ArticleLiterature Review

Risk Factors Contributing to Type 2 Diabetes and Recent Advances in the Treatment and Prevention

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Abstract

Type 2 diabetes is a serious and common chronic disease resulting from a complex inheritance-environment interaction along with other risk factors such as obesity and sedentary lifestyle. Type 2 diabetes and its complications constitute a major worldwide public health problem, affecting almost all populations in both developed and developing countries with high rates of diabetes-related morbidity and mortality. The prevalence of type 2 diabetes has been increasing exponentially, and a high prevalence rate has been observed in developing countries and in populations undergoing "westernization" or modernization. Multiple risk factors of diabetes, delayed diagnosis until micro- and macro-vascular complications arise, life-threatening complications, failure of the current therapies, and financial costs for the treatment of this disease, make it necessary to develop new efficient therapy strategies and appropriate prevention measures for the control of type 2 diabetes. Herein, we summarize our current understanding about the epidemiology of type 2 diabetes, the roles of genes, lifestyle and other factors contributing to rapid increase in the incidence of type 2 diabetes. The core aims are to bring forward the new therapy strategies and cost-effective intervention trials of type 2 diabetes.

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... It can be managed by a healthy diet, maintaining a healthy weight, and exercise. However, more than 90% of diabetic patients experienced T2DM (Deshpande et al., 2008;Wu et al., 2014). Genetic and environmental factors can affect T2DM. ...
... For example, smoking, having alcohol, gaining overweight, and lack of physical activity can develop T2DM, because these factors can change the plasma glucose level. Moreover, these can also impair the beta cell function which may result in glucose intolerance (Martín-Timón et al., 2014;Wu et al., 2014). In addition, acquired organ dysfunction is the third factor. ...
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Diabetes is a global health concern that has affected almost 415 million people globally. Bromocriptine is a dopamine D2 agonist, which is a Food and Drug Administration (FDA)–approved drug to treat type 2 diabetes mellitus (T2DM) patients. However, it is considered that a novel treatment therapy is required which can be used in the treatment of diabetes with or without other antidiabetic agents. Dopamine agonists are usually used in neurological disorders like Parkinson’s disease (PD), restless leg syndrome, and hyperprolactinemia. However, dopamine agonists including bromocriptine and cabergoline are also effective in reducing the glycemic level in T2DM patients. Bromocriptine was formerly used for the treatment of PD, hyperprolactinemia, and restless leg syndrome, but now it is used for improving glycemic levels as well as reducing free fatty acids and triglycerides. In addition, cabergoline has been found to be effective in glycemic control, but this drug is yet to be approved by the FDA due to its limitations and lack of study. Findings of the clinical trials of bromocriptine have suggested that it reduces almost 0.4–0.8% glycated hemoglobin and cardiovascular risk by 40% in insulin-resistant patients. Moreover, the safe use of bromocriptine in obese T2DM patients makes it a more attractive option as it causes weight loss. Indeed, bromocriptine is a novel therapy for T2DM patients, as its mechanism of action is unique in T2DM patients with minimal adverse effects. This review summarizes the potential of dopamine agonists in the treatment of T2DM.
... Diabetes Mellitus (DM) is characterized as a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action (American Diabetes Association, 2009). The pathophysiology of T2DM has not been completely elucidated until now, but influencing factors include genetic susceptibility, environmental and behavioural factors such as sedentary lifestyle, nutrition and gut metagenome (Wu et al., 2014;Zimmet et al., 2001). A variety of lifestyle factors such as sedentary lifestyle (Zimmet et al., 2001), smoking (Mansonet al., 2000 and alcohol consumption (Cullmann et al., 2012), are of importance to the development of T2DM (Pan et al., 1997;The Diabetes Prevention Program, 1999;Tuomilehto et al., 2001;Wu et al., 2014;Zimmet et al., 2001;P. ...
... The pathophysiology of T2DM has not been completely elucidated until now, but influencing factors include genetic susceptibility, environmental and behavioural factors such as sedentary lifestyle, nutrition and gut metagenome (Wu et al., 2014;Zimmet et al., 2001). A variety of lifestyle factors such as sedentary lifestyle (Zimmet et al., 2001), smoking (Mansonet al., 2000 and alcohol consumption (Cullmann et al., 2012), are of importance to the development of T2DM (Pan et al., 1997;The Diabetes Prevention Program, 1999;Tuomilehto et al., 2001;Wu et al., 2014;Zimmet et al., 2001;P. Z. Zimmet, 1999). ...
... Chronic hyperglycemia is associated with end organ damage including retina, kidney, nervous system, heart and blood vessels (1,2). Type 2 DM (T2DM) accounts for ∼90% of all DM cases with a variety of modifiable and non-modifiable risk factors Non-modifiable risk factors include age, genetic and sociodemographic factors while modifiable risk factors are unhealthy diet, obesity, physical inactivity, tobacco use and alcohol (3)(4)(5). Globally, ∼462 million individuals are affected by T2DM, corresponding to 6.28% of the world's population. In addition, >1 million deaths were attributed to T2DM in 2017, ranking it as the ninth major cause of mortality (6)(7)(8). ...
... Since the self-care techniques in DM require behavior modification, professional Health Care Workers' (HCWs) must assist patients to become aware of self-care and to solve the challenges diabetes presents. Moreover, the management of diabetes can improve when HCWs provide measures to promote self-care activities in patients (4). HCWs play a crucial role in facilitating patients' capability by providing necessary information and supporting patients' initiatives to make lifestyle changes (7). ...
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Background Type 2 Diabetes Mellitus (T2DM) is known as a major cause of mortality globally. Diabetes self-management refers to daily activities undertaken to control or reduce the impact of diabetes on health and well-being to avoid further illness. Health Care Workers' (HCWs) can assist patients to be aware of self-care and solve the challenges diabetes presents. The management of diabetes can improve once HCWs promote measures that facilitate self-care activities by providing necessary information and supporting patients' initiatives to make lifestyle changes. This study aimed to explore HCWs perceptions on factors affecting diabetes self-management among T2DM patients of Fiji. Methods A qualitative study design was conducted to explore HCWs perceptions on factors affecting diabetes self-management using two Focus Group Discussions (FGDs) in Labasa, Fiji in 2021. The study settings were the Diabetic Hub Center, special outpatient department Labasa hospital and Nasea health Center Labasa. The study settings are located in an urban area. These health facilities provide special outpatient clinics to T2DM patients including clinics for other medical conditions. Nasea Health Center had 1,300 patients, the special outpatient's department Labasa hospital had 560 patients and the diabetic hub center Labasa had 295 patients at the time of the study. These patients either had T2DM or T2DM with other medical conditions. Purposive sampling was employed to recruit HCWs. The data were collected using an interview guide in semi-structured interviews and the interviews were audio recorded. The recorded data was transcribed verbatim and analyzed using thematic analysis process. Results The participants were 9 HCWs with age range of 25-49 years. A counselor, a medical officer, physiotherapist, nurses and dieticians were among the HCWs. Three major themes and seven sub themes were identified. These included Theme 1- “availability of services” with the sub themes of clinical services for T2DM and other support services available for T2DM patients. Theme 2- “barriers and challenges to diabetes self-management” with the sub themes of health system factors, socioeconomic factors and health system factors. Theme 3- “Needs for diabetes management” with the sub themes resources and skilled personnel. Conclusion The findings of this study demonstrate health system challenges such as lack of material resources and human resources compounded the factors affecting diabetes self-management. HCWs training as diabetes educators and developing policy on diabetes self-management are highly recommended to facilitate diabetes self-management.
... To study and dissect the role of PFKFB3 from HIF1α in the survival of damaged β-cells under diabetogenic stress in vivo, we generated mice with β-cell-specific conditional disruption of the Pfkfb3 gene on a hIAPP +/− background and exposed them to a high-fat diet (HFD) for 13 weeks (PFKFB3 βKO DS). Diabetogenic stress was deemed high since it involved insulin resistance (obesity) and exposure to misfolded proteins through hIAPP +/− expression, that altogether with advanced age (44-50 weeks), are known as cumulative risk factors in diabetes [20][21][22] . ...
... Efficient disruption of PFKFB3 expression was confirmed by PFKFB3 immunostaining of the pancreatic sections of the PFKFB3 βKO DS mice ( Fig. 1a and Supplementary Information). Diabetogenic stress led to 33.9 ± 6.4% PFKFB3 immunolabelling of β-cells in PFKFB3 WT DS mice (**p = 0.0015), similar to the proportion of PFKFB3-positive β-cells previously reported in humans with T2D 22 . The proportion of PFKFB3-positive β-cells in WT mice was 3.7 ± 1.9%, while in PFKFB3 βKO DS mice, it was successfully abolished and accounted for 1.0 ± 0.8% (***p = 0.0006, Fig. 1a, b). ...
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HIF1α and PFKFB3 play a critical role in the survival of damaged β-cells in type–2 diabetes while rendering β-cells non-responsive to glucose stimulation. To discriminate the role of PFKFB3 from HIF1α in vivo, we generated mice with conditional β-cell specific disruption of the Pfkfb3 gene on a human islet pancreatic polypeptide (hIAPP +/− ) background and a high-fat diet (HFD) [PFKFB3 βKO + diabetogenic stress (DS)]. PFKFB3 disruption in β-cells under DS led to selective purging of hIAPP-damaged β-cells and the disappearance of insulin- and glucagon positive bihormonal cells. PFKFB3 disruption induced a three-fold increase in β-cell replication as evidenced by minichromosome maintenance 2 protein (MCM2) expression. Unlike high-, lower DS or switch to restricted chow diet abolished HIF1α levels and reversed glucose intolerance of PFKFB3 βKO DS mice. Our data suggest that replication and functional recovery of β-cells under DS depend on β-cell competitive and selective purification of HIF1α and PFKFB3-positive β-cells.
... The prevalence of type 2 diabetes has increased along with the rising incidence of obesity, and high body mass index (BMI), as a measure for excess adiposity, is a major risk factor for type 2 diabetes [1,2]. Both the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommend changes in lifestyle as the first step in prevention and treatment of type 2 diabetes [3]. ...
... The aim of this review was therefore to investigate the safety of TRE interventions in people with type 2 diabetes treated with antidiabetic drugs. Specific objectives were: (1) to identify published and ongoing studies in this area and to assess the safety of TRE in these studies; (2) to identify the commonly used antidiabetic drugs and discuss the safety of TRE in people with type 2 diabetes considering the use of these antidiabetic drugs; (3) to discuss which research is needed before TRE can be recommended in the treatment of type 2 diabetes. ...
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Time-restricted eating (TRE) has been shown to improve body weight and glucose metabolism in people at high risk of type 2 diabetes. However, the safety of TRE in the treatment of type 2 diabetes is unclear. We investigated the safety of TRE interventions in people with type 2 diabetes by identifying published and ongoing studies. Moreover, we identified the commonly used antidiabetic drugs and discussed the safety of TRE in people with type 2 diabetes considering the use of these drugs. In addition, we addressed the research needed before TRE can be recommended in the treatment of type 2 diabetes. A literature search was conducted to identify published (MEDLINE PubMed, 17 November 2021) and ongoing studies (ClinicalTrials.gov, 21 December 2021) on TRE in people with type 2 diabetes. To assess the usage of antidiabetic drugs and to discuss pharmacodynamics and pharmacokinetics in a TRE context, the most used antidiabetic drugs were identified and analysed. Statistics regarding sale of pharmaceuticals were obtained from MEDSTAT.DK which are based on data from the national Register of Medicinal Product Statistics, and from published studies on medication use in different countries. Four published studies investigating TRE in people with type 2 diabetes were identified as well as 14 ongoing studies. The completed studies suggested that TRE is safe among people with type 2 diabetes. Common antidiabetic drugs between 2010 and 2019 were metformin, insulin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sulfonylureas, and sodium-glucose cotransporter-2 inhibitors. Existing studies suggest that TRE is not associated with major safety issues in people with type 2 diabetes as long as medication is monitored and adjusted. However, because of low generalisability of the few studies available, more studies are needed to make concrete recommendations regarding efficacy and safety of TRE in people with type 2 diabetes.
