management; (iii) strategies to reduce PPG excursions and improve patient quality of life; and (iv) education and clinical tools to support endocrinologists in improving PPG management. We concluded that managing PPG to minimize or prevent diabetes-related complications will require elucidating fundamental questions about optimal ways to quantify and clinically assess the metabolic dysregulation and consequences of the abnormal postprandial state in diabetes and recommend research strategies to address these questions. We also identified practical strategies and tools that are already available to reduce barriers to effective PPG management, optimize use of new and emerging clinical tools, and improve patient self-management and quality of life.

Sodium-Glucose Cotransporter 2 Inhibitor Protection Against Adverse Cardiovascular and Renal Outcomes in Patients With Type 2 Diabetes.

IN BRIEF New treatments for type 2 diabetes are required to demonstrate cardiovascular safety in dedicated cardiovascular outcomes trials (CVOTs). This article reviews available evidence on cardiovascular, renal, and safety outcomes from CVOTs and real-world analyses of sodium-glucose cotransporter 2 inhibitors, along with considerations for their use in clinical practice.

ß-Cell mass restoration by α7 nicotinic acetylcholine receptor activation.

Although it is well-established how nutrients, growth factors, and hormones impact functional ß-cell mass (BCM), the influence of the central nervous system in this regard, and especially in the context of islet immune modulation, has been understudied. Here we investigated the expression and activity of pancreatic islet α7 nicotinic acetylcholine receptor (α7nAChR) in islet anti-inflammatory and prosurvival signaling. Systemic administration of α7nAChR agonists in mice improved glucose tolerance and curtailed streptozotocin-induced hyperglycemia by retaining BCM, in part through maintaining Pdx1 and MafA expression and reducing apoptosis. α7nAChR activation of mouse islets ex vivo led to reduced inflammatory drive through a JAK2-STAT3 pathway that couples with CREB/Irs2/Akt survival signaling. Because the vagus nerve conveys anti-inflammatory signals to immune cells of the spleen and other nonneural tissues in the viscera by activating α7nAChR agonists, our study suggests a novel role for ß-cell α7nAChR that functions to maintain ß-cell survival and mass homeostasis through modulating islet cytokine and phosphatidylinositol 3-kinase-dependent signaling pathways. Exploiting these pathways may have therapeutic potential for the treatment of autoimmune diabetes.

Direct autocrine action of insulin on ß-cells: does it make physiological sense?

In recent years there has been a growing interest in the possibility of a direct autocrine effect of insulin on the pancreatic ß-cell. Indeed, there have been numerous intriguing articles and several eloquent reviews written on the subject (1-3); however, the concept is still controversial. Although many in vitro experiments, a few transgenic mouse studies, and some human investigations would be supportive of the notion, there exist different insights, other studies, and circumstantial evidence that question the concept. Therefore, the idea of autocrine action of insulin remains a conundrum. Here we outline a series of thoughts, insights, and alternative interpretations of the available experimental evidence. We ask, how convincing are these, and what are the confusing issues? We agree that there is a clear contribution of certain downstream elements in the insulin signaling pathway for ß-cell function and survival, but the question of whether insulin itself is actually the physiologically relevant ligand that triggers this signal transduction remains unsettled.

International Forum for the Advancement of Diabetes Research and Care, April 29-30, 2011, Athens, Greece.

The International Forum for the Advancement of Diabetes Research and Care brought together distinguished international experts in diabetes to discuss diverse trends and emerging issues in diabetes therapy and management. The plenary sessions on the first day focused on trends in insulin therapy, the role of glucagon-like peptide-1 receptor agonists in diabetes treatment, the relationship between diabetes and cardiovascular risk, and the challenges associated with the development of clinically relevant treatment guidelines. Interactive breakout sessions addressed the following topics: microvascular complications of diabetes; the need for a team approach to patient education; optimal management of Asian people with diabetes; the role of continuous glucose monitoring in assessing glucose variability; and lessons learned from biosimilar drugs. The plenary sessions on the second day covered self-monitoring of blood glucose, treatment and prevention of type 1 diabetes, and future directions for diabetes therapy. The meeting represented an excellent forum for the presentation of new research and the exchange of ideas aimed at improving outcomes for people with diabetes.

Heartwatch: a secondary prevention programme in primary care in Ireland.

BACKGROUND: Heartwatch, a secondary prevention programme in primary care was initiated in 2003, based on the second European Joint Task Force recommendations for secondary prevention of coronary heart disease (CHD). The aim was to examine the effect of the first 2 years of the Heartwatch programme on cardiovascular risk factors and treatments. DESIGN: Prospective cohort study of patients with established CHD enrolled into the Heartwatch programme. METHODS: Four hundred and seventy (20%) general practitioners nationwide participated in the programme, recruiting 11,542 patients with established CHD (earlier myocardial infarction, coronary intervention or coronary artery bypass surgery). Clinical data were electronically transferred by each general practitioner to a central database. Comparison of changes in risk factors and treatments at 1-year and 2-year follow-up from baseline were made using paired t-test for continuous and McNemar's test for categorical data. RESULTS: Statistically significant changes in systolic blood pressure, diastolic blood pressure, total and low-density lipoprotien cholesterol and smoking status at 1 and 2 years (P <0.0001) were observed. Little or no improvements were shown for exercise, BMI or waist circumference. Increases in the prescribing of statins, angiotensin-converting enzyme inhibitors and beta-blockers over the course of the study were observed. CONCLUSION: The Heartwatch programme has demonstrated significant improvements in the main risk factors and treatments for CHD. More effective interventions are required to reduce BMI, waist circumference and physical inactivity in this population. The increases in treatment uptake are approaching the optimal levels in this population.

Insulin treatment in managing type 2 diabetes: challenges and opportunities.

Type 2 diabetes is a progressive disease in which diminishing pancreatic beta-cell failure can induce acute and chronic complications many years prior to diagnosis. Therefore, adhering to recommended standards of care and following a stepwise approach to the management of type 2 diabetes, with early initiation of insulin therapy that ameliorates both fasting and postprandial hyperglycemia, can address the progressive increase in insulin resistance and decline in insulin secretion. An insulin regimen that introduces basal and prandial doses of insulin gradually to sustain daytime glycemic control is both practical and effective.

Secondary prevention of cardiovascular disease--a possible model for Australian general practice.

Heartwatch is a national program in Irish general practice for the secondary prevention of cardiovascular disease. The program--a joint initiative of the Irish Department of Health and Children, the Irish College of General Practitioners, and the Irish Heart Foundation--has a number of key components, many of which may be suitable for adapting to Australian primary care.

Hibernating myocardium in heart failure.

Ischemic left ventricular systolic dysfunction may result from myocardial necrosis or from hypocontractile areas of viable myocardium. In some cases, recovery of contractility may occur on revascularization--this reversibly dysfunctional tissue is commonly referred to as hibernating myocardium. Observational data suggest that revascularization of patients with ischemic left ventricular systolic dysfunction and known viable myocardium provides a survival benefit over medical therapy. Identification of viable, dysfunctional myocardium may be especially worthwhile in deciding which patients with ischemic left ventricular systolic dysfunction will benefit from revascularization procedures. Randomized, prospective trials evaluating this are currently ongoing. This review will provide an overview of the complex pathophysiology of viable, dysfunctional myocardium, and will discuss outcomes after revascularization. Of the techniques used to determine the presence of hibernating myocardium, functional methods such as stress echocardiography and cardiac magnetic resonance appear more specific, but less sensitive, than the nuclear modalities, which assess perfusion and metabolic activity. Currently, the availability of all methods is variable.