Type 1 Diabetes Mellitus In Adults Research Articles

Contribution of environmental determinants to the risk of developing type 2 diabetes mellitus in a life-course perspective: a systematic review protocol

BackgroundPrevention policies against type 2 diabetes mellitus (T2DM) focus solely on individual healthy lifestyle behaviours, while an increasing body of research recognises the involvement of environmental determinants (ED) (cultural norms of land management and planning, local foodscape, built environment, pollution, and neighbourhood deprivation). Precise knowledge of this relationship is essential to proposing a prevention strategy integrating public health and spatial planning. Unfortunately, issues related to the consistency and synthesis of methods, and results in this field of research limit the development of preventive strategies. This systematic review aims to improve knowledge about the relationship between the risk of developing T2DM in adulthood and long-term exposure to its ED during childhood or teenage years.MethodsThis protocol is presented according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) tools. PubMed, Embase, CINAHL, Web of Science, EBSCO, and grey literature from the Laval University Libraries databases will be used for data collection on main concepts such as ‘type 2 diabetes mellitus’, ‘zoning’ or ‘regional, urban, or rural areas land uses’, ‘local food landscape’, ‘built environment’, ‘pollution’, and ‘deprivation’. The Covidence application will store the collected data for selection and extraction based on the Population Exposure Comparator Outcome and Study design approach (PECOS). Studies published until December 31, 2023, in English or French, used quantitative data about individuals aged 18 and over that report on T2DM, ED (cultural norms of land management and planning, local foodscape, built environment, and neighbourhood deprivation), and their association (involving only risk estimators) will be included. Then, study quality and risk of bias will be conducted according to the combined criteria and ratings from the ROBINS-E (Risk of Bias in Non-randomised Studies—of Exposures) tools and the ‘Effective Public Health Practice Project’ (EPHPP). Finally, the analytical synthesis will be produced using the ‘Synthesis Without Meta-analysis’ (SWiM) guidelines.DiscussionThis systematic review will summarise available evidence on ED associated with T2DM. The results will contribute to improving current knowledge and developing more efficient cross-sectoral interventions in land management and public health in this field of research.Systematic review registrationPROSPERO CRD42023392073.

Diagnostic Challenge of Adult-onset Type 1 Diabetes Mellitus in a Remote Hospital

Type 1 Diabetes Mellitus (T1DM) is a chronic endocrinological disease due to an autoimmune process. The prevalence of T1DM is 9.5% worldwide, with the incidence of 15 out of 100,000 people, ranging from childhood to 40 years of age. Autoimmunity-related late-onset Diabetes Mellitus (DM) patients could be diagnosed as classic T1DM or latent autoimmune diabetes in adults (LADA). A 30-year-old male patient with unremarkable previous medical history was admitted to the emergency room with dyspnea for the last three days that was worsened six-hour before admission. Physical examinations showed a body Mass Index (BMI) of 18.75 kg/m2, irregular pulse, and Kussmaul breathing. The patient was diagnosed with diabetic ketoacidosis (DKA) on May 23, 2019. He was discharged with subcutaneous insulin pen injections. Two years later, he was readmitted with DKA due to discontinuing his treatment. He stated that the reason for stopping the insulin was because he was tired of injecting it. The patient was hospitalized and was discharged with oral antidiabetic agents to cope with his injection tiredness issue. One week later, the patient complained of dyspnea and was diagnosed with recurrent DKA. He was hospitalized and prescribed subcutaneous insulin. In this kind of situation, a diagnosis of LADA for patients presenting with DKA without prior history of DM in early adulthood needs to be considered. In contrast to the classic T1DM, the need for insulin occurs late in LADA. Affordable and widely available ancillary examinations are needed, including in remote hospitals. Finally, motivational support for patients is as important as the pharmacological treatment since lifelong insulin injections are needed.