... Among diabetic patients, type 2 diabetes mellitus is the most prevalent type of diabetes, accounting for 90-95% (Henning 2018). Type 2 diabetes mellitus patients are more susceptible to different forms of complications, e.g., cardiovascular diseases (hypertension, hyperlipidemia, heart attacks, coronary artery disease, strokes, cerebral vascular disease, and peripheral vascular disease), nephropathy, retinopathy, neuropathy, and cancers (Wu et al. 2014;Sandholm and Forsblom 2020). ...
... However, glycemic parameters changed for the worse in patients with type 2 diabetes during the lockdown (Eberle and Stichling 2021). In addition, the increasing prevalence of diabetes is due to the aging population (Sun et al. 2022), obesity, and unhealthy lifestyle (such as sedentary lifestyle, physical inactivity, smoking, and alcohol consumption) (Wu et al. 2014). ...
Article
Distichochlamys citrea M.F. Newman (commonly known as "Black Ginger") is an endemic plant to Vietnam and has been extensively exploited by folk medication for treatments of infection-related diseases and diabetes. In this work, its rhizomes were subjected to fractionated extraction, phytochemical examination, evaluation of antioxidant effect by DDPH free radical neutralization, and inhibitory activity toward α-glucosidase. The compositional components were subjected to in silico screening, including density functional theory calculation, molecular docking simulation, physicochemical analysis, and pharmacokinetic regression. In the trials, EtOAc fraction is found as the bioactive part of most effectiveness, regarding both antioxidant effect (IC50 = 90.27 µg mL-1) and α-glucosidase inhibitory activity (IC50 = 115.75 μg mL-1). Chemical determination reveals there are 13 components of its composition. DFT-based calculations find no abnormal constraints in their structures. Docking-based simulation provides order of inhibitory effectiveness: 3-P53341 > 12-P53341 > 7-P53341 > 4-P53341 > 11-P53341 > 10-P53341. QSARIS-based investigations implicate their biocompatibility. ADMET-based regressions indicate that all candidates are generally safe for medicinal applications. The findings would contribute to the basis for further studies on the chemical compositions of Distichochlamys citrea and their biological activities. Supplementary information: The online version contains supplementary material available at 10.1007/s11696-022-02273-2.
... Diabetes mellitus (DM) is a collection of chronic metabolic conditions, characterised by elevated blood glucose levels resulting from the body's inability to produce insulin or resistance to insulin action or both. 1 There are two primary forms of DM, insulindependent DM (type 1 diabetes mellitus, T1DM) and non-insulin-dependent DM (type 2 diabetes mellitus, T2DM). T2DM is the most common form, making up 90%-95% of all patients with diabetes. ...
... T2DM is the most common form, making up 90%-95% of all patients with diabetes. 1 DM and its complications can result in disability and premature death, 2 as well as enormous economic and social burdens. 3 There is no cure for DM; thus, prevention is the best intervention. ...
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Objectives With body mass index (BMI) failing to distinguish the mass of fat from lean, several novel predicted equations for predicted fat mass (FM), predicted lean mass (LM) and predicted per cent fat (PF) were recently developed and validated. Our aim was to explore whether the three novel parameters could better predict diabetes mellitus (DM) than the commonly used obesity indicators, including BMI, waist circumference, hip circumference and waist-hip ratio. Design A 15-year prospective cohort was used. Setting It was a prospective cohort, consisting of a general Chinese population from 1992 to 2007. Participants This cohort enrolled 711 people. People suffering from DM at baseline (n=24) were excluded, and 687 non-diabetics with complete data were included to the analysis. Primary outcome New-onset DM. Results After the follow-up, 74 (48 men and 26 women) incidences of DM were documented. For men, the adjusted HRs were 1, 5.19 (p=0.003) and 7.67 (p<0.001) across predicted PF tertiles; 1, 2.86 (p=0.029) and 5.60 (p<0.001) across predicted FM tertiles; 1, 1.21 (p=0.646) and 2.27 (p=0.025) across predicted LM tertiles. Predicted FM performed better than other commonly used obesity indicators in discrimination with the highest Harrell’s C-statistic among all the body composition parameters. Whereas, for women, none of the three novel parameters was the independent predictor. Conclusion Predicted PF, predicted LM and predicted FM could independently predict the risk of DM for men, with predicted FM performing better in discrimination than other commonly used obesity indicators. For women, larger samples were further needed.
... With such tools, a two-step procedure could be used: first, subjects would be screened with a risk score, and then those individuals identified to have a high risk for T2DM would have their glycemic status assessed by FBG, 2-h post-load glucose (2hPG) using the oral glucose tolerance test (OGTT), or hemoglobin (Hb)A1c measurements (15). However, due to differences in diet, lifestyle, social environment, and genetic susceptibility of different populations, the applicability of the model is limited (16). Therefore, various regions need to continue to explore T2DM assessment models that are suitable for local populations. ...
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Aims This study aimed to compare the diagnostic accuracy of the metabolic syndrome with the Finnish Diabetes Risk Score (FINDRISC) to screen for type 2 diabetes mellitus (T2DM) in a Shanghai population. Methods Participants aged 25-64 years were recruited from a Shanghai population from July 2019 to March 2020. Each participant underwent a standard metabolic work-up, including clinical examination with anthropometry. Glucose status was tested using hemoglobin A1c (HbAlc), 2h-post-load glucose (2hPG), and fasting blood glucose (FBG). The FINDRISC questionnaire and the metabolic syndrome were examined. The performance of the FINDRISC was assessed using the area under the receiver operating characteristic curve (AUC-ROC). Results Of the 713 subjects, 9.1% were diagnosed with prediabetes, whereas 5.2% were diagnosed with T2DM. A total of 172 subjects had the metabolic syndrome. A higher FINDRISC score was positively associated with the prevalence of T2DM and the metabolic syndrome. Multivariable linear regression analysis demonstrated that the FINDRISC had a linear regression relationship with 2hPG levels (b’= 036, p < 0.0001). The AUC-ROC of the FINDRISC to identify subjects with T2DM among the total population was 0.708 (95% CI 0.639–0.776), the sensitivity was 44.6%, and the specificity was 90.1%, with 11 as the cut-off point. After adding FBG or 2hPG to the FINDRISC, the AUC-ROC among the total population significantly increased to 0.785 (95% CI 0.671–0.899) and 0.731 (95% CI 0.619–0.843), respectively, while the AUC-ROC among the female group increased to 0.858 (95% CI 0.753–0.964) and 0.823 (95% CI 0.730–0.916), respectively (p < 0.001). The AUC-ROC of the metabolic syndrome to identify subjects with T2DM among the total and female population was 0.805 (95% CI 0.767–0.844) and 0.830 (95% CI 0.788–0.872), respectively, with seven as the cut-off point. Conclusions The metabolic syndrome performed better than the FINDRISC model. The metabolic syndrome and the FINDRISC with FBG or 2hPG in a two-step screening model are both efficacious clinical practices for predicting T2DM in a Shanghai population.
... Consider also the hypothesis that obesity is causally relevant for type 2 diabetes. Although this is a well-confirmed scientific hypothesis, many overweight individuals never actually become diabetic (Wu et al., 2014). Accordingly, there is an ongoing search for additional factors that become causally relevant whenever they co-occur with obesity. ...
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Models developed using machine learning are increasingly prevalent in scientific research. At the same time, these models are notoriously opaque. Explainable AI aims to mitigate the impact of opacity by rendering opaque models transparent. More than being just the solution to a problem, however, Explainable AI can also play an invaluable role in scientific exploration. This paper describes how post-hoc analytic techniques from Explainable AI can be used to refine target phenomena in medical science, to identify starting points for future investigations of (potentially) causal relationships, and to generate possible explanations of target phenomena in cognitive science. In this way, this paper describes how Explainable AI—over and above machine learning itself—contributes to the efficiency and scope of data-driven scientific research.
... T2DM and its complications constitute a major public health problem worldwide, affecting almost all populations in both developed and developing countries, with high rates of diabetes-related morbidity and mortality [4]. In Italy, diabetes is the leading cause of blindness, the second-leading cause of end-stage renal failure requiring dialysis or transplantation, the leading cause of non-traumatic amputation of the lower limbs, and a contributing cause in 50% of heart attacks and strokes [5]. ...
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Dietary behaviour is a core element in diabetes self-management. There are no remarkable differences between nutritional guidelines for people with type 2 diabetes and healthy eating recommendations for the general public. This study aimed to evaluate dietary differences between subjects with and without diabetes and to describe any emerging dietary patterns characterizing diabetic subjects. In this cross-sectional study conducted on older adults from Southern Italy, eating habits in the “Diabetic” and “Not Diabetic” groups were assessed with FFQ, and dietary patterns were derived using an unsupervised learning algorithm: principal component analysis. Diabetic subjects (n = 187) were more likely to be male, slightly older, and with a slightly lower level of education than subjects without diabetes. The diet of diabetic subjects reflected a high-frequency intake of dairy products, eggs, vegetables and greens, fresh fruit and nuts, and olive oil. On the other hand, the consumption of sweets and sugary foods was reduced compared to non-diabetics (23.74 ± 35.81 vs. 16.52 ± 22.87; 11.08 ± 21.85 vs. 7.22 ± 15.96). The subjects without diabetes had a higher consumption of red meat, processed meat, ready-to-eat dishes, alcoholic drinks, and lower vegetable consumption. The present study demonstrated that, in areas around the Mediterranean Sea, older subjects with diabetes had a healthier diet than their non-diabetic counterparts.
... caused by a combination of environmental, lifestyle, dietary, and genetic factors (Wu et al., 2014). Here, insulin resistance in peripheral organs such as the liver and muscles, decreased insulin release from the pancreas, or both, and contribute to its pathophysiology. ...
Article
Evidence supports a strong bidirectional association between depression and Type 2 diabetes mellitus (T2DM). The harmful impact of oxidative stress and chronic inflammation on the development of both disorders is widely accepted. Nuclear factor erythroid 2-related factor 2 (NRF2) is a pertinent target in disease management owing to its reputation as the master regulator of antioxidant responses. NRF2 influences the expression of various cytoprotective phase 2 antioxidant genes, which is hampered in both depression and T2DM. Through interaction and crosstalk with several signaling pathways, NRF2 endeavors to contain the widespread oxidative damage and persistent inflammation involved in the pathophysiology of depression and T2DM. NRF2 promotes the neuroprotective and insulin-sensitizing properties of its upstream and downstream targets, thereby interrupting and preventing disease advancement. Standard antidepressant and antidiabetic drugs may be powerful against these disorders, but unfortunately, they come bearing distressing side effects. Therefore, exploiting the therapeutic potential of NRF2 activators presents an exciting opportunity to manage such bidirectional and comorbid conditions.
... In both type I and type II diabetes produced polyuria, polydipsia and polyphagia clinical symptoms [4]. Many factors have been involved in progression of diabetes such as long term hyperglycaemia, environmental and genetic factor are the main component [5]. The alteration in genetic material such as changes in nucleotide sequences may lead to alteration in protein ultimately which directly affect the signalling process could be the determining factor for complication of diabetic [6]. ...
