Gluco-regulation & type 2 diabetes: entrenched misconceptions updated to new governing principles for gold standard management.

Our understanding of type 2 diabetes (T2D) has evolved dramatically. Advances have upended entrenched dogmas pertaining to the onset and progression of T2D, beliefs that have prevailed from the early era of diabetes research-and continue to populate our medical textbooks and continuing medical education materials. This review article highlights key insights that lend new governing principles for gold standard management of T2D. From the historical context upon which old beliefs arose to new findings, this article outlines evidence and perspectives on beta cell function, the underlying defects in glucoregulation, the remediable nature of T2D, and, the rationale supporting the shift to complication-centric prescribing. Practical approaches translate this rectified understanding of T2D into strategies that fill gaps in current management practices of prediabetes through late type 2 diabetes.

Maternal Metabolic Health, Lifestyle, and Environment - Understanding How Epigenetics Drives Future Offspring Health.

The incidence of metabolic disorders, such as obesity and type two diabetes (T2DM), continues to increase worldwide, and their onset is often attributed to adherence to a western diet and a sedentary lifestyle. However, large variability exists in one's likelihood of developing metabolic dysregulation, illustrating that our understanding of heritability patterns remains poorly understood. Diabetes and obesity are multifactorial diseases, and their onset is influenced by both genetic and environmental factors. Genome-wide association studies report a number of alterations in the coding sequence associated with the onset of T2DM and obesity. However, these genes explain only a fraction of the cases, leaving the majority unaccounted for. The missing heritability question implies that other factors are responsible for the onset and development of the disease. Given that the developing fetus is susceptible to the maternal environment, a growing body of evidence demonstrates that maternal metabolic characteristics as well as disruptions to the prenatal environment may induce long-term genetic, phenotypic, and physiologic adaptations in the developing fetus, which could have a permanent effect on its future health. This phenomenon is known as developmental programming and is mediated through epigenetic modifications, which include modulation of gene expressions that do not alter the original deoxyribonucleic (DNA) sequence. Epigenetic modifications are capable of changing gene expression in metabolism-related genes and are accomplished through DNA methylation, histone acetylation, and ribonucleic acid (RNA) mechanisms. In this review, we discuss maternal metabolic factors, such as obesity, dyslipidemia, and gestational diabetes (GDM) that lead to epigenetic changes in the offspring and predispose future generations to metabolic abnormalities. We will also describe the association between maternal lifestyle factors and exposure to toxins with epigenetic modulations in the offspring. Lastly, we will provide a brief review of the possibility of using epigenetics as potential interventions and therapeutic modalities to help in early diagnosis and prevention of metabolic disorders.

The time is now for new, lower diabetes diagnostic thresholds.

Current thresholds for diagnosing diabetes are outdated and do not represent advancements in disease understanding or ability to impact course. Today, evidence supports intervening earlier along the disease continuum to mitigate transition to frank disease and delay/reduce adverse clinical outcomes. We believe it is time for lower diabetes diagnostic criteria.

The Diabetes Syndrome - A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms.

The four basic pathophysiologic mechanisms which damage the ß-cell within diabetes (ie, genetic and epigenetic changes, inflammation, an abnormal environment, and insulin resistance [IR]) also contribute to cell and tissue damage and elevate the risk of developing all typical diabetes-related complications. Genetic susceptibility to damage from abnormal external and internal environmental factors has been described including inflammation and IR. All these mechanisms can promote epigenetic changes, and in total, these pathophysiologic mechanisms interact and react with each other to cause damage to cells and tissues ultimately leading to disease. Importantly, these pathophysiologic mechanisms also serve to link other common conditions including cancer, dementia, psoriasis, atherosclerotic cardiovascular disease (ASCVD), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). The "Diabetes Syndrome", an overarching group of interrelated conditions linked by these overlapping mechanisms, can be viewed as a conceptual framework that can facilitate understanding of the inter-relationships of superficially disparate conditions. Recognizing the association of the conditions within the Diabetes Syndrome due to common pathophysiologies has the potential to provide both benefit to the patient (eg, prevention, early detection, precision medicine) and to the advancement of medicine (eg, driving education, research, and dynamic decision-based medical practice).

Diabetes and Psoriasis: Different Sides of the Same Prism.