Teplizumab in Type 1 Diabetes Mellitus: An Updated Review.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition characterized by the irreversible destruction of the β cells of the pancreas, which leads to a lifelong dependency on exogenous insulin. Despite the advancements in insulin delivery methods, the suboptimal outcomes of these methods have triggered the search for therapies that may prevent or reverse the disease. Given the autoimmune aetiology of T1DM, therapies counteracting the immune-mediated destruction of the β-cells are the obvious target. Although several treatment strategies have been attempted to target cellular, humoral and innate immunity, very few have had a clinically meaningful impact. Of all the available immunomodulatory agents, cluster of differentiation (CD) 3 antibodies have exhibited the most promising preclinical and clinical results. Muromonab-CD3, which also happened to be a murine CD3 antibody, was the first monoclonal antibody approved for clinical use and was primarily indicated for graft rejection. The adverse effects associated with muromonab-CD3 led to its withdrawal. Teplizumab, a newer CD3 antibody, has a better side-effect profile because of its humanized nature and non-Fc-receptor-binding domain. In November 2022, teplizumab became the first immunomodulatory agent to be licensed by the US Food and Drug Administration for delaying the onset of T1DM in high-risk adults and children over 8 years old. The mechanism seems to be enhancing regulatory T-cell activity and promoting immune tolerance. This article reviews the mechanism of action and the clinical trials of teplizumab in individuals with T1DM or at risk of developing the disease.

Birth weight is associated with obesity and T2DM in adulthood among Chinese women

BackgroundPrevious studies have indicated an association between birth weight (BW) and type 2 diabetes mellitus (T2DM), but few studies have explored this relationship under different conditions of obesity in adulthood.MethodsA total of 4,005 individuals from ten provinces of China were randomly selected to participate in this study. We used a questionnaire to collect age, BW, current weight, height, T2DM history, age at T2DM diagnosis, and other variables. The participants were divided into three groups were according to BW trisection (BW ≤ 2500 g for the lower BW group, 2500 g < BW ≤ 3500 g for the normal BW group, and BW > 3500 g for the higher BW group). The cutoff of overweight and obesity were 25 kg/m2 and 28 kg/m2, respectively.ResultsThe prevalence rates of T2DM among women with lower BW, normal BW and higher BW were 5.2%, 3.6% and 2.0%, respectively. The obesity prevalence rates in the lower BW, normal BW and higher BW groups were 8.1%, 6.7% and 9.0%, respectively. In the obese population, we did not find a relationship between BW and T2DM, but in the nonobese population, we found that with increasing BW, the risk of developing T2DM was reduced. Obese status in adulthood modified the association between BW and the risk of T2DM.ConclusionThere is a “U” shape association between BW and risk of adulthood obesity in Chinese women, but this trend is not existed between BW and risk of developing T2DM. In non-overweight females, the risk of developing T2DM decreased with increasing BW, but this trend was not observed in overweight females.

Twenty-four-hour movement guidelines during middle adolescence and their association with glucose outcomes and type 2 diabetes mellitus in adulthood

PurposeThe aim of the present study was to determine the association between adherence to the 24-h movement guidelines during middle adolescence and glucose outcomes (glycated hemoglobin and fasting glucose) and type 2 diabetes mellitus (T2DM) in adulthood, 14 and 22 years later. MethodsWe analyzed data from apparently healthy adolescents aged 12–18 years who participated in Waves I and II (1994–1996, n = 14,738), Wave IV (2008–2009, n = 8913), and Wave V (2016–2018, n = 3457) of the National Longitudinal Study of Adolescent to Adult Health (Add Health) in the United States. Physical activity, screen time, and sleep duration were measured using questionnaires, and the 24-h guidelines were defined as: 5 or more times moderate-to-vigorous physical activity per week, ≤2 h per day of screen time, and 9–11 h of sleep for 12–13 years and 8–10 h for 14–17 years. Capillary and venous whole blood was collected and analyzed to determine glycated hemoglobin and fasting glucose for Waves IV and V, respectively. ResultsOnly 2.1% of the adolescents met all the 3 guidelines, and 37.8% met none of them. In both waves IV and V, adolescents who met physical activity and screen time guidelines had lower odds of T2DM in adulthood than those who did not meet any of these guidelines (Wave IV; prevalence ratio (PR) = 0.57, 95% confidence interval (95%CI): 0.21–0.89; Wave V: PR = 0.43, 95%CI: 0.32–0.74). Only for Wave V did adolescents who met all 3 guidelines have lower odds of T2DM at follow-up compared with those who did not meet any of these guidelines (PR = 0.47, 95%CI: 0.24–0.91). Also, for each increase in meeting one of the 24-h recommendations, the odds of T2DM decreased by 18% (PR = 0.82, 95%CI: 0.61–0.99) and 15% (PR = 0.85, 95%CI: 0.65–0.98) in adulthood for Waves IV and V, respectively. ConclusionPromoting all 24-h movement guidelines in adolescence, especially physical activity and screen time, is important for lowering the potential risk of T2DM in adulthood.