Article
Objective Type 2 Diabetes is a glucose metabolic disorder occurred by insulin insensitivity in which folate metabolism plays an important role. it is believed that polymorphism of Methylenetetrahydrofolate reductase (MTHFR) C677T linked with type 2 diabetes mellitus. However, results are conficted. therefore, in this study we re-examine the relationship between MTHFR C677T in type 2 diabetes mellitus patients. Methods Present research work included 100 newly diagnosed type 2 diabetic mellitus (T2DM) cases and 100 healthy individuals. After the blood sample collection all the biochemical parameters were evaluated among the T2DM cases and healthy individuals. DNA and RNA extraction from whole blood was done to study the MTHFR gene polymorphism by allele specifc polymerase chain reaction method and its expression analysis was done by quantitative real time polymerase chain reaction method. Results The signifcant diference was observed in genotype distribution among case and control group (p=0.0002). Compared with wildtype CC genotype, CT heterozygous (OR=2.95, 95% Cl=1.62-5.38) and TT homozygous (OR=3.20, CI=1.79-5.73) suggest to have efect of MTHFR polymorphism on type 2 mellitus risk. Moreover, relative MTHFR mRNA expression was found for wild type CC genotype 3.02-fold, CT heterozygous genotype 2.57 fold and mutant TT homozygous genotype 0.50-fold which is down regulated (p<0.0001). Conclusion Our results indicates that the polymorphism in MTHFR C677T plays signifcant role in type II diabetes risk. MTHFR CT heterozygous and mutant TT genotype showed reduced mRNA expression among the T2DM patients. However, large scale case–control studies are needed to strengthen such conclusion in the future.
... The incidence of hyperglycemia is steadily growing all over the world due to increased obesity, a sedentary life style and the aging of populations all over the world. Hyperglycemia becomes a critical factor contributing to obesity development and leading to adipose tissue metabolism deterioration [25,26]. This subsequently strongly impairs the cytophysiological features of residing adipose tissue stem progenitor cells (ASCs) that under hyperglycaemic conditions are losing their unique properties [27]. ...
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Hyperglycaemia and its resulting glucotoxicity are among the most prominent hallmarks of diabetes mellitus (DM) development. Persistent hyperglycaemia further leads to oxidative stress via mitochondrial dysfunction and subsequent ER stress onset, while associated hyperlipidaemia triggers the adipose tissue to secrete pro-inflammatory cytokines. In this study, the effect of calystegines has been investigated in an experimental model of hyperglycaemia induced on human ASCs cells. Different cellular pathways including apoptosis, oxidative and ER stress, inflammation as well as Pi3K/AKT/mTOR metabolic-associated axis have been evaluated by means on RT-qPCR, western blot, and flow cytometry techniques. Treatment of HuASCs cells with calystegines strongly promoted the hyperglycaemic cells survival and significantly diminished oxidative stress, mitochondrial dynamics failure and ER stress, while improving the endogenous cellular antioxidant defenses. Interestingly, nortropane alkaloids efficiently prevented the hyperglycaemia-mediated inflammatory response, as evidenced by the regulation of the pro- and anti-inflammatory response in HuASCs cells. Finally, we evidenced that calystegines may exert their protective effect on HuASCs cells metabolic functions through the restoration of the defective PI3K/AKT/mTOR pathway. Overall, the present investigation demonstrated that calystegines possess important abilities to protect HuASCs against hyperglycaemia-induced cellular dysfunction, and it evidenced that the observed effects are associated to the promotion of PI3K/AKT/mTOR pathway.
... Type 2 diabetes is resulting from a complex inheritance-environment interaction along with other risk factors such as obesity and a sedentary lifestyle. Type 2 diabetes and its complications constitute a major worldwide public health problem, affecting almost all populations in both developed and developing countries with high rates of diabetes-related morbidity and mortality (5). Type 2 diabetes was once called adult-onset diabetes. ...
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Diabetes is a complex condition with several types and no clear cause, genetic factors can make some people more vulnerable to some types of diabetes. This study was aimed to determine complications of diabetes type 2 in the elderly, and the relationship of the disease to heredity. 185 adult patients (110 male; 75 female; age range, 45-89 years), a multi-were centered randomized trial of type 2 diabetes patients. The highest cause of diabetes was found with family history (70.3%), followed by advanced age (63.2%), obesity and inactivity (44.3%), psychological stress (37.3%), smoking (27.6%), Fast food (17.8%) and frequent intake of sugars (13.0%). As for complications arising from diabetes, the most common were retinopathy (56.80%), followed by nephropathy (48.10%), heart disease (43.20%), and decreased sense of the hand and feet (28.10%). The elderly citizens must raise awareness of the seriousness of diabetes complications, and urge them to reduce sugar intake, and everyone who has a family history should reduce their intake of sugars so that they do not develop diabetes.
... Hyperglycemia occurring at the onset of acute myocardial infarction seems to be related to the stress mechanism, which is recognized by high free fatty acids, steroid hormones and insulin resistance [6]. Stress hyperglycemia seems to be a protective mechanism by creating a new glucose balance, allowing a higher blood glucose diffusion gradient that increases cellular glucose uptake in the face of mal-distributed micro-vascular flow [7]. ...
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Background: Stress hyperglycemia is a common finding during acute myocardial infarction and associated with poor prognosis. To reduce the occurrence of no-reflow, prognostic factors must be identified before primary percutaneous coronary intervention (PPCI). Our objective was to investigate the impact of stress hyperglycemia in non-diabetic and diabetic patients on no-reflow phenomenon after PPCI. Methods: The study comprised 480 patients with ST elevation myocardial infarction (STEMI) who were managed by PPCI. Patients were classified into two groups according to thrombolysis in myocardial infarction (TIMI) flow grade: Group I (Patients with normal flow, TIMI 3 flow) and Group II (Patients with no-reflow, TIMI 0-2 flow). Patients were analyzed for clinical outcomes including mortality and major adverse cardiac events. Results: Incidence of stress hyperglycemia was 14.8% in non-diabetic patients and 22.2% in diabetic patients; the incidence of no-reflow phenomenon was 13.5% and no-reflow was significantly higher in patients with stress hyperglycemia. Multivariate regression analysis identified the independent predictors of no-reflow phenomenon: stress hyperglycemia OR 3.247 (CI95% 1.656-6.368, P = 0.001), Killip class >1 OR 1.893 (CI95% 1.004-3.570, P = 0.049) and cardiogenic shock OR 3.778 (CI95% 1.458-9.790, P = 0.006). Conclusion: Stress hyperglycemia was associated with higher incidence of no-reflow phenomenon. The independent predictors of no-reflow were stress hyperglycemia, Killip class >1 and cardiogenic shock.
... In recent decades, the incidence of diabetes has increased tremendously (40,41). The onset risk has presented an evident upward trend. ...
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Background Some studies have shown that, the circulating vitamin D (Vit D) concentration in the body exerts a crucial role in regulating the pancreatic β-cell function. Meanwhile, the role of magnesium is important in the synthesis of Vit D, since it is an essential element for activating Vit D. Nevertheless, there remains insufficient studies concerning whether dietary Magnesium intake influences the association between Vit D and risk of pancreatic β-cell dysfunction. Hence, this cross-sectional study aimed to assess the effect of Magnesium intake alterations on the association between serum Vit D levels and the risk of pancreatic β-cell dysfunction.Methods This large-scale cross-sectional study involves four cycles of National Health and Nutrition Examination Survey (NHANES) (2007–2014), with totally 4,878 participants. Groups were divided depending on the median daily intake of Magnesium, namely, the low intake group (Magnesium intake <267 Magnesium/d) and the high intake group (Magnesium intake ≥ 267 Magnesium/d). By constructing multiple multivariate linear and logistics regression models, the associations between serum Vit D levels and HOMA-β, as well as between serum Vit D levels and the risk of pancreatic β-cell dysfunction were explored at different Magnesium intakes.ResultsIn this cross-sectional study, the serum Vit D level is independently correlated with the HOMA-β index [β: 0.65 (0.40–0.90)] and the risk of pancreatic β-cell dysfunction [OR: 0.95 (0.92–0.98)]. Moreover, such correlations are affected by different dietary Magnesium intakes (P for interaction < 0.001).Conclusion According to the results of this study, the dietary Magnesium intake influences the associations of serum Vit D levels with HOMA-β index and pancreatic β-cell dysfunction. Besides, the finding requires validation through more RCT or cohort studies.
... Diabetes mellitus is characterized by chronic hyperglycemia and impaired carbohydrate, lipid, and protein metabolism caused by complete or partial insufficiency of insulin secretion and/or insulin action. 1 Reduction of body weight has been a key strategy in mitigating the risk of developing diabetes. 2 Amongst obese and people with prediabetes, a weight loss of 5-7% improves fasting glucose and insulin sensitivity. ...
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Aim: Intermittent fasting, a dietary intervention of alternate eating and fasting, has gained popularity in people trying to lose weight. Intermittent fasting could provide an alternative to classic caloric restriction in people with type 2 diabetes mellitus . The aim of the study is to determine the impact of a 12 weeks intermittent fasting regimen compared to usual care in people with type 2 diabetes mellitus receiving insulin therapy. Methods: This open, single-centre, randomized controlled trial investigates participants with type 2 diabetes mellitus on insulin therapy and a glycated haemoglobin A1c (HbA1c) of ≥53 mmol/mol (≥7.0 %) and a minimum insulin dose of 0.3 IU/kg body weight per day. Participants are randomized in a 1:1 ratio to either 12 weeks of intermittent fasting or the standard care group. All participants receive dietary counselling, continuous glucose monitoring (CGM), measurement of the resting metabolic rate, an oral glucose tolerance test (oGTT), body composition measurement via dual-energy x-ray absorptiometry (DXA) and stool samples for microbiome analyses at the beginning and at the end of the intervention. Two co-primary outcomes (analysed in hierarchical order) were chosen for the study: i.) the difference in the change of HbA1c from baseline to 12 weeks and ii.) the difference in the number of participants achieving a combined endpoint encompassing a body weight reduction of at least 2%, an insulin dose reduction of at least 10% and an absolute HbA1c reduction of at least 3 mmol/mol (0.3%) between the two groups.
... Impaired insulin secretion (β-cell dysfunction) and increased insulin resistance play an important role in the development of type 2 diabetes mellitus (T2DM). 1 Due to the associated micro and macro vascular complications, T2DM is recognised to have a considerable impact on morbidity, mortality and health expenditure. 2 The role of diet in the etiology of T2DM is well established, 3 and evidence shows that a diet high in flavonoids 4,5 and low in refined grains, alcohol and processed meat 4,6 is associated with a 0.53-0.89 fold lower risk of developing diabetes. ...
Article
This study provides evidence that consuming flavonoid-rich food may be protective against type 2 diabetes (T2DM) through mechanisms related to better glucose tolerance and insulin sensitivity.
... There are four classes of DM (including Type 1 diabetes mellitus, Type 2 diabetes mellitus, secondary diabetes mellitus, and gestational diabetes mellitus). Type 2 diabetes mellitus (T2DM) is the most predominant type, which accounted for more than 90% (2). Previous studies revealed that T2DM was related to cardiovascular diseases (CVD), blindness, kidney failure, periodontal disease, cancer, and even death (3,4). ...
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Background This study was designed to investigate the global emerging trends of physical activity therapy for diabetes based on a bibliometric analysis of the publications. Methods Publication papers from 2011 to 2020 were retrieved from the database of “Web of Science Core Collection” with the topic search. A number of papers, citations, authors, countries, institutions, and references were extracted. CiteSpace was used to analyze co-citation on authors, collaborations between countries and institutions, and detect the emerging trends of burst keywords and references. Results A total of 2651 publications were recruited in this study and showed an upward trend of annual publications. Diabetes obesity & metabolism (journal), the United States (country), Harvard University (institution), and Kaku K (author) published the most papers in this research field. “Impaired glucose tolerance” (2011–2012) was the highest strength burst keyword, while “cardiovascular outcome” (2017–2020) was the most burst keyword in the last 5 years. Moreover, “Standards of medical care in diabetes – 2014” was the strongest burst reference. Conclusion “Physical activity therapy for diabetes” has been accepted remarkably over the last 10 years. The keywords of “impaired glucose tolerance,” “Cardiovascular outcome,” “improves glycemic control,” “Self-management,” and exercise type including “Aerobic exercise, muscle strength” may be the latest research frontiers.
