PHC6315 FIU Differentiation Of Diabetes Article Review

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Question Description

Please go through the attached article and post your comments (200-250 words) addressing the following (you may cite the references to support your conclusion/argument).

  1. The key message the article wants to convey about diabetes 1 and 2
  2. Your conclusion on the most vulnerable populations/ethnicity/age group for Diabetes 1 and 2
  3. Environmental and biological markers as risk factors suggesting that one may develop diabetes
  4. Current trend in the incidence of diabetes in adolescents in US

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Diabetes Volume 66, February 2017 241 Jay S. Skyler,1 George L. Bakris,2 Ezio Bonifacio,3 Tamara Darsow,4 Robert H. Eckel,5 Leif Groop,6 Per-Henrik Groop,7,8,9 Yehuda Handelsman,10 Richard A. Insel,11 Chantal Mathieu,12 Allison T. McElvaine,4 Jerry P. Palmer,13 Alberto Pugliese,1 Desmond A. Schatz,14 Jay M. Sosenko,15 John P.H. Wilding,16 and Robert E. Ratner 4 Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis Diabetes 2017;66:241–255 | DOI: 10.2337/db16-0806 Though therapeutic algorithms for diabetes encourage individualization of approaches (1), they are often broadly applied in treatment and reimbursement decisions, reinforcing the “one-size-fits-all” approach (2). However, if individualized approaches are successful 1Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 2The University of Chicago Medicine, Chicago, IL 3Technische Universität Dresden, Dresden, Germany 4American Diabetes Association, Arlington, VA 5University of Colorado Anschutz Medical Campus, Aurora, CO 6Lund University, Skåne University Hospital, Malmö, Sweden 7Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland 8Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland 9Baker IDI Heart and Diabetes Institute, Melbourne, Australia 10Metabolic Institute of America, Tarzana, CA 11JDRF, New York, NY 12Katholieke Universiteit Leuven, Leuven, Belgium (if they improve morbidity/mortality and are costeffective), health care systems are persuaded to adopt them. For example, better insights into the pathophysiology of different types of cancer have led to tailored diagnostic tools and therapies, which have dramatically improved outcomes (3). A similar approach should be realized for diabetes. Many different paths, driven by various genetic and environmental factors, result in the progressive loss of b-cell mass (4,5) and/or function (6) that manifests clinically as hyperglycemia. Once hyperglycemia occurs, people with all forms of diabetes are at risk for developing the same complications (Fig. 1), though rates of progression may differ. The present challenge is to characterize the many paths to b-cell dysfunction or demise and identify therapeutic approaches that best target each path. By reviewing the current evidence and addressing remaining research gaps, we aim to identify subtypes of diabetes that may be associated with differential rates of progression and differential risks of complications. A personalized approach to intensive therapy to prevent or treat specific complications may help resolve the burden of diabetes complications, particularly in those at highest risk. 13University of Washington and VA Puget Sound Health Care System, Seattle, WA of Florida College of Medicine, Gainesville, FL 15University of Miami Miller School of Medicine, Miami, FL 16University Hospital Aintree, Liverpool, U.K. 14University Corresponding author: Allison T. McElvaine, Received 1 July 2016 and accepted 23 November 2016. This article contains Supplementary Data online at http://diabetes © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. PERSPECTIVES IN DIABETES The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, “The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis” on 10–12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment. 242 Differentiation of Diabetes Diabetes Volume 66, February 2017 Figure 1—Genetic and environmental risk factors impact inflammation, autoimmunity, and metabolic stress. These states affect b-cell mass and/or function such that insulin levels are eventually unable to respond sufficiently to insulin demands, leading to hyperglycemia levels sufficient to diagnose diabetes. In some cases, genetic and environmental risk factors and gene–environment interactions can directly impact b-cell mass and/or function. Regardless of the pathophysiology of diabetes, chronic high blood glucose levels are associated with microvascular and macrovascular complications that increase morbidity and mortality for people with diabetes. This model positions b-cell destruction and/or dysfunction as the necessary common factor to all forms of diabetes. PATHOPHYSIOLOGY OF DIABETES Demographics Type 1 diabetes and type 2 diabetes differentially impact populations based on age, race, ethnicity, geography, and socioeconomic status. Type 1 Diabetes Between 2001 and 2009, there was a 21% increase in the number of youth with type 1 diabetes in the U.S. (7). Its prevalence is increasing at a rate of ;3% per year globally (8). Though diagnosis of type 1 diabetes