A mouse model of gestation-specific transient hyperglycemia for translational studies

The prevalence of gestational diabetes mellitus (GDM) is estimated at 14% globally, and in some countries, such as Singapore, exceeds 20%. Both women and children exposed to GDM have an increased risk of later metabolic diseases, cardiovascular disease and other health issues. Beyond lifestyle changes and pharmaceutical intervention using existing type 2 diabetes medications for expecting women, there are limited treatment options for women with GDM; targeting better outcomes of potentially affected infants is unexplored. Numerous animal models have been generated for understanding of pathological processes of GDM development and for development of treatment strategies. These models, however, suffer from limited windows of opportunity to examine risk factors and potential intervention options. By combining short-term high-fat diet (HFD) feeding and low-dose streptozotocin (STZ) treatments before pregnancy, we have established a mouse model with marked transient gestation-specific hyperglycemia, which allows testing of nutritional and pharmacological interventions before, during and beyond pregnancy.

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Outcomes of a digitally delivered, culturally-sensitive behaviour change platform for BAME adults with type 2 diabetes: 1 year health and engagement outcomes (Preprint)

10.2196/preprints.18674 ◽

2020 ◽

Author(s):

Charlotte Summers

Keyword(s):

Type 2 Diabetes ◽

Body Weight ◽

Health Outcomes ◽

Behavioural Change ◽

Culturally Sensitive ◽

Lifestyle Changes ◽

Haemoglobin A1c ◽

Central Asian ◽

Increased Risk

BACKGROUND People from Black, Asian and Minority Ethnic (BAME) groups are known to have an increased risk of developing type 2 diabetes and face greater barriers to accessing healthcare resources compared to their “white British” counterparts. The main mediators of lifestyle behavioural change are gender, generation, geography, genes, God/religion, and gaps in knowledge and economic resources. Dietary and cultural practices of these individuals significantly vary according to gender, generation, geographical origin and religion. Recognition of these factors and implementing culturally sensitive interventions for type 2 diabetes prevention and management is essential in increasing knowledge of healthy eating, engagement in physical activity and improving health outcomes in BAME communities. Few health apps are tailored for BAME populations, and BAME communities are considered hard-to-reach. OBJECTIVE Our objective was to establish whether the Low Carb Program is a viable scalable solution that can be used as an effective tailored type 2 diabetes intervention for BAME communities. We hypothesized that by taking into account cultural sensitivities, providing the platform in native languages and personalising the platform in accordance with known barriers to health disparities including gender, generation, dietary preferences and religion, the app would engage BAME communities and improve type 2 diabetes related health outcomes. METHODS The study used a quasi-experimental research design comprised of an open-label, single-arm, pre-post intervention using a sample of convenience. All 705 adults with type 2 diabetes who had activated their referral to the Low Carb Program as a result of an NHS consultation between September 2018 and March 2019 were followed for a period of 12 months; mean age 54.61 (SD 16.69) years; 58.2% (410/705) women; 45.1% (318/705) white, 28.5% (201/705) Indian/Pakistani/Bangladeshi/Other Central Asian, 10.8% (76/705) Arab, 6.2% (44/705) Mixed/Multiple ethnic groups, 6% (43/705) black, 1.8% (13/705) other, (7/705) 1% Chinese/Japanese/Other East Asian. Mean starting glycated haemoglobin A1c (HbA1c) 7.99% (SD 2.05%); mean body weight 88.96kg (SD 23.25kg). RESULTS Of the 705 study participants, 513 (72.76%) had completed the Low Carb Program at 12 months. There were statistically significant reductions in body weight and HbA1c in white, Indian/Pakistani/Bangladeshi/Other Central Asian, Arabic and black participants with the most significant differences in the Indian/Pakistani/Bangladeshi/Other Central Asian population HbA1c -1.18% (SD 1.49%) and weight 8.03kg (SD 10.65kg). 82.9% of all participants (419/705) of all participants lost at least 5% of their body weight. CONCLUSIONS Offering the culturally tailored Low Carb Program that empowers members to make dietary and lifestyle changes to different BAME groups is an effective and engaging tool in the management of type 2 diabetes. Most importantly, BAME populations in particular people from Indian/Pakistani/Bangladeshi and Arabic groups who achieve better health outcomes than their white counterparts.