... 2,331,332 The key driving factors endorsing this epidemic are the sedentary lifestyles, genetic history, alarming upsurge in obesity, lack of physical activity, high caloric fast food-based diets, and an increasing aged population, which have magnified the onset and prevalence of T2Dm worldwide ( Figure 39). 333,334 According to the International Diabetes Federation (IDF), in 2019, ∼463 million adults of 20−80 years age had been detected with diabetes, while 1 in 3 people remain underdiagnosed and 2019 itself had seen the death of ∼4.2 million individuals caused by T2Dm only, which is likely to escalate up to 700 million by 2045. 333 India, the second largest country for diabetic patients, expects an alarming growth up to 109.0 million by 2035. ...
... Diabetes mellitus is one of the most serious metabolic diseases in the world, with a high incidence [1]. It is characterized either by insufficient insulin production or insulin resistance caused by genetic and environmental factors, such as obesity, oxidative stress, incorrect dietary components [2,3]. At present, there is a variety of antidiabetic drugs in clinical use, but most of the synthetic antidiabetic drugs have limited therapeutic efficacy and are accompanied by many side effects, such as hypoglycemia, gastrointestinal side effects, and weight gain [4,5]. ...
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Traditionally, Cymbopogon citratus is used to treat a variety of ailments, including cough, indigestion, fever, and diabetes. The previous chemical and bioactive research on C. citratus mainly focused on its volatile oil. In this study, 20 non-volatile known compounds were isolated from the dried aerial part of C. citratus, and their structures were elucidated by MS, NMR spectroscopy, and comparison with the published spectroscopic data. Among them, 16 compounds were reported for the first time from this plant. The screening results for antioxidant and α-glucosidase inhibitory activities indicated that compounds caffeic acid (5), 1-O-p-coumaroyl-3-O-caffeoylglycerol (8), 1,3-O-dicaffeoylglycerol (9) and luteolin-7-O-β-D-glucopyranoside (12) had potent antioxidant capacities, with IC50 values from 7.28 to 14.81 μM, 1.70 to 2.15 mol Trolox/mol and 1.31 to 2.42 mol Trolox/mol for DPPH, ABTS, and FRAP, respectively. Meanwhile, compounds 8 and 9 also exhibited significant inhibitory activities against α-glucosidase, with IC50 values of 11.45 ± 1.82 μM and 5.46 ± 0.25 μM, respectively, which were reported for the first time for their α-glucosidase inhibitory activities. The molecular docking result provided a molecular comprehension of the interaction between compounds (8 and 9) and α-glucosidase. The significant antioxidant and α-glucosidase inhibitory activities of compounds 8 and 9 suggested that they could be developed into antidiabetic drugs because of their potential regulatory roles on oxidative stress and digestive enzyme.
... t is evaluated that diabetes influences around 150 million individuals around the world, and this figure is expected to be multiplied in the next 20 years. Around 90-95% of all North American instances of diabetes are type 2 diabetes mellitus (T2DM), and about 20% of the populace beyond 65 years old has T2DM [1][2][3] . Around 5-10% of the aggregate social insurance spending plan has I ISSN: 2320-4850 ...
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Background: Pioglitazone is a drug that belongs to the category of thiazolidinedione (TZD) and is used for its hypoglycemic activity that is very-well associated with some serious adverse drug reactions (ADR). Previous studies have dealt with country-specific pharmacovigilance databases to assess the ADR profile of pioglitazone but none of them utilized a scholarly literature database. Objective: This study was conducted to assess the safety profile of pioglitazone in terms of expectedness, causality, and the seriousness of ADR by using a literature database. Methods: The published literature cases of pioglitazone-induced ADR from the PubMed database (between 1993 and 2020) were retrieved by using Medical Subject Headings (MeSH) terms.Only the valid cases (as per the ICH validity criteria) were analyzed. Following this, valid cases were further assessed for the expectedness of ADR by using the "Summary of Product Characteristics" document of Takeda Pharmaceuticals UK Ltd. Seriousness criteria of WHO for ADR were used for assessing the seriousness of ADR while the Naranjo's scale was used for causality assessment. Results: A total of 871 results were found of which only 26 valid ICSRs cases were found. Of the total 168 ADRs, a total of 131 (77.97%) and 37 (22.02%) unexpected and expected ADRs were found. Only two of the events were found to be non-serious and they were Iatrogenic lipomatosis and Angioneurotic edema. 1 (32.5 %), 24 (77.4 %), 6 (19.35 %) reactions were serious due to death, important medical event, and hospitalization, respectively. There were, in total, 7 (27 %) and 19 (74 %) cases that belonged to a possible and probable category, respectively. Conclusion: It is worth mentioning that pioglitazone is associated with the risk of heart failure and edema besides causing bladder cancer. The patient should be evaluated for the possible adverse effects of proper monitoring and follow-ups.
... Type 1 is less common [1,2]. Aging populations and their increased exposure to diabetes and cardiovascular disease risk factors such as smoking, overweight and obesity, physical inactivity, stress, and inadequate diet favor this meteoric rise [3][4][5][6][7][8][9]. The best weapons to fight this increasing are information and education [10,11]. ...
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Introduction: the simplified diabetes knowledge scale is used to obtain a general assessment of diabetic´s knowledge about diabetes and its care. For clinical and methodological purposes, it was relevant and necessary to develop an Arabic version of this instrument. Thus, the aim of this study was to translate and validate the Simplified Diabetes Knowmedge Scale into Arabic to measure the knowledge of Arabic-speaking diabetics. Methods: a methodological validation study of the simplified diabetes knowledge scale, following the guidelines of Vallerand was carried out. A convenience sample of diabetics followed in eight basic health centers in Sousse region and in Farhat Hached and Sahloul University Hospitals was recruited. An arabic questionnaire including the demographic and clinical data of the diabetic and the final experimental version of the simplified diabetes knowledge scale was used. Results: a sample of 333 diabetics was recruited. Content validity of the final experimental version was 0.94. Reliability assessed by Cronbach´s alpha coefficient (0.812), by test-retest correlation coefficient (> 0.60) and by internal consistency after deletion of each item (from 0.788 to 0.816) were acceptable except items 19 and 20 which had to be reformulated. Construct validity analysis identified that three items among the 20 ones (12, 17 and 20) required reformulation. Inter-item correlation matrix showed that the majority of items were not correlated with each other. Validation process was ended by establishing standards table. Conclusion: this study showed the Arabic version of the simplified diabetes knowledge scale had good validity and reliability.
... The causes of diabetes mellitus type 2 are not fully understood. The risk factors include, among others, genetic and environmental factors such as inadequate diet, lack of physical activity, and stress [3]. For this reason, the number of studies of new diagnostic and therapeutic strategies have recently increased. ...
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Nowadays, diabetes mellitus is one of the most common chronic diseases in the world. Current research on the treatment of diabetes combines many fields of science, such as biotechnology, transplantology or engineering. Therefore, it is necessary to develop new therapeutic strategies and preventive methods. A newly discovered class of lipids—Palmitic Acid Hydroxy Stearic Acid (PAHSA) has recently been proposed as an agent with potential therapeutic properties. In this research, we used an islet-on-a-chip microfluidic 3D model of pancreatic islets (pseudoislets) to study two isomers of PAHSA: 5-PAHSA and 9-PAHSA as potential regulators of proliferation, viability, insulin and glucagon expression, and glucose-stimulated insulin and glucagon secretion. Due to the use of the Lab-on-a-chip systems and flow conditions, we were able to reflect conditions similar to in vivo. In addition, we significantly shortened the time of pseudoislet production, and we were able to carry out cell culture, microscopic analysis and measurements using a multi-well plate reader at the same time on one device. In this report we showed that under microfluidic conditions PAHSA, especially 5-PAHSA, has a positive effect on pseudoislet proliferation, increase in cell number and mass, and glucose-stimulated insulin secretion, which may qualify it as a compound with potential therapeutic properties.
... While both T1D and T2D are metabolic diseases that occur when the body cannot properly convert glucose into energy, their causes, consequences and treatment vary significantly. T2D is caused by a combination of insulin deficiency and insulin resistance and is often (though not necessarily) related to obesity and lack of physical exercise (Wu et al. 2014). The disease is primarily treated through dietary restrictions, exercise regimens and light medication, with insulin treatment often being unnecessary if the patient makes sufficient lifestyle adjustments. ...
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In this study, we analyse how collective illness identities are created and sustained among people with type 1 diabetes using sociological perspectives on identity formation and symbolic boundaries. Drawing on 24 in-depth interviews, we show how collective illness identities are established and maintained through both inclusionary and exclusionary mechanisms. Informants discussed their collective illness identity by invoking common experiences and interests while also establishing experiential, biomedical and moral boundaries that distinguished them from other social groups. In particular, we highlight how the informants distanced themselves from type 2 diabetes on the basis of the latter’s status as a ‘lifestyle disease’. Our findings demonstrate the importance of boundary work for collective illness identity formation and the management of stigma, and the ambivalent relationship between illness identities and biomedical knowledge.
... Diabetes mellitus, a lifestyle-related disease that affects 8.3% of the world's adult population and is growing at an alarming rate, is one of the most prevalent non-communicable diseases due to lifestyle transitions and eating habits (Hameed et al.,2015). Diabetes mellitus (DM) is characterized by chronic hyperglycemia and impaired carbohydrates, lipids, and proteins metabolism caused by complete or partial insufficiency of insulin secretion and/or insulin action (Wu et al., 2014). Unregulated levels of blood glucose can lead to several debilitating conditions such as nephropathy, neuropathy, retinopathy, cardiovascular disease, stroke, and amputations of extremities (Sanjeevi et al.,2018). ...
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Diabetes mellitus is a metabolic disorder characterized by the presence of chronic hyperglycemia due to lack of insulin secretion, insulin action, or both. It can be immune-mediated (type 1 diabetes) or result from a combination of insulin deficiency and insulin resistance (type 2 diabetes). Hypomagnesemia has been reported with increased frequency in patients with type 2 diabetes. This electrolyte imbalance is often neglected and subcontracted. Magnesium (Mg2+) is an electrolyte of vital physiological importance in the body. It is the most abundant divalent intracellular cation in cells, the second ion after potassium, and the fourth most common cation in the human body. Magnesium is a cofactor in more than 300 enzyme systems that participates in an astonishing array of biochemical reactions in the body, including protein synthesis, muscle and nerve functions, blood glucose control, and blood pressure regulation. Magnesium is also required for energy production, oxidative phosphorylation, and glycolysis. An adult body contains approximately 25 g magnesium, with 50% to 60% present in the bones and the rest in soft tissues. Less than 1% of total magnesium is available in the blood serum. In plants, a magnesium ion is at the center of every molecule of chlorophyll, essential for creating energy from sunlight. Magnesium is an essential element for animals and plants, involved in hundreds of enzymatic reactions that affect virtually every aspect of life. Magnesium deficiency (MgD) is associated with insulin resistance (IR), induces an inflammatory response is strongly associated with stress levels, and an increased risk of type 2 diabetes. Several factors can negatively affect the balance of Mg2+ in the body and, in the long run, can result in MgD. These factors may be decreased intake of Mg2+ from food or drinking water, increased loss of Mg2+ by renal excretion, insufficient absorption of Mg2+ in the gut, and prolonged use of certain drugs causing hypomagnesemia. Magnesium supplementation or increased consumption of magnesium-rich foods may be an important tool in the therapeutic management and prevention of type 2 diabetes. In this article, I reviewed the role played by magnesium in the pathogenesis of oxidative stress, systemic inflammation, and insulin resistance.
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Persistent organic pollutants (POPs) are a diverse family of contaminants that show widespread global dispersion and bioaccumulation. Humans are continuously exposed to POPs through diet, air particles, and household and commercial products; POPs are consistently detected in human tissues, including the pancreas. Epidemiological studies show a modest but consistent correlation between exposure to POPs and increased diabetes risk. The goal of this review is to provide an overview of epidemiological evidence and an in-depth evaluation of the in vivo and in vitro evidence for POPs as potential b-cell toxins. We review evidence for 6 classes of POPs: dioxins, polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), organophosphate pesticides (OPPs), flame retardants, and per- and polyfluoroalkyl substances (PFAS). The available data provide convincing evidence implicating POPs as a contributing factor driving impaired glucose homeostasis, b-cell dysfunction, and altered metabolic and oxidative stress pathways in islets. These findings support epidemiological data showing that POPs increase diabetes risk and emphasize the need to consider the endocrine pancreas in toxicity assessments. However, our review also highlights significant gaps in the literature assessing islet-specific endpoints following both in vivo and in vitro POP exposure. In addition, most rodent studies do not consider the impact of biological sex or secondary metabolic stressors in mediating the effects of POPs on glucose homeostasis and b-cell function. We discuss key gaps and limitations that should be assessed in future studies.