Effects of incretin-based therapies on β-cell function in type 1 diabetes mellitus: a systematic review and meta-analysis.

AimTo assess the effects of incretin-based therapies on β-cell function in patients with type 1 diabetes mellitus (T1DM).MethodsWe searched the PubMed, Cochrane Library, Embase, and Web of Knowledge databases for eligible randomized clinical trials published up to July 2021. The inclusion criteria were patients with T1DM or latent autoimmune diabetes in adults, patients treated with dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists, and outcomes included one of the following: fasting plasma glucose, fasting C-peptide, postprandial C-peptide, C-peptide area under the curve (AUC), homeostasis model assessment for β cell function, and insulin resistance. The effects were analyzed using a random effect model with STATA 11.0.ResultsEight trials including 427 participants were included in the final analysis. A pooled analysis found no significant difference in fasting plasma glucose, fasting C-peptide, postprandial C-peptide, or C-peptide AUC between patients treated with incretin-based therapies and placebo. The two trials that reported changes in 2-hour postprandial C-peptide and two of the four trials that reported changes in C-peptide AUC reported increases after incretin-based therapies.ConclusionThis meta-analysis showed that incretin-based therapies did not preserve β-cell function in patients with T1DM.

Autoimmune Nature of Type I Diabetes Mellitus

Type 1 diabetes Mellitus (T1DM) is a chronic autoimmune disease in which pancreatic β‐cell destruction results in loss of endogenous insulin production. Already one of the most prevalent chronic childhood diseases, the incidence of T1DM in children and young adults is projected to continue to increase over the next several decades. Although advances in technology have allowed for improved glucose monitoring and insulin delivery, no curative therapy is currently available for this growing patient population. Moreover, patients continue to experience long‐term complications such as blindness and kidney failure, even with the most intensive insulin regimens currently available.T1DM predominantly originates when insulin‐producing beta (β)‐cells in the pancreas are destroyed or suppressed due to an autoimmune response caused by the auto‐reactive T‐helper 1 (Th1) cells. Interestingly, the antigens responsible for this immune response, glutamic acid decarboxylase, are normally present in β‐cells; however, their destructive capabilities are restrained by the regulatory mechanisms of the body. When a person has certain genetic factors (e.g. the absence of certain protective histocompatibility locus antigen) and exposure to certain environmental factors, they are predisposed to immunologic injury of β‐cells. Furthermore, the odds of presenting with T1DM diminish with treatment with immune‐suppressive regimens that specifically target T‐cells. As a result, Th1 cells dominate the protective regulatory T‐cells. In turn, Th1 cells secrete cytokines, interleukin 2, and interferon gamma, which initiate inflammation of the islet cells that appears to result in the development of T1DM.In 2001 it was found that diabetes might be the first disease for which stem cell therapy is an option, when insulin‐producing embryonic stem cells of R1‐mice were transplanted into streptozotocin‐induced diabetic animals and normal blood glucose levels were achieved, and in other studies implantation of embryonic Sertoli cells into diabetic db mice also resulted in amelioration of the diabetic state. In contrast, infusion of cord blood derived stem cells in the absence of immunomodulation was without lasting effect on the diabetic state. Minor complications in R1‐mice aside, this event once again renewed the quest to find more practical and functional means to create human islets to treat diabetes.Can pancreatic stem cell transplant be used as a cure for T1DM, an autoimmune disease, and how does it stand against other cell transplants and other treatment modalities in the US? The bulk of preliminary evidence to date suggests encouraging potential for such approaches in the treatment of T1DM.Support or Funding InformationSupported by Institutional Resources of USAT, the Einstein Institute, and the University of Massassachusetts.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Association between famine exposure in early life and type 2 diabetes mellitus and hyperglycemia in adulthood: Results from the China Health And Retirement Longitudinal Study (CHARLS).