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Pharmacological Interventions for Pulmonary Involvement in Rheumatic Diseases

Pharmaceuticals ◽

10.3390/ph14030251 ◽

2021 ◽

Vol 14 (3) ◽

pp. 251 ◽

Cited By ~ 1

Author(s):

Eun Ha Kang ◽

Yeong Wook Song

Keyword(s):

Rheumatic Diseases ◽

Treatment Options ◽

Treatment Strategies ◽

Pulmonary Involvement ◽

Current Treatment ◽

Targeted Agents ◽

Pharmacological Interventions ◽

Inflammatory Processes ◽

Pulmonary Arterial ◽

Epidemiologic Features

Among the diverse forms of lung involvement, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are two important conditions in patients with rheumatic diseases that are associated with significant morbidity and mortality. The management of ILD and PAH is challenging because the current treatment often provides only limited patient survival benefits. Such challenges derive from their common pathogenic mechanisms, where not only the inflammatory processes of immune cells but also the fibrotic and proliferative processes of nonimmune cells play critical roles in disease progression, making immunosuppressive therapy less effective. Recently, updated treatment strategies adopting targeted agents have been introduced with promising results in clinical trials for ILD ad PAH. This review discusses the epidemiologic features of ILD and PAH among patients with rheumatic diseases (rheumatoid arthritis, myositis, and systemic sclerosis) and the state-of-the-art treatment options, focusing on targeted agents including biologics, antifibrotic agents, and vasodilatory drugs.

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The Risks of Cardiovascular Disease and Mortality Following Weight Change in Adults with Diabetes: Results from ADVANCE

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz045 ◽

2019 ◽

Vol 105 (1) ◽

pp. 152-162 ◽

Cited By ~ 1

Author(s):

Alexandra K Lee ◽

Mark Woodward ◽

Dan Wang ◽

Toshiaki Ohkuma ◽

Bethany Warren ◽

...

Keyword(s):

Type 2 Diabetes ◽

Weight Loss ◽

Weight Change ◽

Cox Regression ◽

Lifestyle Changes ◽

Baseline Body Mass Index ◽

Diabetes Medication ◽

Increased Risk ◽

All Cause Mortality

Abstract Context Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes. Objective To evaluate 2-year weight change and subsequent risk of cardiovascular events and mortality in established type 2 diabetes. Design and Setting The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation was an international, multisite 2×2 factorial trial of intensive glucose control and blood pressure control. We examined 5 categories of 2-year weight change: >10% loss, 4% to 10% loss, stable (±<4%), 4% to 10% gain, and >10% gain. We used Cox regression with follow-up time starting at 2 years, adjusting for intervention arm, demographics, cardiovascular risk factors, and diabetes medication use from the 2-year visit. Results Among 10 081 participants with valid weight measurements, average age was 66 years. By the 2-year examination, 4.3% had >10% weight loss, 18.4% had 4% to 10% weight loss, and 5.3% had >10% weight gain. Over the following 3 years of the trial, >10% weight loss was strongly associated with major macrovascular events (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.26-2.44), cardiovascular mortality (HR, 2.76; 95% CI, 1.87-4.09), all-cause mortality (HR, 2.79; 95% CI, 2.10-3.71), but not major microvascular events (HR, 0.91; 95% CI, 0.61-1.36), compared with stable weight. There was no evidence of effect modification by baseline body mass index, age, or type of diabetes medication. Conclusions In the absence of substantial lifestyle changes, weight loss may be a warning sign of poor health meriting further workup in patients with type 2 diabetes.