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Objectives To examine the effect of aerobic and resistant exercise intervention on inflammaging in middle-aged and older adults with type 2 diabetes mellitus (T2DM) using inflammatory cytokines, such as interleukin (IL)-1 β, IL-6, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) as biomarkers. Design Systematic review and meta-analysis. Setting and Participants Middle-aged and older adults with T2DM in the community. Methods Articles were searched from 8 electronic databases. Randomized control trials (RCTs) published in English, from inception to October 31, 2021, were included in this review. Two authors conducted data extraction and quality appraisal independently following guidelines in the Cochrane Handbook for Systematic Reviews of Interventions. Meta-analysis was conducted using Review Manager. Heterogeneity was investigated using subgroup and sensitivity analysis. Results This review included 14 RCTs. The meta-analysis showed significant improvement in IL-6 (Z = 3.05; 95% confidence interval [CI]: −3.60 to −0.79; P = .002), CRP (Z = 2.44; 95% CI: −0.55 to −0.06; P = .01) and TNF-α levels (Z = 2.96; 95% CI: −2.21 to −0.45; P = .003) post-exercise programs. Subgroup analysis revealed that combined aerobic and resistance exercises and long-term exercises have more significant improvement to the outcomes than usual care. Based on the Grades of Recommendation, Assessment, Development and Evaluation system, considerable risk of bias and low level of certainty were revealed in all biomarker outcomes. Conclusions and Implications Exercise intervention is effective in improving inflammatory, metabolic, and lipid markers in middle-aged and older adults with T2DM. By modifying the levels of these markers with exercise, inflammation and insulin resistance can be improved. Long-term, combined aerobic and resistance exercise interventions have more significant effect on biomarkers. The small sample size of this meta-analysis limited the generalizability of the results. Future studies can consider adopting a more optimized exercise regimen to achieve effective T2DM management in middle-aged and older adults. Similar studies should expand to other populations and larger sample sizes to explore replicability of these effects.
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Noncommunicable diseases such as diabetes are strongly associated with the insulin resistance (IR) status of an individual. However, the prevalence of insulin resistance in Southeast Asia is poorly reported. Hence, this study investigated the prevalence of IR in Southeast Asia from the year 2016 to 2021. This study was carried out according to PRISMA guidelines. The literature search was conducted utilizing the PubMed and SCOPUS databases from the year 2016 to 2021 using the keywords ‘(insulin AND resistance) OR (insulin AND sensitivity) OR (prevalence OR incidence) AND (Malaysia OR Thailand OR Singapore OR Brunei OR Cambodia OR Indonesia OR Laos OR Myanmar OR Philippines OR Timor leste OR Vietnam)’. Funnel plot and publication bias were assessed using Egger’s tests. Data were expressed as the prevalence rate. A total of 12 studies with 2198 subjects were considered in the meta-analysis. Significant heterogeneity (I2 > 94% and p-value < 0.001) was observed in the meta-analysis. The overall prevalence of IR in Southeast Asia was 44.3%, with Malaysia having the highest prevalence rate at 50.4%, followed by Indonesia at 44.2%. No significant bias was detected in the meta-analysis. It may be that reports published before the year 2016 met the study selection criteria, but were excluded from the meta-analysis. The results from the meta-analysis indicate that the prevalence of IR in Southeast Asia is very high. This provided insights for healthcare policy makers and public health officials in designing IR screening programs.
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Diabetes mellitus is a metabolic disorder that causes health concerns worldwide. Patients with diabetes exhibit multisystemic symptoms, including loss of bone quality over time. The progressive deterioration of bone promotes failure to withstand damage and increases the risk of fractures. Much of the molecular and metabolic mechanism(s) in diabetic bone remains unclear. In vitro studies suggest that hyperglycemia inhibits mineralization, affecting bone formation and function. In this study, inhibition of osteoblast differentiation was induced using hyperglycemia to assess whether high glucose promotes mitochondrial impairment along with altered bone matrix formation. It was hypothesized that bone energy metabolism would be altered in these cells as calcium deposition, a key phase for bone function, is suppressed. Early passages of osteoblast like MC3T3-E1 cells were differentiated under normal and high glucose conditions. To investigate osteoblast differentiation, we quantified calcium accumulation by alizarin red staining and analyzed immunoblots of key proteins. To assess mitochondrial function, we quantified mitochondrial DNA (mtDNA), detected expression and function of key proteins from the Tricarboxylic (TCA) cycle, measured mitochondrial respiration, and fuel oxidation of alternative nutrients. Results confirmed previous work showing that mineralization was inhibited and AKT expression was reduced in high glucose-treated bone cells. Unexpectedly, high glucose-treated osteoblast cells utilize both mitochondrial respiration and glycolysis to maintain energy demands with partial help of fatty acid for reliance of baseline bioenergetics. These metabolic shifts suggest that hyperglycemia maintain bone metabolic needs in an early differentiated state concurrent to the inhibition in bone matrix formation.
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Great advances in type 1 diabetes (T1D) and type 2 diabetes (T2D) treatment have been made to this day. However, modern diabetes therapy based on insulin injections and cadaveric islets transplantation has many disadvantages. That is why researchers are developing new methods to regenerate the pancreatic hormone-producing cells in vitro. The most promising approach is the generation of stem cell-derived beta cells that could provide an unlimited source of insulin-secreting cells. Recent studies provide methods to produce beta-like cell clusters that display glucose-stimulated insulin secretion—one of the key characteristics of the beta cell. However, in comparison with native beta cells, stem cell-derived beta cells do not undergo full functional maturation. In this paper we review the development and current state of various protocols, consider advantages, and propose ways to improve them. We examine molecular pathways, epigenetic modifications, intracellular components, and the microenvironment as a possible leverage to promote beta cell functional maturation. A possibility to create islet organoids from stem cell-derived components, as well as their encapsulation and further transplantation, is also examined. We try to combine modern research on beta cells and their crosstalk to create a holistic overview of developing insulin-secreting systems.
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Type 2 diabetes mellitus (T2DM) is a widely prevalent chronic disease and risk factor for several other diseases, such as cardiovascular diseases, neuropathy, nephropathy, and retinopathy. Apoptosis is a homeostatic mechanism to maintain cell numbers at a certain level in tissues. Chronic high blood glucose levels might lead to mitochondrial dysfunction and trigger undesirable apoptosis in T2DM. The pineal hormone melatonin has been shown to regulate apoptosis. The aim of this study was to investigate the impact of the melatonin MT2 receptor in the role of melatonin to prevent undesirable apotosis in different tissues of diabetic rats. Male Sprague Dawley rats were randomly divided into 4 groups; 1. Control group (only vehicle), 2. Diabetic group (streptozotozin/nicotimamide treated), 3. Diabetic group treated with melatonin (500 µg/kg/day), and 4. Diabetic group treated with melatonin (500 µg/kg/day for 6 weeks) and the selective MT2 receptor antagonist luzindole (0.25 g/kg/day for 6 weeks). Various tissue samples (kidney, liver, adipose tissue, pancreas) were removed after 6 weeks for immunohistochemistry and western blot analysis. Our results demonstrated an increased rate of apoptosis in different tissues of diabetic rats compared to controls with melatonin reducing the apoptotic rate in the tissues of rats with T2DM. Furthermore, the anti-apoptotic effects of melatonin were partly mediated by the melatonin MT2 receptor.
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The prevalence of Diabetes Mellitus (DM) is still high. DM can cause changes in lipid profiles such as hypercholesterolemia, hypertriglyceridemia, and increased LDL levels. This study aimed to test the ability of kapok banana peel extract in reducing glucose, triglyceride, and LDL cholesterol levels in streptozotocine-induced Rattus norvegicus. This type of research is an experimental design with pre and post-test control design. Twenty-five male subjects were Rattus norvegicus. Data were analyzed by the Wilcoxon test, Kruskal Wallis test, and Mann Whitney test. The length of the study was 21 days. The results of the analysis of the use of banana peel extract can reduce levels of glucose, triglycerides, and LDL cholesterol (p= 0.025, p = 0.043, p=0.043). Kepok banana peel extract has the potential as antihyperglycemic and antilipidemic in diabetic rats.
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Background Diabetes mellitus (DM) is one of the most defying health risk in the twenty-first century promoting a high rate of morbidity and mortality that could possibly increase if no intervention is in place. However, drugs for curing DM are available but are associated with adverse side effect necessitating the pursuit for a safe antidiabetic drugs. The present study was conducted in order to develop a QSAR model that would be used to predict the activities of salicylic acid derivatives, as well as to determine the binding interactions of the compounds with α-glucosidase using molecular docking studies. Results Model one was selected and reported as the best model based on its fitness with the following validation keys: R ² (trng set) = 0.968, R ² (adj) = 0.957, Q ² (cv) = 0.932, LOF = 0.085 and R ² (test set) = 0.864. Five potent analogues were designed using the ligand-based method with their predicted activities been calculated and found to be higher compared to the lead compound. Furthermore, binding interactions of the designed analogues within the active site of α -glucosidase (pdb id:3L4V) illustrate a good binding affinities than kotalanol and acarbose. However, the ADMET and drug-likeness properties predicted the design analogues to be pharmacologically and orally safe by not having more than one violation of Lipinski’s (Ro5) criteria. Conclusions The present findings therefore showed that the salicylic acid derivatives could serve as α -glucosidase inhibitors. The compounds can be studied further for a hunts of promising drug candidates against diabetes mellitus.
Article
Background: A novel scoring system called Non-invasive Diabetes Score (NDS) was developed. The model showed prominent discrimination and calibration in the original study population. However, before a new model could be adopted in clinical practice and acquire widespread use, it is necessary to confirm that it also performs well in external validations in different settings of people. The aim of this study was to investigate whether the novel user-friendly score predicting diabetes mellitus (DM) could have satisfying performance in predicting DM in Southwest China in a 15-year prospective cohort study. Methods: This prospective cohort study was carried out based on a general Chinese population of 711 individuals from 1992 to 2007. We excluded 24 of them at baseline because they were diabetics. The end point was DM, and the risk was calculated using the model formula. Results: During a follow-up of 15 years, 74 (10.77%) patients reached the end point. Evaluation of this model in our cohort, with Harrell's C-index of 0.662 (95% CI: 0.600-0.723) for the whole cohort and 0.695 (95% CI: 0.635-0.756) in sensitivity analysis, indicated the possibly helpful discrimination. The calibration capability in our cohort was useful that the observed incidence of diabetes mellitus was near the predicted. Conclusions: Our external validation suggested NDS had possibly helpful discrimination and satisfying calibration for predicting DM during 15-year follow-up.