frequently occurs in childhood, 84% of people living with type 1 diabetes are adults (9). Type 1 diabetes affects males and females equally (10) and decreases life expectancy by an estimated 13 years (11). An estimated 5–15% of adults diagnosed with type 2 diabetes actually have type 1 diabetes or latent autoimmune diabetes of adults (LADA) (12). Europoid Caucasians have the highest prevalence of type 1 diabetes among U.S. youth, representing 72% of reported cases. Hispanic Caucasians represent 16%, and non-Hispanic blacks represent 9% (7). Skyler and Associates 243 Incidence and prevalence rates for type 1 diabetes vary dramatically across the globe. At the extremes, China has an incidence of 0.1/100,000 per year and Finland has an incidence of 60/100,000 per year (13). With some exceptions, type 1 diabetes incidence is positively related to geographic distance north of the equator (13). Colder seasons are correlated with diagnosis and progression of type 1 diabetes. Both onset of disease and the appearance of islet autoimmunity appear to be higher in autumn and winter than in spring and summer (14). diabetes and higher if the mother has the disease (18). The risk for type 1 diabetes is ;5% if a parent has type 1 diabetes and higher if the father has the disease (19). Maturity-onset diabetes of the young (MODY) is a monogenic disease and has a high h2 of ;50 (20). Mutations in any 1 of 13 different individual genes have been identified to cause MODY (21), and a genetic diagnosis can be critical for selecting the most appropriate therapy. For example, children with mutations in KCJN11 causing MODY should be treated with sulfonylureas rather than insulin. Type 2 Diabetes Type 1 Diabetes In the U.S., an estimated 95% of the nearly 30 million people living with diabetes have type 2 diabetes. An additional 86 million have prediabetes, putting them at high risk for developing type 2 diabetes (9). Among the demographic associations for type 2 diabetes are older age, race/ ethnicity, male sex, and socioeconomic status (9). Type 2 diabetes incidence is increasing in youth, especially among the racial and ethnic groups with disproportionately high risk for developing type 2 diabetes and its complications: American Indians, African Americans, Hispanics/Latinos, Asians, and Pacific Islanders (9). Older age is very closely correlated to risk for developing type 2 diabetes. More than one in four Americans over the age of 65 years have diabetes, and more than half in this agegroup have prediabetes (9). The prevalence of type 2 diabetes in the U.S. is higher for males (6.9%) than for females (5.9%) (15). There is a high degree of variability for prevalence of type 2 diabetes across the globe. East Asia, South Asia, and Australia have more adults with diabetes than any other region (153 million). North America and the Caribbean have the highest prevalence rate, with one in eight affected (8). Independent of geography, the risk of developing type 2 diabetes is associated with low socioeconomic status. Low educational level increases risk by 41%, low occupation level by 31%, and low income level by 40% (16). The higher type 1 diabetes prevalence observed in relatives implies a genetic risk, and the degree of genetic identity with the proband correlates with risk (22–26). Gene variants in one major locus, human leukocyte antigen (HLA) (27), confer 50–60% of the genetic risk by affecting HLA protein binding to antigenic peptides and antigen presentation to T cells (28). Approximately 50 additional genes individually contribute smaller effects (25,29). These contributors include gene variants that modulate immune regulation and tolerance (30–33), variants that modify viral responses (34,35), and variants that influence responses to environmental signals and endocrine function (36), as well as some that are expressed in pancreatic b-cells (37). Genetic influences on the triggering of islet autoimmunity and disease progression are being defined in relatives (38,39). Together, these gene variants explain ;80% of type 1 diabetes heritability. Epigenetic (40), gene expression, and regulatory RNA profiles (36) may vary over time and reflect disease activity, providing a dynamic readout of risk. Genetic variants can also identify patients at higher risk, predict rates of C-peptide decline, and predict response to various therapies (41). With a better understanding of inheritance profiles, it may become possible to realize new targets for individualized intervention. Research Gaps The assembled experts agreed that research efforts are needed to define causative factors that account for the established correlations among different demographic subsets and the corresponding variable risks for diabetes. Factors associated with race/ethnicity and geography that differentially increase risk for type 1 diabetes and for type 2 diabetes need to be defined. For type 2 diabetes, the drivers of increased risk in individuals of low socioeconomic status also need to be established. Genetics Both type 1 and type 2 diabetes are polygenic diseases where many common variants, largely with small effect size, contribute to overall disease risk. Disease heritability (h2), defined