Simona Cernea

Diabetes: insulin resistance and derangements in lipid metabolism. Cure through intervention in fat transport and storage

We present multiple findings on derangements in lipid metabolism in type 2 diabetes. The increase in the intracellular deposition of triglycerides (TG) in muscles, liver and pancreas in subjects prone to diabetes is well documented and demonstrated to attenuate glucose metabolism by interfering with insulin signaling and insulin secretion. The obesity often associated with type 2 diabetes is mainly central, resulting in the overload of abdominal adipocytes with TG and reducing fat depot capacity to protect other tissues from utilizing a large proportion of dietary fat. In contrast to subcutaneous adipocytes, the central adipocytes exhibit a high rate of basal lipolysis and are highly sensitive to fat mobilizing hormones, but respond poorly to lipolysis restraining insulin. The enlarged visceral adipocytes are flooding the portal circulation with free fatty acids (FFA) at metabolically inappropriate time, when FFA should be oxidized, thus exposing nonadipose tissues to fat excess. This leads to ectopic TG accumulation in muscles, liver and pancreatic beta‐cells, resulting in insulin resistance and beta‐cell dysfunction. This situation, based on a large number of observations in humans and experimental animals, confirms that peripheral adipose tissue is closely regulated, performing a vital role of buffering fluxes of FFA in the circulation. The central adipose tissues tend to upset this balance by releasing large amounts of FFA. To reduce the excessive fat outflow from the abdominal depots and prevent the ectopic fat deposition it is important to decrease the volume of central fat stores or increase the peripheral fat stores. One possibility is to downregulate the activity of lipoprotein lipase, which is overexpressed in abdominal relatively to subcutaneous fat stores. This can be achieved by gastrointestinal bypass or gastroplasty, which decrease dietary fat absorption, or by direct means that include surgical removal of mesenteric fat. Indirect treatment consists of the compliant application of drastic lifestyle change comprising both diet and exercise and pharmacotherapy that reduces mesenteric fat mass and activity. The first step should be an attempt to effectively induce a lifestyle change. Next comes pharmacotherapy including acarbose, metformin, PPARγ, or PPARγα agonists, statins and orlistat, estrogens in postmenopausal women or testosterone in men. Among surgical procedures, gastric bypass has been proven to produce beneficial results in advance of other surgical techniques, the evidence basis of which still needs strengthening. Copyright

Therapy in the Early Stage: Incretins

The complex pathological mechanisms responsible for development of type 2 diabetes are not fully addressed by conventional drugs, which are also associated with inconvenient side effects such as weight gain or hypoglycemia. Two types of incretin-based therapies are now in use: incretin mimetics (glucagon-like peptide-1 [GLP-1] receptor agonists that bind specific receptors and mimic the action of natural GLP-1) and incretin enhancers (inhibitors of the enzyme that degrade the incretin hormones and thus prolong their activity). Both offer important advantages over previous agents. In addition to the proven glucose-lowering efficacy, they promote weight loss (or are weight neutral) by slowing gastric emptying and inducing satiety, inhibit glucagon secretion with maintenance of counterregulatory mechanisms, and exhibit cardiovascular benefits, while having a low risk profile. Importantly, short-term studies have shown that incretins/incretin-based therapies protect β-cells (by enhancing cell proliferation and differentiation and inhibiting apoptosis) and stimulate their function (by recruiting β-cells to the secretory process and increasing insulin biosynthesis/secretion). These therapies have the opportunity to interfere with the disease progression if used as an early intervention, when enough β-cell mass/function can still be preserved or restored.

Diabetes and beta cell function: from mechanisms to evaluation and clinical implications

Diabetes is a complex, heterogeneous condition that has beta cell dysfunction at its core. Many factors (e.g. hyperglycemia/glucotoxicity, lipotoxicity, autoimmunity, inflammation, adipokines, islet amyloid, incretins and insulin resistance) influence the function of pancreatic beta cells. Chronic hyperglycaemia may result in detrimental effects on insulin synthesis/secretion, cell survival and insulin sensitivity through multiple mechanisms: gradual loss of insulin gene expression and other beta-cell specific genes; chronic endoplasmic reticulum stress and oxidative stress; changes in mitochondrial number, morphology and function; disruption in calcium homeostasis. In the presence of hyperglycaemia, prolonged exposure to increased free fatty acids result in accumulation of toxic metabolites in the cells (“lipotoxicity”), finally causing decreased insulin gene expression and impairment of insulin secretion. The rest of the factors/mechanisms which impact on the course of the disease are also discusses in detail. The correct assessment of beta cell function requires a concomitant quantification of insulin secretion and insulin sensitivity, because the two variables are closely interrelated. In order to better understand the fundamental pathogenetic mechanisms that contribute to disease development in a certain individual with diabetes, additional markers could be used, apart from those that evaluate beta cell function. The aim of the paper was to overview the relevant mechanisms/factors that influence beta cell function and to discuss the available methods of its assessment. In addition, clinical considerations are made regarding the therapeutical options that have potential protective effects on beta cell function/mass by targeting various underlying factors and mechanisms with a role in disease progression.