Studies have revealed the association between famine in early life and type 2 diabetes mellitus (T2DM) in adulthood. However, studies on the Great Chinese Famine were not conducted nationwide. Because of regional variations in the severity of this famine, the results of regional studies are limited. This study explored associations between famine and T2DM in adulthood in a nationwide study. The present study was performed on 7262 participants who were born between 1 October 1949 and 1 July 1966 using baseline data collected for the China Health And Retirement Longitudinal Study (CHARLS) in 2011. Participants were divided according to birthdate into cohorts with fetal, late, middle, and early childhood exposure and no exposure to famine. Logistic regression models were used to analyze the association between famine exposure in early life and the risk of T2DM and hyperglycemia in adulthood. For females, the risk of hyperglycemia was higher for famine-exposed than not exposed cohort (odds ratios [OR] 1.34 and 95% confidence intervals [CIs]: 1.34 [1.04-1.74], 1.48 [1.15-1.90], 1.38 [1.06-1.79], and 1.57 [1.25-1.98] for fetal, early, middle, and late childhood exposure, respectively), and this association was even stronger in female participants who lived in rural areas before the age of 16 years. In males, the risk of T2DM was lower for the early and late childhood exposure than no exposure cohorts (OR [95% CIs]: 0.65 [0.49-0.86] and 0.74 [0.56-0.98], respectively). [Correction added on 23 July 2018, after first online publication: Parts of the above 'Results' section have been corrected to interchange the citation of the words 'late' and 'early'.] CONCLUSION: Exposure to famine during early life can increase the risk of hyperglycemia in female adults, but may decrease the risk of T2DM in males.

Dipeptidyl peptidase-4 inhibitors (DPP-4i) combined with vitamin D3: An exploration to treat new-onset type 1 diabetes mellitus and latent autoimmune diabetes in adults in the future

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by destruction of pancreatic beta cells through cell injury caused primarily by cytotoxic T lymphocytes (CD8+). The pathophysiological basis of T1DM seems to be an imbalance between a reduced function of T regulatory lymphocytes and an increased inflammatory activity of Th17 lymphocytes caused by increased production of inflammatory cytokines, as IL-1β, IL-6, IL-17 and IFN-gamma due to environmental factors and genetic predisposition. The preservation of the reserve of beta cells in new-onset T1DM and latent autoimmune diabetes in adults (LADA) by immunomodulation in addition to the incretin effect seems to be possible with an association of DPP-4 inhibitors and vitamin D3. In this review, we discuss the effects of both drugs on the immune system and on beta cell function and their eventual additive effects in preserving the residual function of beta cells in new-onset T1DM and LADA.

Both youth and long-term vitamin D status is associated with risk of type 2 diabetes mellitus in adulthood: a cohort study

Objectives: To determine whether vitamin D status in childhood and adolescence (herein collectively referred to as youth) and the long-term status from youth to adulthood is associated with risk of developing type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) in adulthood.Materials and methods: This was a 31-year follow-up study of 2300 participants aged 3–18 years. Multinomial logistic regression was used to assess the association of both (a) baseline 25-hydroxyvitamin D (25OHD) levels and (b) the mean of baseline and the latest follow-up 25OHD levels (continuous variable and quartiles) with incident T2DM and IFG (cut-off = 5.6 mmol/L) in adult life.Results: High serum 25OHD levels in youth and also mean values from youth to adulthood were associated with reduced risk of developing T2DM in adulthood (odds ratio, 95% confidence interval= 0.73, 0.57–0.95 and 0.65, 0.51–0.84, respectively, for each SD increment in 25OHD). Compared to Q1, a dose-dependent negative association was observed across other quartiles of youth 25OHD, while the strongest association was found in the Q3 for the mean 25OHD levels. Neither youth nor the mean 25OHD was associated with IFG.Conclusions: High serum 25OHD levels in youth, and from child to adult life, were associated with a reduced risk of developing T2DM in adulthood.Key MessagesHigh serum 25OHD levels in youth, and between youth and adulthood, were associated with a lower risk of T2DM in adulthood.Each SD (15.2 nmol/L) increment in youth serum 25OHD levels was associated with a 26% reduction in odds for T2DM, which was independent of a number of confounding variables and other risk factors for T2DM. A similar magnitude of association was observed for the long-term 25OHD levels between youth and adulthood.These findings suggest a potentially simple and cost-effective strategy for reducing adulthood risk of T2DM starting in an earlier stage of life – improving and maintaining vitamin D status throughout youth and early adulthood.

Type 1 Diabetes Mellitus and Cognitive Impairments: A Systematic Review.