as sibling-relative risk, is 3 for type 2 diabetes and 15 for type 1 diabetes (17). The lifetime risk of developing type 2 diabetes is ;40% if one parent has type 2 Type 2 Diabetes While a subset of genetic variants are linked to both type 1 and type 2 diabetes (42,43), the two diseases have a largely distinct genetic basis, which could be leveraged toward classification of diabetes (44). Genome-wide association studies have identified more than 130 genetic variants associated with type 2 diabetes, glucose levels, or insulin levels; however, these variants explain less than 15% of disease heritability (45–47). There are many possibilities for explaining the majority of type 2 diabetes heritability, including disease heterogeneity, gene–gene interactions, and epigenetics. Most type 2 variants are in noncoding genomic regions. Some variants, such as those in KCNQ1, show strong parent-of-origin effects (48). It is possible that children of mothers carrying KCNQ1 are born with a reduced functional b-cell mass and thereby are less able to increase their insulin secretion when exposed to insulin resistance (49). Another area of particular interest has been the search for 244 Differentiation of Diabetes rare variants protecting from type 2 diabetes, such as loss-of-function mutations in SLC30A8 (50), which could offer potential new drug targets for type 2 diabetes. To date, however, the improvement in predictive value of known genetic variants over that of classic clinical risk factors (BMI, family history, glucose) has proven minimal in type 2 diabetes. The rapid development of molecular genetic tools and decreasing costs for next-generation sequencing should make dissection of the black box of genetics of diabetes possible in the near future, but at this point, apart from the profiles that distinguish between type 1 and type 2 diabetes and a limited number of specific variants that identify small subgroups of patients (MODY), genetics has not been successful in further differentiating subclasses of diabetes. Research Gaps After consideration of the known genetic associations with diabetes risk, consensus developed that the field is not yet at a place where genetics has provided actionable information to guide treatment decisions, with a few notable exceptions, namely in MODY. The experts agreed there is a need to use the increasingly accessible and affordable technologies to further refine our understanding of how genetic variations affect the rate of progression of diabetes and its complications. The expert committee also highlighted the importance of determining categorical phenotypic subtypes of diabetes in order to link specific genetic associations to these phenotypic subtypes. These types of information are necessary to develop the tools to predict response to—and side effects of—therapeutic approaches for diabetes in patient populations. Environmental Influences Despite the genetic underpinnings of the diseases, the prevalence of both type 1 and type 2 diabetes is increasing globally at a rate that outpaces genetic variation, suggesting that environmental factors also play a key role in both types of diabetes. Common environmental factors are associated with type 1 and type 2 diabetes, including dietary factors, endocrine disruptors and other environmental polluters, and gut microbiome composition. In addition to well-established roles in type 2 diabetes, obesity and insulin resistance may be accelerators of type 1 diabetes. Conversely, islet autoimmunity associated with possible environmental triggers (e.g., diet, infection) may have a role in a subset of people diagnosed with type 2 diabetes. Type 1 Diabetes Discordance rates in twins, the rise in global incidence, variance in geographic prevalence, and assimilation of local disease incidence rates when individuals migrate from low- to high-incidence countries all support an environmental influence on risk for developing type 1 diabetes. Furthermore, many lines of evidence suggest that Diabetes Volume 66, February 2017 environmental factors interact with genetic factors in both the triggering of autoimmunity and the subsequent progression to type 1 diabetes. Supporting this gene–environment interaction is the fact that most subjects with the highest-risk HLA haplotypes do not develop type 1 diabetes. The timing of exposure to environmental triggers may also be critical. The variability of age at disease onset complicates the study of environmental exposures, though the early age of onset of islet autoantibodies associated with childhood-onset type 1 diabetes suggests that environmental exposures in the first few years of life may be contributors. Among the environmental associations linked to type 1 diabetes are enteroviral and other infections (51,52) and altered intestinal microbiome composition (53). The timing of exposure to foods including cereal (54) and nutrients such as gluten (55) may influence b-cell autoimmunity. Low serum concentrations of vitamin D have been linked to type 1 diabetes. Perinatal risk factors and toxic doses of nitrosamine compounds have been implicated in the genesis of diabetes. The effects of any environmental toxin on type 1 diabetes