Monitoring of antigen-specific CD8 T cells in patients with type 1 diabetes treated with antiCD3 monoclonal antibodies.

The way in which anti-CD3 monoclonal antibodies (mAbs) modify human immune responses in type 1 diabetes (T1DM) is not known. We prepared a panel of Class I HLA-A2.1 tetramers with peptides from diabetes-associated antigens and studied the frequency and phenotype of the cells in patients with T1DM and blood donors and in patients treated with anti-CD3 mAb (Teplizumab). More patients with T1DM showed positive staining for at least 1 tetramer using frozen and fresh samples (p<0.05). Three months following treatment with anti-CD3 mAb, the proportion of GAD65- and InsB-peptide reactive CD8+ T cells increased (p<0.05). The phenotype of these cells was modulated from naïve to effector memoryRA+. We concludethat Class I MHC tetramers can identify antigen specific CD8+ T cells in patients with T1DM. The frequency of certain specificities increases after treatment with anti-CD3 mAb. Their modulated phenotype may have functional consequences for their pathogenicity.

β-Cell Protection and Therapy for Latent Autoimmune Diabetes in Adults

Latent autoimmune diabetes in adults (LADA) is a term used to describe a form of autoimmune diabetes that resembles type 1 diabetes, but has a later onset and slower progression toward an absolute insulin requirement. Controversies have been surrounding this concept and several attempts have been made to better characterize and classify it. But LADA still remains poorly understood and defined (1). It was even debated whether LADA exists as a distinct disease entity or it just represents the end of a wide spectrum of heterogeneous immune-mediated diabetes (2,3). Uncertainties concern almost all aspects of this disease, including the nomenclature, diagnostic criteria, epidemiology, natural history, and pathogenesis with genetic, metabolical, and immunological aspects. As a consequence, there is no clear management strategy for it, in terms of therapy and prevention. An ideal therapeutic approach would aim not only at obtaining a good metabolic control, but also at protecting residual β-cell mass and function. Even though ∼10% of adults with presumed type 2 diabetes at diagnosis in fact have LADA, only a few studies so far have evaluated therapeutic interventions for LADA, using a hypoglycemic or an immunomodulatory agent. Obviously, an important impediment in establishing adequate and effective management strategies is the lack of a good understanding of the disease development and of a clear definition. Difficulties reside from the fact that LADA has features of an autoimmune disease (mainly presence of autoantibodies at onset), with many genetic, immune, and metabolic features of type 1 diabetes, but also shares some clinical, anthropometric, and metabolic traits with type 2 diabetes (Table 1) (2,4). As a matter of fact, LADA was first identified in a subset of phenotypic type 2 diabetes individuals who were positive for islet cells antibodies (ICAs), failed sulfonylurea therapy, and needed insulin replacement earlier than …

New potential treatments for protection of pancreatic B-cell function in Type 1 diabetes.

Type 1 diabetes mellitus results from the progressive and specific autoimmune destruction of insulin‐secreting pancreatic B‐cells, which develops over a period of years and continues after the initial clinical presentation. The ultimate goal of therapeutic intervention is prevention or reversal of the disease by the arrest of autoimmunity and by preservation/restoration of B‐cell mass and function. Recent clinical trials of antigen‐specific or non‐specific immune therapies have proved that modulation of islet specific autoimmunity in humans and prevention of insulin secretion loss in the short term after the onset of disease is achievable. The identification of suitable candidates for therapy, appropriate dosage and timing, specificity of intervention and the side‐effect profile are crucial for the success of any approach. Considering the complexity of the disease, it is likely that a rationally designed approach of combined immune‐based therapies that target suppression of B‐cell specific autoreactivity and maintenance of immune tolerance, coupled with islet regeneration or replacement of the destroyed B‐cell mass, will prove to be most effective in causing remission/reversal of disease in a durable fashion.