Thesis
L’hyperglycémie chronique est impliquée dans le développement de complications associées au DT2 et la variabilité glycémique (VG) apparait comme une composante à part entière de l'homéostasie du glucose. Les mesures hygiéno-diététiques, en première ligne dans la prise en charge du DT2, passent entre autres par une modification de l’alimentation, dans laquelle les glucides occupent une place prépondérante. Au-delà de la quantité, la qualité des glucides a été mise en avant comme ayant un impact déterminant sur les excursions glycémiques. Notamment, la digestibilité des produits à base d’amidon pourrait alors avoir un impact sur le contrôle glycémique chez les patients atteints de DT2. Mais il y a aujourd’hui un réel besoin d’apporter une caractérisation des produits plus complète sur cet aspect et de mener des études de faisabilité et d’efficacité de tels régimes modulant la digestibilité de l’amidon. Mes travaux de thèse montrent qu’il est possible de concevoir un régime riche en amidon lentement digestible (SDS), grâce à des choix de produits amylacés disponibles dans le commerce, des conseils de cuisson et des recommandations adaptées. Pour la première fois, nous avons montré que le contrôle de la digestibilité de l'amidon de produits amylacés avec des instructions de cuisson appropriées dans une population atteinte de DT2 augmentait la consommation de contenu en SDS dans un contexte de vie réelle et que ce type de régime était bien accepté dans telle population. De plus, nous avons montré que l’augmentation du rapport SDS/glucides était associée à une amélioration du contrôle glycémique postprandial et qu’il existait une corrélation linéaire inverse entre les paramètres de VG et la teneur en SDS. La mise en œuvre d’un régime riche en amidon lentement digestible dans une population atteinte de DT2, a montré une différence significative sur le profil de variabilité glycémique, mais également sur les excursions glycémiques postprandiales, évalués par le CGMS, en comparaison avec un régime pauvre en amidon lentement digestible. Ce type de régime a également permis aux patients d’atteindre des cibles glycémiques postprandiales plus appropriées. Grâce à un travail de revue de la littérature, nous avons mis en évidence que la déviation standard (SD), le coefficient de variation (CV), l’amplitude moyenne des excursions glycémiques (MAGE) et la moyenne glycémique (MBG) étaient les paramètres de VG les plus étudiés en termes de relation avec les paramètres de diagnostic du DT2 et les complications liées au DT2 et qu’ils montraient des relations fortes, en particulier avec l’HbA1c. Dans les études interventionnelles, nous avons pu voir que la SD, le MAGE et le temps dans la cible (TIR) étaient les paramètres les plus utilisés comme critères d’évaluation, montrant des améliorations significatives suite aux interventions pharmacologiques ou nutritionnelles, souvent en lien avec des paramètres de contrôle glycémique comme l’HbA1c, la glycémie à jeun ou en postprandial. La VG apparaît donc comme une composante clé de la dysglycémie du DT2. Au-delà de son utilisation par le patient comme support du contrôle glycémique, le CGMS apparait comme un outil pertinent en recherche clinique pour évaluer l’efficacité des interventions même si à ce jour, il reste encore très peu utilisé pour les interventions nutritionnelles. Des études plus approfondies seront cependant nécessaires pour confirmer l'impact bénéfique de telles interventions alimentaires à long terme. Nous avons conçu une étude à plus grande échelle pour étudier l'impact à long terme d’un régime riche en SDS sur la variabilité et le contrôle glycémiques (CGMS) et les complications et comorbidités associées chez le patient atteint de DT2. La modulation de la digestibilité de l'amidon dans l'alimentation pourrait alors être utilisée comme un outil nutritionnel simple et approprié pour améliorer l'homéostasie glucidique au quotidien dans le DT2.
Article
Background: This study aimed to determine the rate, timing, and predictors of diabetes and exocrine pancreatic insufficiency after pancreatectomy in order to inform preoperative patient counseling and risk management strategies. Methods: Using prescription claims as a surrogate for disease prevalence, IBM Watson Health MarketScan was queried for claims patterns pre- and post-pancreatectomy. Multivariable models explored associations between clinical characteristics and medication use within 2 years of surgery. Results: In total, 18.96% of 2,848 pancreaticoduodenectomy (PD) patients and 18.95% of 1,858 distal pancreatectomy (DP) patients had preoperative diabetic medication prescription claims. Fewer (6.6% and 3.88%, respectively) had pancreatic enzyme replacement therapy (PERT) claims. Diabetic medication claims increased to 28.69% after PD and 38.59% after DP [adjusted relative risk (aRR) = 1.36 (95% CI 1.27, 1.46)]. Other associated factors included age > 45, medical comorbidity, and obesity. The incidence of new diabetic medication claims among medication naïve patients was 13.78% for PD and 24.7% for DP (p < 0.001) with a median 4.7 and 4.9 months post-operatively. The prevalence of PERT claims was 55.97% after PD and 17.06% after DP [aRR = 0.32 (0.29, 0.36)]. The incidence of postoperative PERT claims 53.98% (PD) and 14.84% (DP) (p < 0.0001). The median time to new PERT claim was 3.0 (PD) and 3.2 (DP) months, respectively. Claims for both diabetic medications and PERT rose sharply after surgery and plateaued within 6 months. Conclusions: This study defines prevalence, timing, and predictors for post-pancreatectomy insufficiency to inform preoperative counseling, risk modification strategies, and interventions related to quality of life.
Article
Background and aims Controlling glycemic levels is crucial for patients with diabetes mellitus to improve their disease management and health outcomes. Beyond lifestyle modification and pharmacotherapy, some supplements have been shown to lower blood glucose as well as mitigate diabetic complications. Methods Information was primarily gathered by employing various PubMed scholarly articles for real-world examples in addition to data extraction from supplementary manuscripts. Only original human trials were used, and those published within the past two decades were primarily chosen. However, background information may contains review articles. Results Some non-herbal supplements have been suggested to lower fasting blood glucose, postprandial glucose, glycated glucose (HbA1c), lipid profiles, oxidative stress, and inflammation, as well as improving body composition, insulin sensitivity, blood pressure, and nephropathy. Conclusion This review discusses ten non-herbal supplements that have been reported to have beneficial effects among different types of patients with diabetes as well as potiential future clinical application. However, more long-term studies with a larger amount and more diverse participants need to be conducted for a robust conclusion. Also, mechanisms of action of antidiabetic effects are poorly understood and need further research.
Article
Background And Objectives: Systemic Hypertension (HTN) is one of the most common co-morbidities in Diabetes Mellitus (DM). It has been suggested that ambulatory blood pressure monitoring (ABPM) be used for hypertension assessment. Hence the present study was carried out to estimate the prevalence of hypertension in normotensive type 2 diabetic patients by using a 24-hour ambulatory blood pressure machine and also to assess the relationship between blood pressure patterns and anthropometric measurements. Materials And Methods: A 1-year cross-sectional hospital-based study was conducted on 162 people, over the age of 18, who had type 2 diabetes and a Body Mass Index (BMI) of 25 to 40 kg/m2). All subjects underwent a standardized medical examination including anthropometric measurements, laboratory investigations and 24-hour ambulatory blood pressure monitoring. Descriptive analysis was carried out by mean and standard deviation for quantitative variables, frequency, and proportion for categorical variables. P value <0.05 was considered statistically signicant. Results: The mean all day SBP was 133.66 ± 13.53 mm/hg while the mean all day DBP was 76.45 ± 10.99 mm/hg. The prevalence of HTN as measured by all day SBP was 77.78% while it was 42.59% for all day DBP. Systolic non-dipping was seen in 93.39% of overweight and 90.24% of obese subjects as classied by BMI, respectively. Diastolic non-dipping was seen in 76.86% of overweight and 73.17% of obese subjects. There was a statistically signicant association between all-day SBP/DBP, day SBP/DBP with BMI in males and in females, there was a statistically signicant association between all day SBP and day SBP with BMI. Conclusion: Patients with T2DM can benet from routineABPM by early identication and management of Hypertension in Type 2 DM
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The purpose of this work is to design a suitable and environmentally friendly approach for synthesizing Selenium NPs from aqueous flower extract of cassica auriculata ([email protected]) and to assess the extract for anti-microbial, antioxidant, and anti-diabetic behaviour. The [email protected] nanoparticles were characterised using UV–vis spectrophotometer, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and energy dispersive X-ray spectroscopy (EDX), High transmission electron microscopy (HRTEM) and Atomic microscopy analysis (AFM). The findings revealed that the synthesised particles were globular and nanoscale in size. The particles have elevated amounts of a-amylase and a-glucosidase inhibitory effects, according to the in vitro antidiabetic functions research. Furthermore, it had higher antioxidant activity and lower cytotoxicity. The green synthesised selenium nanoparticles were proved to be a promising phyto-medicine for the diabetes mellitus.
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Diabetic kidney disease (DKD) is the most common cause of renal failure and a major contributor to the socioeconomic burden in chronic kidney disease (CKD) patients worldwide. The pathogenesis of DKD involves all the structures in the nephron, and it is indicated by proteinuria, hypertension, and progressive decline in renal function, leading to substantial morbidity and mortality. Due to the limitations of currently available standard markers (albuminuria and glomerular filtration rate) in the diagnosis and clinical grading of DKD, it’s time to have novel biomarkers for early detection, targeted and effective therapy to prevent the progression. Microparticles (MPs) are extracellular vesicles measuring 0.1 to 1 micron derived by cytoskeletal reorganization in the form of cytoplasmic blebs which alters the phospholipid cytochemistry of the cell membrane. They are shed during cell activation and apoptosis as well as plays an important role in cell-to-cell communication. Over the last few decades, both plasma and urinary MPs have been investigated, validated and the preliminary research looks promising. With alterations in their number and composition documented in clinical situations involving both Type1 and 2 diabetes mellitus, microparticles assay appears to be promising in early diagnosis and prognostication of DKD. We cover the basics of microparticles and their involvement in DKD in this review article.
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Objective This study aimed to investigate the serum irisin levels and diet quality of newly-diagnosed type 2 diabetes mellitus (T2DM) patients in comparison with healthy controls and to identify the correlations between serum irisin levels with diet quality, anthropometric measurements and biochemical parameters. Subjects/methods This case–control study was conducted with 38 newly-diagnosed T2DM patients and 38 healthy control individuals. Diet quality was calculated from the semi-quantitative food frequency questionnaire by using the Healthy Eating Index (HEI) 2015. The anthropometric measurements were taken and body composition was analyzed with bioelectric impedance analysis (BIA) method. Biochemical parameters and serum irisin levels were analyzed in blood samples which were obtained after overnight fasting. Results Irisin levels were higher in the T2DM group compared to the healthy control group (2.57 ± 0.44 ng/mL and 2.15 ± 0.44 ng/mL, respectively; p < 0.001). The optimal cut-off value for irisin to predict T2DM was 2.195 ng/mL (specificity = 71.1%, sensitivity = 78.9%). In both groups, irisin levels were not associated with overall HEI 2015; however, they were positively associated with total and whole fruit scores in the T2DM group (p < 0.05). After adjustment according to age, sex and BMI, in the T2DM group HDL cholesterol positively affected by irisin levels, while in the control group triglyceride positively affected irisin levels (p < 0.05). Conclusion High levels of irisin in newly diagnosed T2DM patients compared to healthy individuals indicate that irisin may have a role in the monitoring and treatment of T2DM. Though irisin levels were not associated with total diet quality, they were associated with fruit consumption.
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Introduction: The clinical benefits of insulin glargine 300 U/mL (Gla-300) have been confirmed in randomised clinical trials (EDITION programme and BRIGHT) and real-world studies in the USA and Western Europe. ATOS evaluated the real-world effectiveness and safety of Gla-300 in wider geographic regions (Asia, the Middle East, North Africa, Latin America and Eastern Europe). Methods: This prospective observational, international study enrolled adults (≥ 18 years) with type 2 diabetes mellitus (T2DM) uncontrolled [haemoglobin A1c (HbA1c) > 7% to ≤ 11%] on one or more oral anti-hyperglycaemic drugs (OADs) who had been advised by their treating physician to add Gla-300 to their existing treatment. The primary endpoint was achievement of a pre-defined individualised HbA1c target at month 6. Results: Of the 4550 participants included, 4422 (51.8% female) were eligible for assessment. The mean ± standard deviation (SD) age was 57.2 ± 10.8 years, duration of diabetes was 10.2 ± 6.2 years and baseline HbA1c was 9.28 ± 1.0%. The proportion of participants reaching their individualised glycaemic target was 25.2% [95% confidence interval (CI) 23.8-26.6%] at month 6 and 44.5% (95% CI 42.9-46.1%) at month 12. At months 6 and 12, reductions were observed in HbA1c (-1.50% and -1.87%) and fasting plasma glucose (-3.42 and -3.94 mmol/L). Hypoglycaemia incidence was low, and body weight change was minimal. Adverse events were reported in 283 (6.4%) participants, with 57 (1.3%) experiencing serious adverse events. Conclusion: In a real-world setting, initiation of Gla-300 in people with T2DM uncontrolled on OADs resulted in improved glycaemic control and low rates of hypoglycaemia with minimal weight change. Trial registration: Clinicaltrials.gov number NCT03703869.