need further exploration. Studies on the environmental contributions to type 1 diabetes have been small and somewhat contradictory, highlighting the need for larger collaborative investigations such as The Environmental Determinants of Diabetes in the Young (TEDDY) (56), which aims to identify infectious agents, dietary factors, and other environmental factors that trigger islet autoimmunity and/or type 1 diabetes. Type 2 Diabetes Type 2 diabetes develops when b-cells fail to secrete sufficient insulin to keep up with demand, usually in the context of increased insulin resistance. A minority of people diagnosed with type 2 diabetes also have evidence of islet autoimmunity (57,58). Obesity is a major risk factor for type 2 diabetes (59,60) with complex genetic and environmental etiology. Insulin resistance develops with ectopic fat deposition in the liver and muscle. Fat may also accumulate in the pancreas and contribute to the decline in b-cell function, islet inflammation, and eventual b-cell death (61). Type 2 diabetes occurs at different levels of BMI/body fat composition in different individuals and at lower BMI for Asians and Asian Americans (62). For susceptible people, there may be a personal “fat threshold” at which ectopic fat accumulation occurs, worsening insulin resistance and resulting in b-cell decompensation. Weight loss improves insulin sensitivity in liver and skeletal muscle (63) and may also reduce pancreatic fat accumulation (64). Defects in insulin secretion are at least partially reversible with energy restriction and weight loss in prediabetes and recent-onset type 2 diabetes (65). Unfortunately, it is difficult to reverse long-standing diabetes, even with the large weight loss associated with bariatric surgery (66). Both reduced sleep time and increased sleep time are associated with the development of obesity and diabetes. Obstructive sleep apnea reduces sleep time and sleep quality and is associated with type 2 diabetes and metabolic syndrome. The modern “24-hour culture” may reduce sleep time and thereby also contribute to increased risk of type 2 diabetes. And while associations with additional environmental factors exist, there have been no direct causal relationships defined to date. Research Gaps There is a clear correlation of environmental influences to diabetes risk. Yet, the assembled experts agreed that hypothesis-driven research is needed to define direct causal relationships between specific environmental factors and pathophysiologies leading to diabetes. Research efforts need to address environmental etiologies of type 1 diabetes and determine their relative contribution to onset of autoimmunity and progression to symptomatic disease. Whether there is a direct causal role of the intestinal microbiota in pathogenesis of type 1 and type 2 diabetes and response to therapies needs to be determined. Public health interventions that successfully reduce the levels of consumption of energy-dense foods and/or reduce sedentary time and increase time spent in physical activity need to be evaluated to determine whether they can reduce type 2 diabetes incidence at a population level. NATURAL HISTORY AND PROGNOSIS Regardless of the particular pathophysiology of an individual’s diabetes, the unifying characteristic of the vast majority of diabetes is hyperglycemia resulting from b-cell destruction or dysfunction. There is a continuum of progressive dysglycemia as insulin insufficiency increases over time. Understanding the natural history related to b-cell mass and function is key to staging the diseases and identifying where and how interventions can best be made to prev ...
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Tutor Answer

School: UT Austin



Article Review: Differentiation of Diabetes
Student’s Name
Institutional Affiliation




Article Review: Differentiation of Diabetes
Key Message of the article
The authors of the paper want to highlight the different paths through which β-cell
demise or dysfunction occurs. In this vein, the different subtypes of diabetes will have been
identified, especially by considering the differential risks of complications and differential rates
of progression. The study’s core objective is hinged on the fact that diabetes 1 and 2 have
significant differences in the way they affect people of different races, ages, geographies,
ethnicities, and socioeconomic statuses. These are the key elements that are considered when
examining the epidemiology of any disease, and they play a pivotal role when trying to
determine the specific ways in which a particular risk factor can be dealt with in the furtherance
of the quality of healthcare interventions. The overall message is that when this differentiation is
made between diabetes 1 and 2 and their related subtypes, it will be easier for professionals to
come up wi...

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Tutor went the extra mile to help me with this essay. Citations were a bit shaky but I appreciated how well he handled APA styles and how ok he was to change them even though I didnt specify. Got a B+ which is believable and acceptable.

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