Prevention of type 1 diabetes: today and tomorrow

The aim of therapeutic interventions for type 1 diabetes is to suppress pathogenic autoreactivity and to preserve/restore beta‐cell mass and function to physiologically sufficient levels to maintain good metabolic control. During the natural history of type 1 diabetes, several strategies have been applied at various stages in the form of primary, secondary or tertiary prevention approaches. Clinical trials using antigen‐specific (e.g. DiaPep277, human glutamic acid decarboxylase 65 (GAD65)) or non‐specific immune therapies (e.g. anti‐CD3 monoclonal antibodies) have shown some benefit in the modulation of the autoimmune process and prevention of the insulin secretion loss in the short term after diagnosis of diabetes. A single long‐term effective therapy has not been identified yet, and it is likely that in most cases a rationally designed combinatorial approach using immunotherapeutic methods coupled with islet regeneration or replacement will prove to be most effective. Copyright

Challenges in developing endpoints for type 1 diabetes intervention studies

Development of efficient and safe intervention strategies for preserving and/or restoring endogenous insulin production in type 1 diabetes has encountered a wide range of challenges, including lack of standardized trial protocols and of consensus on appropriate efficacy endpoints. For the greatest part, difficulties resided in choosing the most suitable assay(s) and parameter(s) to assess the β‐cell function. It is now an accepted approach to evaluate endogenous insulin secretion by measuring C‐peptide levels (with highly sensitive and normalized measurement methods) in response to a physiologic stimulus (liquid mixed‐meal) under standardized conditions. Preventive interventions mandate the identification of well‐defined, reliable and validated mechanistic or immunological markers of efficacy that would correlate with (and predict) the clinical outcome. This has not been consistently achieved to date. However, it has been generally agreed that for preventive studies performed very early in the disease course (in subjects without signs of autoimmunity against β‐cells) development of two or more islet related autoantibodies could be employed as biomarkers of disease and thereafter, diagnostic criteria of diabetes serve as suitable endpoints.

An update on DPP-4 inhibitors in the management of type 2 diabetes.

ABSTRACT Introduction: DPP-4 inhibitors are a class of compounds used for the treatment of type 2 diabetes. The drugs inhibit the degradation of GLP-1, thus amplifying the incretin effect. They have moderate glycemic efficacy, a low propensity of causing hypoglycaemia and are weight neutral. The drugs are often used as second line therapy after metformin. Areas covered: This review summarizes the available compounds in the market and discusses the novel compounds that are currently under development. Several large cardiovascular outcome trials with some of the compounds have been completed, and their results and implications are considered. Fixed dose combination pills are currently the main focus of research and the contribution of these to the care of patients with diabetes is further discussed. Expert opinion: The DPP-4 inhibitors have been a successful class in drug development for diabetes. Taken orally and available as fixed dose combinations with metformin or with SGLT-2 inhibitors, they have reached a large market share of over 7 billion dollars. Other than retagliptin, it does not appear that any additional compound will be launched soon. Currently, the main focus is on the development of additional fixed dose combinations with SGLT-2 inhibitors, but the success of these combinations remains to be seen.

Drug Insight: new immunomodulatory therapies in type 1 diabetes

Animal models and human studies have provided strong evidence that the immune response that causes type 1A diabetes is initiated against a limited array of antigens but acquires breadth and depth until β-cell mass has been critically compromised. Two recent trials confirmed the ability to identify relatives at risk for development of diabetes, but were unsuccessful in preventing disease. Treatment of at-risk individuals with oral insulin, which is postulated to be an antigen in the disease, did however show efficacy in a subgroup of these subjects, suggesting that antigen-specific prevention approaches might be successful in the right group of subjects at the right time. Earlier trials showed that the natural progression of disease can be altered with conventional immune suppression but these approaches have been supplanted by tolerance-induction strategies. Anti-CD3 monoclonal antibodies have shown efficacy in preventing the loss of insulin production over the first 2 years of disease without chronic immune suppression. The mechanisms are novel, and appear to involve induction of immune regulation by the monoclonal antibody. Ultimately, preservation and even improvement in β-cell mass is the goal of therapy. The means needed to achieve this will depend on the timing and mechanisms of the immune intervention and might require combinations of agents.