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We previously reported that the canonical Wnt signaling pathway is activated during compensatory islet hyperplasia in prediabetic mice. Here, we aimed to expand our knowledge concerning the Wnt signaling partners and counter partners involved in this process. We report here that Axin1, Axin2, and DACT1, inhibitors of the canonical Wnt signaling pathway, displayed no change in their expression, while GSK-3β, a multi-functional kinase that acts as a negative regulator of this pathway as well as affects insulin secretion/action, was up-regulated in hyperplastic islets of prediabetic mice. We also observed that COUP-TFII, a protein that acts positively on Wnt-target genes related to cell proliferation, displays a significant increase in gene expression and protein content and is highly immunolabeled in islet cell nuclei of prediabetic mice compared to control islets. These findings suggest that GSK-3β and COUP-TFII may play a role in beta-cell dysfunction and hyperplasia during type 2 prediabetes.
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Background Increasing evidence shows that genetic variants of genes in the diabetes mellitus (DM) metabolic pathway, such as the vitamin D receptor (VDR) gene rs739837 polymorphism, increase the risk of DM susceptibility. However, the findings have been inconsistent. The present study was performed to evaluate the association of VDR gene rs739837 and type 2 diabetes (T2DM) or gestational diabetes mellitus (GDM) risk. Methods A comprehensive meta-analysis and a subgroup analysis were conducted to assess the association between VDR rs739837 and T2DM or GDM among five genetic models (dominant, recessive, homozygote heterozygote, and allele models) using a fixed or random model. Results The meta-analysis included 9 studies. In the overall analysis, the results showed that VDR rs739837 was associated with an increased risk of T2DM or GDM in the allele model (T vs. G: OR = 1.088; 95% CI: 1.018–1.163; P = 0.012) and dominant model (TT + GT vs. GG: OR = 1.095; 95% CI: 1.001–1.197; P = 0.047). In the subgroup analysis, VDR rs739837 was also associated with an increased risk of T2DM in the allele model (T vs. G: OR = 1.159; 95% CI: 1.055–1.273; P = 0.002) and dominant model (TT + GT vs. GG: OR = 1.198; 95% CI: 1.048–1.370; P = 0.008). However, VDR rs739837 was not associated with GDM. Conclusions Significant associations were found between the VDR rs739837 polymorphism and T2DM susceptibility, but not with GDM.
Article
The present study investigated the effect of apple consumption on postprandial blood glucose and insulin levels in subjects with normal versus impaired glucose tolerance. The study participants were ten healthy subjects with no glucose intolerance (normal subjects) (mean, 24.4 ± 4.8 years) and nine subjects with impaired glucose tolerance (mean, 45.2 ± 11.1 years, including 2 on insulin therapy). The test meal included white rice (148 g) and a Fuji apple (150 g). The normal subjects were randomly divided into two groups: the apple-first group, wherein the subjects consumed white rice 5 min after consuming the apple, and the rice-first group, wherein the subjects consumed an apple 5 min after consuming the white rice. Blood samples were then taken from both groups for 3 h. In addition, the subjects with impaired glucose tolerance received the same treatment as the normal subjects, with the difference being glucose level monitoring according to the order in which the apples were consumed. In the normal subjects, the Cmax of Δblood glucose and Δinsulin levels were 54.0 ± 5.0 mg/dL and 61.9 ± 7.2 µU/dL versus 46.2 ± 5.9 mg/dL and 49.8 ± 8.5 µU/dL in the rice-first and apple-first groups, respectively. The incremental area under the curve (iAUC) of insulin tended to decrease in the apple-first group. In the impaired glucose tolerance subjects, the Cmax of Δblood glucose was 75.2 ± 7.2 mg/dL in the apple-first group compared to 90.0 ± 10.0 mg/dL in the rice-first group, which was a significant difference (p < 0.05). The iAUC of blood glucose was lower in the apple-first group. Eating an apple before a meal may be a simple and effective strategy for managing the glycaemic response in individuals with impaired glucose tolerance.
Article
Type 2 diabetes (T2D) is caused by genetic and environmental factors as well as gene‐environment interactions. However, these interactions have not been systematically investigated. We analyzed these interactions for T2D and fasting glucose levels in three Korean cohorts, HEXA, KARE, and CAVAS, using the baseline data with a multiple regression model. Two polygenic risk scores for T2D (PRST2D) and fasting glucose (PRSFG) were calculated using 488 and 82 single nucleotide polymorphisms (SNP) for T2D and fasting glucose, respectively, which were extracted from large‐scaled genome‐wide association studies with multiethnic data. Both lifestyle risk factors and T2D‐related biochemical measurements were assessed. The effect of interactions between PRST2D‐triglyceride (TG) and PRST2D‐total cholesterol (TC) on fasting glucose levels was observed as follows: β ± SE = 0.0005 ± 0.0001, p = 1.06 × 10−19 in HEXA, β ± SE = 0.0008 ± 0.0001, p = 2.08 × 10−8 in KARE for TG; β ± SE = 0.0006 ± 0.0001, p = 2.00 × 10−6 in HEXA, β ± SE = 0.0020 ± 0.0004, p = 2.11 × 10−6 in KARE, β ± SE = 0.0007 ± 0.0004, p = 0.045 in CAVAS for TC. PRST2D‐based classification of the participants into four groups showed that the fasting glucose levels in groups with higher PRST2D were more adversely affected by both the TG and TC. In conclusion, blood TG and TC levels may affect the fasting glucose level through interaction with T2D genetic factors, suggesting the importance of consideration of gene‐environment interaction in the preventive medicine of T2D.
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Aims The objective of this scoping review is to synthesize all of the known information about the relationship between diabetes mellitus and voice quality and to explore its potential applications for new technology Methods We conducted a scoping literature review of articles published between March 2000 and September 2021 using the following databases: PubMed, Web of Science, Scopus, and Embase. Additionally, we did a manual search of Google Scholar. The search strategy abides by the PRISMA-ScR guidelines. Studies pertaining to the relationship between diabetes and the voice were categorized separately for further evaluation. Results Out of the 2732 originally identified articles, nine were ultimately included in this scoping review. The chosen articles address both diabetes and its impact on a variety of vocal parameters. Conclusions There is currently very little research investigating the relationship between diabetes, neuropathy, and phonatory symptoms. Additionally, existing publications contain some contradictory findings. Further research that incorporates imaging technology is needed to clarify the physiological explanations for the differences observed between healthy individuals and those with diabetes mellitus. Such information can be used to develop noninvasive technology for diabetes diagnosis and monitoring.
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Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.
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Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
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GPR 40 is a free fatty acid receptor that has been shown to regulate glucose-dependent insulin secretion. This study aimed to discover novel GPR40 agonists and investigate the whole body effect on glucose metabolism of GPR40 activation using these novel GPR40 agonists. To identify novel GPR40-specific agonists, we conducted high-throughput chemical compound screening and evaluated glucose-dependent insulin secretion. To investigate the whole body effect on glucose metabolism of GPR40 activation, we conducted repeat administration of the novel GPR40 agonists to diabetic model ob/ob mice and evaluated metabolic parameters. To characterize the effect of the novel GPR40 agonists more deeply, we conducted an insulin tolerance test and a euglycemic-hyperinsulinaemic clamp test. As a result, we discovered the novel GPR40-specific agonists including AS2034178 and found that its exhibited glucose-dependent insulin secretion enhancement both in vitro and in vivo. In addition, the compounds also decreased plasma glucose and HbA1c levels after repeat administration to ob/ob mice, with favorable oral absorption and pharmacokinetics. Repeat administration of AS2034178 enhanced insulin sensitivity in an insulin tolerance test and a euglycemic-hyperinsulinaemic clamp test. These results indicate that improvement of glucose-dependent insulin secretion leads the improvement of whole-body glucose metabolism chronically. In conclusion, AS2034178 and other GPR40 agonists may become useful therapeutics in the treatment of type 2 diabetes mellitus.
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The prevalence of type 2 diabetes (T2D) is increasing worldwide and creating a significant burden on health systems, highlighting the need for the development of innovative therapeutic approaches to overcome immune dysfunction, which is likely a key factor in the development of insulin resistance in T2D. It suggests that immune modulation may be a useful tool in treating the disease. In an open-label, phase 1/phase 2 study, patients (N = 36) with long-standing T2D were divided into three groups (Group A, oral medications, n = 18; Group B, oral medications + insulin injections, n = 11; Group C having impaired beta-cell function with oral medications + insulin injections, n = 7). All patients received one treatment with the Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, briefly co-cultures them with adherent cord blood-derived multipotent stem cells (CB-SCs), and returns the educated autologous cells to the patient's circulation. Clinical findings indicate that T2D patients achieve improved metabolic control and reduced inflammation markers after receiving Stem Cell Educator therapy. Median glycated hemoglobin (HbA1C) in Group A and B was significantly reduced from 8.61% +/- 1.12 at baseline to 7.25% +/- 0.58 at 12 weeks (P = 2.62E-06), and 7.33% +/- 1.02 at one year post-treatment (P = 0.0002). Homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) demonstrated that insulin sensitivity was improved post-treatment. Notably, the islet beta-cell function in Group C subjects was markedly recovered, as demonstrated by the restoration of C-peptide levels. Mechanistic studies revealed that Stem Cell Educator therapy reverses immune dysfunctions through immune modulation on monocytes and balancing Th1/Th2/Th3 cytokine production. Clinical data from the current phase 1/phase 2 study demonstrate that Stem Cell Educator therapy is a safe approach that produces lasting improvement in metabolic control for individuals with moderate or severe T2D who receive a single treatment. In addition, this approach does not appear to have the safety and ethical concerns associated with conventional stem cell-based approaches.Trial registrationClinicalTrials.gov number, NCT01415726.
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The glucagon-like peptide (GLP)-1 receptor agonist lixisenatide (Lyxumia(®)) was approved for marketing by the European Medicines Agency in February 2013 and has been evaluated in a clinical study program called GetGoal. Lixisenatide activates the GLP-1 receptor and thereby exercises the range of physiological effects generated by GLP-1, which consist of increased insulin secretion, inhibition of glucagon secretion, and decreased gastrointestinal motility alongside the promotion of satiety. In the GetGoal study program, lixisenatide demonstrated significant reductions in glycated hemoglobin (HbA1c), and fasting and postprandial plasma glucose compared with placebo. The effect on glycemia was evident, with both monotherapy and in combination with insulin and various oral antidiabetic agents. Furthermore, a general trend towards reduced bodyweight was reported. In head-to-head trials with the other GLP-1 receptor agonists (exenatide and liraglutide) on the market, lixisenatide demonstrated a superior effect with respect to reduction in postprandial plasma glucose and had a tendency towards fewer adverse events. However, lixisenatide seemed to be less efficient or at best, equivalent to exenatide and liraglutide in reducing HbA1c, fasting plasma glucose, and bodyweight. The combination of a substantial effect on postprandial plasma glucose and a labeling with once daily administration separates lixisenatide from the other GLP-1 receptor agonists. The combination of basal insulin, having a lowering effect on fasting plasma glucose, and lixisenatide, curtailing the postprandial glucose excursions, makes sense from a clinical point of view. Not surprisingly, lixisenatide is undergoing clinical development as a combination product with insulin glargine (Lantus(®)). At present the main place in therapy of lixisenatide seems to be in combination with basal insulin. A large multicenter study will determine the future potential of lixisenatide in preventing cardiovascular events and mortality, in patients with type 2 diabetes and recent acute coronary syndrome.
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Implication for health policy/practice/research/medical education: New strategies need to be examined for treatment of type 2 diabetes. Current evidences show that nitrate/nitrite therapy could be considered as a new treatment for type 2 diabetes, however further researches are needed to explore the issue.