Type 1 diabetes mellitus (T1DM) is a major subtype of diabetes and is usually diagnosed at a young age with insulin deficiency. The life expectancy of T1DM patients has increased substantially in comparison with that three decades ago due to the availability of exogenous insulin, though it is still shorter than that of healthy people. However, the relation remains unclear between T1DM and dementia as an aging-related disease. We conducted a systematic review of existing literature on T1DM and cognition impairments by carrying out searches in electronic databases Medline, EMBASE, and Google Scholar. We restricted our review to studies involving only human subjects and excluded studies on type 2 diabetes mellitus or non-classified diabetes. A meta-analysis was first performed on the relationship between T1DM and cognitive changes in youths and adults respectively. Then the review focused on the cognitive complications of T1DM and their relation with the characteristics of T1DM, glycemic control, diabetic complications, comorbidities, and others. First, age at onset, disease duration, and glycemic dysregulation were delineated for their association with cognitive changes. Then diabetic ketoacidosis, angiopathy, and neuropathy were examined as diabetic complications for their involvement in cognitive impairments. Lastly, body mass index and blood pressure were discussed for their relations with the cognitive changes. Future studies are needed to elucidate the pathogenesis of T1DM-related cognitive impairments or dementia.

Depressive Symptoms During Adolescence and Young Adulthood and the Development of Type 2 Diabetes Mellitus.

Although depression symptoms have been associated with type 2 diabetes mellitus (T2DM) among adults, little is known about the association of adolescent-onset depression and development of T2DM in young adulthood and whether the association differs by sex. We examined the association between high levels of depressive symptoms in adolescence and T2DM in adulthood in the National Longitudinal Study of Adolescent to Adult Health (n = 12,657). Adolescents completed the 20-item version of Center for Epidemiologic Studies Depression Scale during wave 1 (mean age, 16 years) and the 10-item version during follow-up (mean age, 29 years). A high level of depressive symptoms was defined as a score of 16 or higher on the 20-item version or 11 or higher on the 10-item version. T2DM was identified 13 years after baseline on the basis of either a glycated hemoglobin concentration of at least 6.5% or use of hypoglycemic medication (with or without insulin). Participants who reported taking insulin alone were classified as having type 1 diabetes mellitus and excluded. In models adjusted for demographic characteristics, women were at a higher risk of developing T2DM if they experienced high levels of depressive symptoms during both adolescence and adulthood (odds ratio = 1.96, 95% confidence interval: 1.23, 3.11) than were those who did not experience a high level of symptoms at either time point. No statistically significant associations were noted among men (odds ratio = 0.46, 95% confidence interval: 0.20, 1.05).

Integrated sensor-augmented pump therapy systems [the MiniMed® Paradigm™ Veo system and the Vibe™ and G4® PLATINUM CGM (continuous glucose monitoring) system] for managing blood glucose levels in type 1 diabetes: a systematic review and economic evaluation.