Diabetes and psoriasis are prevalent conditions with a spectrum of serious adverse outcomes. Both diseases are common comorbidities for each other, and diabetes is considered as a risk factor for psoriasis and vice versa. However, it is our contention that these diseases are not merely comorbidities of each other but rather share common underlying pathophysiologies (ie, genes and epigenetic changes, inflammation, abnormal environment, and insulin resistance) that drive disease. As such, they can be viewed as facets of the same prism. Genes can cause or permit susceptibility to damage from abnormal external and internal environmental factors, inflammation, and insulin resistance which can also drive epigenetic changes. These co-existing mechanisms act in a vicious cycle over time to potentiate cell and tissue damage to ultimately drive disease. Viewing diabetes and psoriasis through the same prism suggests potential for therapies that could be used to treat both conditions. Although additional controlled trials and research are warranted, we believe that our understanding of the overlapping pathophysiologies continues to grow, so too will our therapeutic options.

Intersections and Clinical Translations of Diabetes Mellitus with Cancer Promotion, Progression and Prognosis.

The association between cancer and dysglycemia has been well documented. It is underappreciated, however, that sustained dysglycemia could potentially be a catalyst toward a pro-cancer physiologic milieu and/or increase the burden of cancer. Hyperglycemia, hyperinsulinemia and energy metabolism at large impact a cascade of growth pathways, epi/genetic modifications, and mitochondrial changes that could feasibly link to tumor processes. Oxidative stress is a recurring motif in cell dysfunction: in diabetes, oxidative stress and reactive oxygen species (ROS) feature prominently in the damage and demise of pancreatic beta cells, as well as cell damage contributing to diabetes-related complications. Oxidative stress may be one intersection at which metabolic and oncogenic processes cross paths with deleterious results in the development of precancer, cancer, and cancer progression. This would augur for tight glucose control. Regrettably, some medical societies have recently relaxed hemoglobin A1c targets. A framework for the hyperglycemic state is presented that helps account and translate the full scope of effects of dysglycemia to ultimately improve clinical best practices.

Type 2 diabetes: Evolving concepts and treatment.

In view of new information, we are revising the way we think about and treat diabetes mellitus. In this new view, the insulin-producing beta cells are key, and preserving beta-cell function is paramount. These insights, together with recent outcome studies provide compelling arguments regarding treatments of choice.

Diabetic Retinopathy-An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes.

Diabetes mellitus is a world-wide epidemic and diabetic retinopathy, a devastating, vision-threatening condition, is one of the most common diabetes-specific complications. Diabetic retinopathy is now recognized to be an inflammatory, neuro-vascular complication with neuronal injury/dysfunction preceding clinical microvascular damage. Importantly, the same pathophysiologic mechanisms that damage the pancreatic ß-cell (e.g., inflammation, epigenetic changes, insulin resistance, fuel excess, and abnormal metabolic environment), also lead to cell and tissue damage causing organ dysfunction, elevating the risk of all complications, including diabetic retinopathy. Viewing diabetic retinopathy within the context whereby diabetes and all its complications arise from common pathophysiologic factors allows for the consideration of a wider array of potential ocular as well as systemic treatments for this common and devastating complication. Moreover, it also raises the importance of the need for methods that will provide more timely detection and prediction of the course in order to address early damage to the neurovascular unit prior to the clinical observation of microangiopathy. Currently, treatment success is limited as it is often initiated far too late and after significant neurodegeneration has occurred. This forward-thinking approach of earlier detection and treatment with a wider array of possible therapies broadens the physician's armamentarium and increases the opportunity for prevention and early treatment of diabetic retinopathy with preservation of good vision, as well the prevention of similar destructive processes occurring among other organs.

Insulin Therapy Increases Cardiovascular Risk in Type 2 Diabetes.

Insulin therapy increased cardiovascular (CV) risk and mortality among type 2 diabetes (T2D) patients in several recently reported clinical outcomes trials. To assess whether this association is causative or coincidental, PubMed searches were used to query the effects of insulin therapy for T2D on CV health and longevity from large-scale outcomes trials, meta-analyses, and patient registry studies, as well as basic research on insulin's direct and pleiotropic actions. Although several old studies provided conflicting results, the majority of large observational studies show strong dose-dependent associations for injected insulin with increased CV risk and worsened mortality. Insulin clearly causes weight gain, recurrent hypoglycemia, and, other potential adverse effects, including iatrogenic hyperinsulinemia. This over-insulinization with use of injected insulin predisposes to inflammation, atherosclerosis, hypertension, dyslipidemia, heart failure (HF), and arrhythmias. These associations support the findings of large-scale evaluations that strongly suggest that insulin therapy has a poorer short- and long-term safety profile than that found to many other anti-T2D therapies. The potential adverse effects of insulin therapy should be weighed against proven CV benefits noted for select other therapies for T2D as reported in recent large randomized controlled trials.