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Vildagliptin is a selective and potent dipeptidyl peptidase-4 inhibitor that improves glycemic control by inhibiting the degradation of both endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. This article is a comprehensive review of the safety and efficacy of vildagliptin in patients with type 2 diabetes. Clinical evidence has proven that it effectively decreases hemoglobin A1c with a low risk of hypoglycemia and is weight neutral. The addition of vildagliptin to metformin improves glucose control and significantly reduces gastrointestinal adverse events, particularly in patients inadequately controlled with metformin monotherapy. Its long-term advantages include preservation of β-cell function, reduction in total cholesterol, decrease in fasting lipolysis in adipose tissue, and triglyceride storage in non-fat tissues. Vildagliptin is well tolerated with a low incidence of AEs, and it does not increase the risk of cardiovascular/cerebrovascular (CCV) events. It can be taken before or after meals, and has little drug interaction, thus it will be well accepted.
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Several studies have been conducted in recent years to evaluate the risk of type 2 diabetes mellitus (T2DM) and polymorphisms of interleukin (IL)-10. However, the results remain conflicting rather than conclusive. This meta-analysis aimed to summarize the current evidence from case-control studies that evaluated this association. We carried out a search in Medline, EMBASE, and the Chinese National Knowledge Infrastructure (CNKI) database for relevant studies. Data were extracted using a standardized form and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association. 10 studies were included in our meta-analysis and systemic review. Our meta-analysis indicated that IL-10 -1082A/G polymorphism was associated with the risk of T2DM (GA vs. AA: OR = 1.21, 95% CI = 1.03-1.14; GA/GG vs. AA: OR = 1.22, 95% CI = 1.05-1.41), whereas there was no association between IL-10 -592C/A (CC/CA vs. AA: OR = 1.07, 95% CI = 0.59-1.93) or -819C/T (CC/CT vs. TT: OR = 0.93, 95% CI = 0.49-1.75) polymorphism and T2DM risk was found in our study. This meta-analysis provides strong evidence that IL-10 -1082A/G polymorphism associated with risk of T2DM. However, no association of the IL-10 -592C/A or -819C/T polymorphism with T2DM risk was found. Additional well-designed large studies were required for the validation of our results.
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BACKGROUND: Despite the favorable effects of behavior change interventions on diabetes risk, lifestyle modification is a complicated process. In this study we therefore investigated opportunities for refining a lifestyle intervention for type 2 diabetes prevention, based on participant perceptions of behavior change progress. METHODS: A 30 month intervention was performed in Dutch primary care among high-risk individuals (FINDRISC-score >= 13) and was compared to usual care. Participant perceptions of behavior change progress for losing weight, dietary modification, and increasing physical activity were assessed after18 months with questionnaires. Based on the response, participants were categorized as 'planners', 'initiators' or 'achievers' and frequencies were evaluated in both study groups. Furthermore, participants reported on barriers for lifestyle change. RESULTS: In both groups, around 80% of all participants (intervention: N = 370; usual care: N = 322) planned change. Except for reducing fat intake (p = 0.08), the number of initiators was significantly higher in the intervention group than in usual care. The percentage of achievers was high for the dietary and exercise objectives (intervention: 81--95%; usual care: 83--93%), but was lower for losing weight (intervention: 67%; usual care: 62%). Important motivational barriers were 'I already meet the standards' and 'I'm satisfied with my current behavior'. Temptation to snack, product taste and lack of time were important volitional barriers. CONCLUSIONS: The results suggest that the intervention supports participants to bridge the gap between motivation and action. Several opportunities for intervention refinement are however revealed, including more stringent criteria for participant inclusion, tools for (self)-monitoring of health, emphasis on the 'small-step-approach', and more attention for stimulus control. Trial registration: Netherlands Trial Register: NTR1082.
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The global epidemic of type 2 diabetes mellitus (T2D) is one of the most challenging problems of the 21(st) century leading cause of and the fifth death worldwide. Substantial evidence suggests that T2D is a multifactorial disease with a strong genetic component. Recent genome-wide association studies (GWAS) have successfully identified and replicated nearly 75 susceptibility loci associated with T2D and related metabolic traits, mostly in Europeans, and some in African, and South Asian populations. The GWAS serve as a starting point for future genetic and functional studies since the mechanisms of action by which these associated loci influence disease is still unclear and it is difficult to predict potential implication of these findings in clinical settings. Despite extensive replication, no study has unequivocally demonstrated their clinical role in the disease management beyond progression to T2D from impaired glucose tolerance. However, these studies are revealing new molecular pathways underlying diabetes etiology, gene-environment interactions, epigenetic modifications, and gene function. This review highlights evolving progress made in the rapidly moving field of T2D genetics that is starting to unravel the pathophysiology of a complex phenotype and has potential to show clinical relevance in the near future.
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In the near future, the majority of patients with diabetes will be adults aged 65 or older. Unlike young adults with diabetes, elderly diabetic people may be affected by a variety of comorbid conditions such as depression, cognitive impairment, muscle weakness (sarcopenia), falls and fractures, and physical frailty. These geriatric syndromes should be considered in the establishment of treatment goals in older adults with diabetes. Although there are several guidelines for the management of diabetes, only a few are specifically designed for the elderly with diabetes. In this review, we present specific conditions of elderly diabetes which should be taken into account in the management of diabetes in older adults. We also present advantages and disadvantages of various glucose-lowering agents that should be considered when choosing a proper regimen for older adults with diabetes.
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There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined 2,000 individuals for each of 7 major diseases and a shared set of 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 10-7: 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10-5 and 5 10-7) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.
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Despite the number of medications for type 2 diabetes, many people with the condition do not achieve good glycaemic control. Some existing glucose-lowering agents have adverse effects such as weight gain or hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most patients require treatment with combinations of glucose-lowering agents. The sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of glucose-lowering agents. To assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. MEDLINE, Embase, Cochrane Library (all sections); Science Citation Index; trial registries; conference abstracts; drug regulatory authorities; bibliographies of retrieved papers. Randomised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy. Systematic review. Quality assessment used the Cochrane risk of bias score. Seven trials, published in full, assessed dapagliflozin and one assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced HbA1c by -0.54% (weighted mean differences (WMD), 95% CI -0.67 to -0.40) compared to placebo, but there was no difference compared to glipizide. Canagliflozin reduced HbA1c slightly more than sitagliptin (up to -0.21% vs sitagliptin). Both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD -1.81 kg (95% CI -2.04 to -1.57), canagliflozin up to -2.3 kg compared to placebo). Long-term trial extensions suggested that effects were maintained over time. Data on canagliflozin are currently available from only one paper. Costs of the drugs are not known so cost-effectiveness cannot be assessed. More data on safety are needed, with the Food and Drug Administration having concerns about breast and bladder cancers. Dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed.
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... 8. Ludwig DS, Peterson KE, Gortmaker SL. Relation between consumption of sugar - sweetened drinks and childhood obesity : a prospective, observational analysis. Lancet. 2001;357:505-508.pmid:11229668. ...
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Type 2 diabetes is a rapidly growing public health issue with a major impact on morbidity and premature mortality worldwide (1). The recent increase in the prevalence of this disease is largely attributable to environmental factors; however, convincing evidence shows that genetic factors also play an important role in causing type 2 diabetes (2, 3). Initial efforts to identify type 2 diabetes susceptibly genes favored genome-wide linkage and candidate gene association studies. These approaches identified common single nucleotide polymorphisms (SNPs) in PPARG, KCNJ11, and TCF7L2, which have been widely replicated in populations of various ethnicity (4 – 6). The advent of genome-wide association studies promises more efficient identification of susceptibility genes. Recent genome-wide association studies have discovered several new potential loci, including HHEX, CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and WFS1 (7–14). Variants in FTO and MC4R were also associated with type 2 diabetes, but the associations were entirely mediated by body mass index (BMI) (15, 16). Given our growing knowledge of the genetic factors that predispose to type 2 diabetes and the decreasing costs of genotyping, genetic screening for persons at high risk for type 2 diabetes has received considerable attention. The risk attributable to an individual variant is modest and unlikely to have important clinical utility. However, a combination of the major genetic factors may contribute substantially to the disease risk and will be useful in characterizing high-risk populations. Although the joint effects of type 2 diabetes loci identified from genome-wide association studies have been investigated previously (17–22), few studies have comprehensively investigated the impact of conventional risk factors, such as BMI, lifestyle, and family history, on these genetic effects. We sought to confirm associations reported by genome-wide association studies and to examine the joint genetic effects of established type 2 diabetes risk variants and their combination with conventional risk factors on type 2 diabetes risk in 2 prospective cohorts: the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS).
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Although hyperglycemia is a key therapeutic focus in the management of patients with type 2 diabetes mellitus (T2DM), many patients experience sub-optimal glycemic control. Current glucose-lowering agents involve the targeting of various body organs. Sodium glucose co-transporter type 2 (SGLT2) inhibitors target the kidney, reduce renal glucose reabsorption, and increase urinary glucose elimination, thus lowering glucose blood levels. This review examines some of the key efficacy and safety data from clinical trials of the main SGLT2 inhibitors approved or currently in development, and provides a rationale for the use of SGLT2 inhibitors in the treatment of T2DM.
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ATP-sensitive potassium channels (KATP channels) link cell metabolism to electrical activity by controlling the cell membrane potential. They participate in many physiological processes but have a particularly important role in systemic glucose homeostasis by regulating hormone secretion from pancreatic islet cells. Glucose-induced closure of KATP channels is crucial for insulin secretion. Emerging data suggest that KATP channels also play a key part in glucagon secretion, although precisely how they do so remains controversial. This Review highlights the role of KATP channels in insulin and glucagon secretion. We discuss how KATP channels might contribute not only to the initiation of insulin release but also to the graded stimulation of insulin secretion that occurs with increasing glucose concentrations. The various hypotheses concerning the role of KATP channels in glucagon release are also reviewed. Furthermore, we illustrate how mutations in KATP channel genes can cause hyposecretion or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, and how defective metabolic regulation of the channel may underlie the hypoinsulinaemia and the hyperglucagonaemia that characterize type 2 diabetes mellitus. Finally, we outline how sulphonylureas, which inhibit KATP channels, stimulate insulin secretion in patients with neonatal diabetes mellitus or type 2 diabetes mellitus, and suggest their potential use to target the glucagon secretory defects found in diabetes mellitus.
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To evaluate the safety and effectiveness of insulin analogues in patients with type 2 diabetes (T2D) from Morocco, Algeria and Tunisia that formed the Maghrebian cohort of the 24-week, non-interventional A1chieve study. Patients starting biphasic insulin aspart, insulin detemir and insulin aspart, alone or in combination, were included. The primary outcome was the incidence of serious adverse drug reactions (SADRs), including major hypoglycaemic events. Secondary outcomes included hypoglycaemia, glycated haemoglobin A1c (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), systolic blood pressure (SBP), body weight and lipids. Quality of life (QoL) was evaluated using the EQ-5D questionnaire. Overall, 3720 patients with a mean age of 58.6 years, body mass index of 27.7 kg/m(2) and diabetes duration of 11.5 years were enrolled. Pre-study, insulin-experienced patients had a mean±SD dose of 0.54±0.27 U/kg. In the entire cohort, the mean dose was 0.42±0.27U/kg at baseline, titrated to 0.55±0.30U/kg by Week 24. Twenty-six SADRs were reported during the study. There was a significant decrease in the proportion of patients reporting overall hypoglycaemia from baseline to Week 24 (18.3% to 13.8%, p < 0.0001). The mean HbA1c improved significantly from 9.5±1.8% to 7.9±1.4% (p < 0.001). The mean FPG, PPPG, SBP, total cholesterol and QoL also improved significantly (all p < 0.001), while the mean body weight increased by 0.9±3.9 kg (p < 0.001). Insulin analogue therapy was well-tolerated and was associated with improved glycaemic control.
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Results At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 per- centage point lower than in the placebo group (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P = 0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P = 0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was