In recent years, meters for continuous monitoring of interstitial fluid glucose have been introduced to help people with type 1 diabetes mellitus (T1DM) to achieve better control of their disease. The objective of this project was to summarise the evidence on the clinical effectiveness and cost-effectiveness of the MiniMed(®) Paradigm™ Veo system (Medtronic Inc., Northridge, CA, USA) and the Vibe™ (Animas(®) Corporation, West Chester, PA, USA) and G4(®) PLATINUM CGM (continuous glucose monitoring) system (Dexcom Inc., San Diego, CA, USA) in comparison with multiple daily insulin injections (MDIs) or continuous subcutaneous insulin infusion (CSII), both with either self-monitoring of blood glucose (SMBG) or CGM, for the management of T1DM in adults and children. A systematic review was conducted in accordance with the principles of the Centre for Reviews and Dissemination guidance and the National Institute for Health and Care Excellence Diagnostic Assessment Programme manual. We searched 14 databases, three trial registries and two conference proceedings from study inception up to September 2014. In addition, reference lists of relevant systematic reviews were checked. In the absence of randomised controlled trials directly comparing Veo or an integrated CSII + CGM system, such as Vibe, with comparator interventions, indirect treatment comparisons were performed if possible. A commercially available cost-effectiveness model, the IMS Centre for Outcomes Research and Effectiveness diabetes model version 8.5 (IMS Health, Danbury, CT, USA), was used for this assessment. This model is an internet-based, interactive simulation model that predicts the long-term health outcomes and costs associated with the management of T1DM and type 2 diabetes. The model consists of 15 submodels designed to simulate diabetes-related complications, non-specific mortality and costs over time. As the model simulates individual patients over time, it updates risk factors and complications to account for disease progression. Fifty-four publications resulting from 19 studies were included in the review. Overall, the evidence suggests that the Veo system reduces hypoglycaemic events more than other treatments, without any differences in other outcomes, including glycated haemoglobin (HbA1c) levels. We also found significant results in favour of the integrated CSII + CGM system over MDIs with SMBG with regard to HbA1c levels and quality of life. However, the evidence base was poor. The quality of the included studies was generally low, often with only one study comparing treatments in a specific population at a specific follow-up time. In particular, there was only one study comparing Veo with an integrated CSII + CGM system and only one study comparing Veo with a CSII + SMBG system in a mixed population. Cost-effectiveness analyses indicated that MDI + SMBG is the option most likely to be cost-effective, given the current threshold of £30,000 per quality-adjusted life-year gained, whereas integrated CSII + CGM systems and Veo are dominated and extendedly dominated, respectively, by stand-alone, non-integrated CSII with CGM. Scenario analyses did not alter these conclusions. No cost-effectiveness modelling was conducted for children or pregnant women. The Veo system does appear to be better than the other systems considered at reducing hypoglycaemic events. However, in adults, it is unlikely to be cost-effective. Integrated systems are also generally unlikely to be cost-effective given that stand-alone systems are cheaper and, possibly, no less effective. However, evidence in this regard is generally lacking, in particular for children. Future trials in specific child, adolescent and adult populations should include longer term follow-up and ratings on the European Quality of Life-5 Dimensions scale at various time points with a view to informing improved cost-effectiveness modelling. PROSPERO Registration Number CRD42014013764. The National Institute for Health Research Health Technology Assessment programme.

A Diagnosis of the Metabolic Syndrome in Youth That Resolves by Adult Life Is Associated With a Normalization of High Carotid Intima-Media Thickness and Type 2 Diabetes Mellitus Risk: The Bogalusa Heart and Cardiovascular Risk in Young Finns Studies

The aim of this study was to examine the effect of resolution from metabolic syndrome (MetS) between youth and adulthood on carotid artery intima-media thickness (IMT) and type 2 diabetes mellitus (T2DM). Published findings demonstrate that youth with MetS are at increased risk of cardio-metabolic outcomes in adulthood. It is not known whether this risk is attenuated in those who resolve their MetS status. Participants (n = 1,757) from 2 prospective cohort studies were examined as youth (when 9 to 18 years of age) and re-examined 14 to 27 years later. The presence of any 3 components (low high-density lipoprotein cholesterol, high triglycerides, high glucose, high blood pressure, or high body mass index) previously shown to predict adult outcomes defined youth MetS; the harmonized MetS criteria defined adulthood MetS. Participants were classified according to their MetS status at baseline and follow-up and examined for risk of high IMT and T2DM. Those with MetS in youth and adulthood were at 3.4 times the risk (95% confidence interval: 2.4 to 4.9) of high IMT and 12.2 times the risk (95% confidence interval: 6.3 to 23.9) of T2DM in adulthood compared with those that did not have MetS at either time-point, whereas those that had resolved their youth MetS status by adulthood showed similar risk to those that did not have MetS at either time-point (p > 0.20 for all comparisons). Although youth with MetS are at increased risk of adult high IMT and T2DM, these data indicate that the resolution of youth MetS by adulthood can go some way to normalize this risk to levels seen in those who have never had MetS.