A Unified Pathophysiological Construct of Diabetes and its Complications.

Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysiology involving metabolic insults, oxidative damage, and vicious cycles that aggravate and intensify organ dysfunction and damage. This new understanding of the disease requires that we revisit existing diagnostics and treatment approaches, which were built upon outmoded assumptions. 'The Common Pathophysiologic Origins of Diabetes Mellitus and its Complications Construct' is presented as a more accurate, foundational, and translatable construct of DM that helps make sense of the hitherto ambiguous findings of long-term outcome studies.

An evidence-based practice-oriented review focusing on canagliflozin in the management of type 2 diabetes.

Caring for patients with type 2 diabetes mellitus (T2DM) has entered an era with many recent additions to the regimens used to clinically control their hyperglycemia. The most recent class of agents approved by the Food and Drug Administration (FDA) for T2DM is the sodium-glucose-linked transporter type 2 (SGLT2) inhibitors, which work principally in the proximal tubule of the kidney to block filtered glucose reabsorption. In the few years attending this new class arrival in the market, there has been a great deal of interest generated by the novel mechanism of action of SGLT2 inhibitors and by recent large outcome trials suggesting benefit on important clinical outcomes such as death, cardiovascular disease and kidney disease progression. In this review, we focus on canagliflozin, the first-in-class marketed SGLT2 inhibitor in the USA. In some cases, we included data from other SGLT2 inhibitors, such as outcomes in clinical trials, important insights on clinical features and benefits, and adverse effects. These agents represent a fundamentally different way of controlling blood glucose and for the first time in T2DM care to offer the opportunity to reduce glucose, blood pressure, and weight with effects sustained for at least 2 years. Important side effects include genital mycotic infections and the potential for orthostatic hypotension and rare instances of normoglycemic ketoacidosis. Active ongoing clinical trials promise to deepen our experience with the potential benefits, as well as the clinical risks attending the use of this new group of antidiabetic agents.

Evidence-based practice use of quick-release bromocriptine across the natural history of type 2 diabetes mellitus.

OBJECTIVES: To provide an evidence-based practice overview on the clinical use of bromocriptine-quick release (QR) across the natural history of type 2 diabetes mellitus (T2DM). METHODS: Articles for inclusion were selected after a comprehensive literature search of English-language PubMed articles and identification of other relevant references through other sources. Inclusion criteria were animal studies examining the mechanism of action and efficacy of bromocriptine, and clinical studies examining the safety and efficacy of bromocriptine-QR in patients with T2DM, without a time limitation. RESULTS: The brain plays a key role in total body metabolism, in particular ensuring that sufficient levels of glucose are available for proper neural functioning. The hypothalamic suprachiasmatic nucleus (SCN), the body's biological clock, plays a key role in the regulation of seasonal and diurnal variations of insulin sensitivity. A daily surge of dopaminergic activity in the SCN upon waking enables insulin sensitivity throughout the day. When this is disrupted (e.g. by a high fat/sugar diet, stress, altered [diminished] exercise, altered sleep/wake cycle, diabetes), insulin resistance persists throughout the day and overnight. Improving the morning surge in dopaminergic activity with the short-acting dopamine D2 receptor agonist bromocriptine-QR can safely and effectively improve glycemic control, while improving cardiovascular disease risk factors and related adverse events, and reducing sympathetic tone, as demonstrated by 5 reports of the Cycloset Safety Trial and 3 additional clinical studies of bromocriptine-QR. CONCLUSIONS: In patients with T2DM, the dopamine D2 receptor agonist bromocriptine-QR has been shown to be well tolerated, efficacious, and a logical treatment option.

Obviating much of the need for insulin therapy in type 2 diabetes mellitus: A re-assessment of insulin therapy's safety profile.

Current processes of care for diabetes mellitus (DM) were shaped during the era when insulin therapy was considered inexorable to the management of advanced stage type 2 (T2DM), though this no longer appears to be categorically true. There are also dashed hopes that insulin therapy can prevent or stall diabetes. While exogenous insulin remains a life-sparing tool for fully insulin-dependent DM, insulin therapy-induced hyperinsulinemia now appears to contribute to serious safety issues beyond hypoglycemia and weight gain. Iatrogenic and compensatory hyperinsulinemia are metabolic disruptors of ß-cells, liver, muscle, kidney, brain, heart and vasculature, inflammation, and lipid homeostasis, among other systems. This may compromise ß-cells, exacerbate insulin resistance (IR), and increase risk of cardiovascular (CV) disease. Striking associations between exogenous insulin and risks of CV events, cancer, and all-cause mortality in clinical trial and real-world cohorts caution that insulin may pose more harm than previously evidenced. At our disposal are numerous alternate tools that, alone or in combination, efficaciously manage hyperglycemia and glucolipotoxicity, and do so without inducing hypoglycemia, weight gain, or hyperinsulinemia. Moreover, these new tools support true precision therapy, as modern day drug classes can be aligned with the various mediating pathways of hyperglycemia at work in any given patient. Some also appear to promote ß-cell survival, with intriguing data being presented for newer agents, such as incretins. As such, we encourage preferential use of non-insulin antidiabetic agents to injected insulin for the management of non-insulin-dependent patients with T2DM, including in advanced stage T2DM. The goal of this article is to augment existing literature to 1) correct misconceptions on the rationale and necessity for insulin therapy in T2DM, 2) discuss emerging negative safety data with insulin therapy, and, 3) offer a practical means to reduce reliance on insulin through delayed initiation, minimized dose, and, drug switching to safer agents, and, potentially, reframes processes of care.

Sodium-glucose cotransporter-2 inhibitor combination therapy to optimize glycemic control and tolerability in patients with type 2 diabetes: focus on dapagliflozin-metformin.

In type 2 diabetes (T2D), early combination therapy using agents that target a number of the underlying pathophysiologic defects contributing to hyperglycemia may improve patient outcomes. For many patients, the combination of metformin with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor may be a good option because these agents have complementary mechanisms of action, neutral-to-positive effects on body weight, and a low risk of hypoglycemia. This review focuses on the combination of metformin with dapagliflozin, a member of the SGLT-2 inhibitor class of antidiabetes agents. In clinical trials, the combination of dapagliflozin with metformin produced significant and sustained reductions in glycated hemoglobin and body weight in a broad range of adult patients with T2D, including those initiating pharmacotherapy and those with more advanced disease. These reductions were accompanied by modest decreases in blood pressure. Dapagliflozin as add-on therapy to metformin was well tolerated and associated with low rates of hypoglycemia. Genital infections and, in some studies, urinary tract infections were more frequent with dapagliflozin than with placebo. Early combination therapy with dapagliflozin and metformin may be a safe and appropriate treatment option that enables patients with T2D to achieve individualized glycemic goals as either initial combination therapy in treatment-naïve patients or as dapagliflozin add-on in patients inadequately controlled with metformin therapy.

Sodium-glucose cotransporter 2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetes.

Objective The sodium-glucose cotransporter 2 (SGLT-2) inhibitors are an important addition to available treatments for patients with type 2 diabetes (T2D) as an adjunct to modifications in diet and exercise. SGLT-2 inhibitors may be prescribed alone or as add-on treatment in patients receiving metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and/or insulin across the natural history of the disease. Inhibition of SGLT-2, which is responsible for approximately 90% of renal glucose reabsorption, increases urinary glucose excretion and lowers blood glucose concentrations. The objective of this review is to discuss the pathophysiology of diabetes and the contribution of the kidney to glucose homeostasis and to provide an evidence-based practice approach to clinical applications of SGLT-2 inhibitors in the treatment of T2D. Methods PubMed and Google Scholar databases were searched to identify literature published from 1990 through September 2015 examining the pathophysiology of T2D, the role of the kidney in regulating glucose concentrations, and clinical evidence for the efficacy and safety of SGLT-2 inhibitors in T2D. Results There is a need for early treatment in patients with T2D to minimize the risk of cardiovascular complications that increase morbidity and mortality. SGLT-2 inhibitors improve glycemic control, reduce body weight and blood pressure, and are associated with a low risk of hypoglycemia. Adverse events associated with SGLT-2 inhibitors include mild to moderate urinary tract and genital infections and mild dehydration potentially leading to orthostatic hypotension. Conclusions An evidence-based practice approach to examining the importance of early, proactive treatment of T2D using SGLT-2 inhibitors from initiation of pharmacotherapy to increasingly more complicated combination therapy regimens, including insulin, suggests that this treatment strategy maximizes benefits and minimizes potential side effects. The SGLT-2 inhibitors augment the arsenal of available antidiabetes agents, facilitating the ability of clinicians to design tailored treatment regimens that help patients achieve therapeutic goals.

The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the ß-Cell-Centric Classification Schema.