The Battered β-Cell: Usual Suspects and Guilt by Association

Does it not astonish us that diabetes was recognized thousands of years ago and in a single century we rapidly developed life-saving therapies, yet we are still trying to identify initial causes of this disease (1–3)? It is true that we have made much more progress in understanding pathophysiological mechanisms for type 1 diabetes mellitus (T1DM) than we have for type 2 diabetes mellitus (T2DM). Perhaps there is a message in this. T2DM is roughly 20 times more common than T1DM, it has at least several different phenotypes in humans, and its prevalence varies significantly among ethnic and racial groups. This suggests that T2DM is not a disease at all, but rather a syndrome—more like an association of signs and symptoms, such as fever, anemia, or pneumonia. In clinics and scientific literature, we tend to refer to T1DM as a single autoimmune disease, but we are vague about T2DM and refer to it as a multifactorial and polygenic disease. This is a reasonable enough concept, but one that opens the door to the possibility that there is no single gene that will explain T2DM. It is true that there are known important mutations in a few transcription factors in a small number of families of humans. Otherwise, however, it may take the loss of more than one gene's expression to develop T2DM in a single human … or it may take overexpression of more than one gene … or it may take a combination of loss and overexpression of different genes to establish the disease. This picture becomes ever more complicated when one adds epigenetic events as a possibility, especially considering how acutely epigenetic changes can come and then go after DNA repair is completed. Small wonder we have not yet identified the genetic cause of human T2DM. Actually, the term T2DM implies that we know more than we do, i.e. that there are only two forms of diabetes. This term arose by default because we decided to change the name of juvenile-onset or insulin-dependent diabetes to “type 1.” The term “type 2” was invented to cover the other 95% of cases of diabetes. That's a pretty large wastebasket and one that invites even worse tongue-in-cheek imprecision, i.e. terms such as type 1 and 1/2 diabetes, which implies an entity midway between type 1 and type 2. Other diabetes phenotypes, such as late onset of T1DM in adults and T2DM in children, clearly provide important pathophysiological clues.

Pediatric Metabolic Syndrome Predicts Adulthood Metabolic Syndrome, Subclinical Atherosclerosis, and Type 2 Diabetes Mellitus but Is No Better Than Body Mass Index Alone

Background— The clinical utility of identifying pediatric metabolic syndrome (MetS) is controversial. This study sought to determine the status of pediatric MetS as a risk factor for adult subclinical atherosclerosis (carotid intima-media thickness [cIMT]) and type 2 diabetes mellitus (T2DM) and compare and contrast this prediction with its individual components. Methods and Results— Using data from the population-based, prospective, observational Bogalusa Heart and Cardiovascular Risk in Young Finns studies, we examined the utility of 4 categorical definitions of youth MetS and their components in predicting adult high cIMT and T2DM among 1781 participants aged 9 to 18 years at baseline (1984 to 1988) who were then examined 14 to 27 years later (2001–2007) when aged 24 to 41 years. Youth with MetS were at 2 to 3 times the risk of having high cIMT and T2DM as adults compared with those free of MetS at youth. Risk estimates with the use of high body mass index were similar to those of MetS phenotypes in predicting adult outcomes. Comparisons of area under the receiver operating characteristic curve and net reclassification index suggested that prediction of adult MetS, high cIMT, and T2DM in adulthood with the use of youth MetS was either equivalent or inferior to classification based on high body mass index or overweight and obesity. Conclusions— Youth with MetS are at increased risk of meaningful adult outcomes; however, the simplicity of screening for high BMI or overweight and obesity in the pediatric setting offers a simpler, equally accurate alternative to identifying youth at risk of developing adult MetS, high cIMT, or T2DM.

Age at Menarche and Risk of Type 2 Diabetes: Results From 2 Large Prospective Cohort Studies

The authors investigated the association between age at menarche and risk of type 2 diabetes mellitus (T2DM) among 101,415 women from the Nurses' Health Study (NHS) aged 34-59 years (1980-2006) and 100,547 women from Nurses' Health Study II (NHS II) aged 26-46 years (1991-2005). During 2,430,274 and 1,373,875 person-years of follow-up, respectively, 7,963 and 2,739 incident cases of T2DM were documented. Young age at menarche was associated with increased risk of T2DM after adjustment for potential confounders, including body figure at age 10 years and body mass index (BMI; weight (kg)/height (m)(2)) at age 18 years. Relative risks of T2DM across age-at-menarche categories (< or =11, 12, 13, 14, and > or =15 years) were 1.18 (95% confidence interval (CI): 1.10, 1.27), 1.09 (95% CI: 1.02, 1.17), 1.00 (referent), 0.92 (95% CI: 0.83, 1.01), and 0.95 (95% CI: 0.84, 1.06), respectively, in the NHS (P for trend < 0.0001) and 1.40 (95% CI: 1.24, 1.57), 1.13 (95% CI: 1.00, 1.27), 1.00 (referent), 0.98 (95% CI: 0.82, 1.18), and 0.96 (95% CI: 0.78, 1.19), respectively, in NHS II (P for trend < 0.0001). Associations were substantially attenuated after additional control for updated time-varying BMI. These data suggest that early menarche is associated with increased risk of T2DM in adulthood. The association may be largely mediated through excessive adult adiposity. The association was stronger among younger women, supporting a role for sex hormones in younger onset of T2DM, in addition to BMI.