The current classification system presents challenges to the diagnosis and treatment of patients with diabetes mellitus (DM), in part due to its conflicting and confounding definitions of type 1 DM, type 2 DM, and latent autoimmune diabetes of adults (LADA). The current schema also lacks a foundation that readily incorporates advances in our understanding of the disease and its treatment. For appropriate and coherent therapy, we propose an alternate classification system. The ß-cell-centric classification of DM is a new approach that obviates the inherent and unintended confusions of the current system. The ß-cell-centric model presupposes that all DM originates from a final common denominator-the abnormal pancreatic ß-cell. It recognizes that interactions between genetically predisposed ß-cells with a number of factors, including insulin resistance (IR), susceptibility to environmental influences, and immune dysregulation/inflammation, lead to the range of hyperglycemic phenotypes within the spectrum of DM. Individually or in concert, and often self-perpetuating, these factors contribute to ß-cell stress, dysfunction, or loss through at least 11 distinct pathways. Available, yet underutilized, treatments provide rational choices for personalized therapies that target the individual mediating pathways of hyperglycemia at work in any given patient, without the risk of drug-related hypoglycemia or weight gain or imposing further burden on the ß-cells. This article issues an urgent call for the review of the current DM classification system toward the consensus on a new, more useful system.

THE RATIONALE FOR USE OF INCRETINS IN THE MANAGEMENT OF NEW ONSET DIABETES AFTER TRANSPLANTATION (NODAT).

OBJECTIVE: Owing to advances in transplant science, increasing numbers of patients are receiving solid organ transplantation. New onset diabetes after transplantation (NODAT) frequently develops in transplant patients and requires acute and often ongoing management of hyperglycemia. The metabolic derangements of NODAT are similar to those of classic type 2 diabetes, and treatment has typically followed diabetes standards of care. Best practices for NODAT management remain to be developed. METHODS: The mechanistic suitability of incretins to treat NODAT pathogenesis has been hitherto underappreciated. This review details the specific mechanistic value of incretins in patients with immunosuppression-associated hyperglycemia. RESULTS: Corticosteroids have long been known to exert their effects on glucose metabolism by decreasing glucose utilization and enhancing hepatic gluconeogenesis. Corticosteroids also significantly and directly reduce insulin secretion, as do calcineurin inhibitors (CNIs), another commonly used group of immunosuppressive drugs that cause hyperglycemia and NODAT. The ability of incretins to counteract immunosuppressant-induced disruptions in insulin secretion suggest that the insulinotropic, glucagonostatic, and glucose-lowering actions of incretins are well suited to treat immunosuppressant-induced hyperglycemia in NODAT. Additional benefits of incretins include decreased glucagon levels and improved insulin resistance. In the case of glucagon-like peptide-1 (GLP-1) receptor agonists, weight loss is another benefit, countering the weight gain that is a common consequence of both hyperglycemia and transplantation. These benefits make incretins very attractive and deserving of more investigation. CONCLUSION: Among diabetes treatment options, incretin therapies uniquely counteract immunosuppressant drugs' interference with insulin secretion. We propose an incretin-based treatment paradigm for NODAT management.

Practical implementation of incretin-based therapy in hospitalized patients with type 2 diabetes.

Hyperglycemia in patients with and without a prior history of diabetes is an independent marker of morbidity and mortality in critically and noncritically ill patients. Improvement of glycemic control with insulin therapy has been shown to reduce hospital complications in patients with diabetes, but also results in increased rates of hypoglycemia, which have been linked to poor outcomes. Thus, alternative treatment options that can normalize blood glucose levels without undue hypoglycemia are being sought. Incretin-based therapies, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, stimulate insulin secretion in a glucose-dependent fashion, thus not causing hypoglycemia. Alternative points of view exist regarding insulin versus incretin therapy for the care of these patients. We have brought together the authors on the opposite sides of this discussion with the objective of providing a rational synthesis on how to achieve the best possible control of glycemia in the hospital, using both standard insulin approaches and incretin-based therapies to improve patient outcomes. This review examines the benefits of incretin-based therapy in improving glycemic control in hospitalized patients with stress-induced diabetes and in diabetic patients in critical care and non-critical care settings.

A practice-based approach to the 2012 position statement of the American Diabetes Association and the European Association for the Study of Diabetes.

The position statement on the management of hyperglycemia in patients with type 2 diabetes mellitus issued in 2012 by the American Diabetes Association and the European Association for the Study of Diabetes contains significant improvements over the 2009 version, including an emphasis on patient-centered care, enhanced strategies for lifestyle modification, a focus on comprehensive cardiovascular risk reduction, and increased pharmacotherapy choices. As diabetes management evolves over time, further improvements may be made in future consensus statements, including a focus on prevention and early treatment and improved glycemic control in all patients, including those with comorbidities. These goals will be achievable by waning use of therapies known to cause hypoglycemia and weight gain and the increased use of therapies that do not carry these risks.