Autoimmune Diabetes Mellitus with Adult Onset and Type 1 Diabetes Mellitus in Children Have Different Genetic Predispositions

Type 1 diabetes with manifestation after 35 years of age is defined by CP <200 pmol/L and institution of insulin therapy within 6 months after diagnosis. Latent autoimmune diabetes mellitus in adults (LADA) manifesting after 35 years of age is defined by minimum 6 months after diagnosis without insulin therapy and C peptide (CP) >200 pmol/L and antiGAD > 50 ng/mL. We aimed to find a possible genetic discrimination among different types of autoimmune diabetes. To accomplish this goal, we analyzed DNA samples from 31 LADA patients, 75 patients with adult-onset type 1 diabetes mellitus, 188 type 1 diabetic children, and 153 healthy adult individuals. We studied five genetic loci on chromosomes 6, 11, 4, and 14: HLA DRB1 and DQB1 alleles, major histocompatibility complex (MHC) class I-related gene-A (MIC-A) microsatellite polymorphism, interleukin (IL)-18 single nucleotide polymorphism, the microsatellite polymorphism of nuclear factor kappa B gene (NF-kappaB1), and the single nucleotide polymorphism of a gene for its inhibitor (NF-kappaBIA). HLA-DR3 was detected as the predisposition allele for LADA (OR = 4.94, P < 0.0001). Further we found a statistically significant increase of NF-kappaBIA AA genotype (OR = 2.68, P < 0.01). On the other hand, DRB1*04, which is linked with DQB1*0302, was observed as a risk factor in patients with type 1 diabetes mellitus (T1DM) onset after 35 years of age (OR = 10.47, P < 0.0001 and OR = 9.49, P < 0.0001, respectively). There was also an association with MIC-A5.1 (OR = 2.14, P < 0.01). Statistically significant difference was found in the distribution of IL-18 promoter -607 (C/A) polymorphism between LADA and T1DM in adults (P < 0.01). We conclude that all subgroups of autoimmune diabetes have partly different immunogenetic predisposition.

HLA, NFKB1 and NFKBIA Gene Polymorphism Profile in Autoimmune Diabetes Mellitus Patients

Type 1 diabetes mellitus (T1DM) is one of the long-time studied autoimmune disorders. The triggering of the autoimmune process has been ascribed to various genes active in the regulation of the cytokine gene transcription including the Rel/NF-kappaB gene family. In our study the gene polymorphism of HLA class II, NFKB1 (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) and NFKBIA (inhibitor of nuclear factor kappa B) was tested. Patients were divided into the subgroups in relation to the disease type: T1DM in children, T1DM in adults, and Latent Autoimmune Diabetes in Adults (LADA). HLA-DRB1 (*)04 and HLA-DQB1 (*)0302 have been detected as risk factors for T1DM in adults and particularly in children (P<0.0001, OR=22.9 and 46.5 respectively). HLA-DRB1 (*)03 has been found as a single risk factor for LADA (P<0.0001, OR=4.9). We detected 15 alleles for the NFKB1 gene polymorphism (CA-repeats) in the Czech population. The alleles were ranging in size from 114-142 bp corresponding to 10-25 CA repeats. Frequency of the A7 allele of NFKB1 gene has been significantly increased in T1DM adults (P<0.01). There was no difference in A and a G allele frequency of NFKBIA gene between the control group and patients, but the association of the AA genotype of NFKBIA gene has been found for LADA (P<0.05). Summarizing our results we concluded that there is a high probability of association of gene polymorphism from Rel/NF-kappaB family with an autoimmune diabetes course. Due to the results obtained in the epidemiological study we have been looking also for the function significance of the genetic predisposition. No significant changes have been observed by real time PCR testing of HLA-DRB1 (*)04 gene and NFKB1 gene expression between T1DM diabetic group with different HLA, NFKB1, NFKBIA genetic background.