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Thrombocytosis: Diagnostic Evaluation, Thrombotic Risk Stratification, and Risk-Based Management Strategies

Thrombosis ◽

10.1155/2011/536062 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 43

Author(s):

Jonathan S. Bleeker ◽

William J. Hogan

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasms ◽

Treatment Options ◽

Treatment Strategies ◽

Diagnostic Evaluation ◽

Diagnostic Process ◽

Special Focus ◽

Thrombotic Risk ◽

Increased Risk

Thrombocytosis is a commonly encountered clinical scenario, with a large proportion of cases discovered incidentally. The differential diagnosis for thrombocytosis is broad and the diagnostic process can be challenging. Thrombocytosis can be spurious, attributed to a reactive process or due to clonal disorder. This distinction is important as it carries implications for evaluation, prognosis, and treatment. Clonal thrombocytosis associated with the myeloproliferative neoplasms, especially essential thrombocythemia and polycythemia vera, carries a unique prognostic profile, with a markedly increased risk of thrombosis. This risk is the driving factor behind treatment strategies in these disorders. Clinical trials utilizing targeted therapies in thrombocytosis are ongoing with new therapeutic targets waiting to be explored. This paper will outline the mechanisms underlying thrombocytosis, the diagnostic evaluation of thrombocytosis, complications of thrombocytosis with a special focus on thrombotic risk as well as treatment options for clonal processes leading to thrombocytosis, including essential thrombocythemia and polycythemia vera.

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The Role of Anti-obesity Drugs in Patients with Type 2 Diabetes

US Endocrinology ◽

10.17925/use.2013.09.02.101 ◽

2013 ◽

Vol 09 (02) ◽

pp. 101 ◽

Cited By ~ 1

Author(s):

Priscilla Hollander ◽

Keyword(s):

Type 2 Diabetes ◽

Glycemic Control ◽

Lifestyle Changes ◽

Important Concern ◽

Increased Risk ◽

The Us ◽

Patients With Diabetes ◽

Obesity Drugs

The prevalence of diabetes continues to rise, following the rising rates of obesity. Obesity is not only associated with an increased risk for developing type 2 diabetes but also an elevated probability of developing long-term complications associated with the disease. Weight gain is also an important concern as a potential side effect of therapies that improve glycemic control in diabetes, including insulin therapy. As a result, patients with type 2 diabetes are at risk for a vicious circle of increasing weight and increasing insulin resistance, thus requiring further intensification of glycemic treatment. It is therefore important to address the problem of obesity in patients with type 2 diabetes. In 2012, the US Food and Drug Administration (FDA) approved two new anti-obesity medications: lorcaserin and phentermine/topiramate extended-release. Both agents have demonstrated clinically meaningful weight reduction as well as significant improvements in glycemic control in obese patients with diabetes. Liraglutide has also shown weight loss and improvements in glycemic control in patients with diabetes. Anti-obesity drugs, in conjunction with lifestyle changes, may play a valuable role in the management of diabetes.

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Diet composition and the risk of type 2 diabetes: epidemiological and clinical evidence

British Journal Of Nutrition ◽

10.1079/bjn20041117 ◽

2004 ◽

Vol 92 (1) ◽

pp. 7-19 ◽

Cited By ~ 111

Author(s):

M. Parillo ◽

G. Riccardi

Keyword(s):

Type 2 Diabetes ◽

Weight Loss ◽

Diet Composition ◽

Intervention Studies ◽

Epidemiological Studies ◽

Lifestyle Changes ◽

Lifestyle Modifications ◽

Body Weight Reduction ◽

Increased Risk

In the last 10 years nutritional research on diabetes has improved dramatically in terms of both number of studies produced and quality of methodologies employed. Therefore, it is now possible to attempt to provide the evidence on which nutritional recommendations for the prevention of type 2 diabetes could be based. We therefore performed a literature search and, among the papers published in indexed journals, we selected relevant epidemiological (mostly prospective) and controlled intervention studies. Lifestyle factors that have, so far, been consistently associated with increased risk of type 2 diabetes are overweight and physical inactivity. However, recent evidence from epidemiological studies has shown that the risk of type 2 diabetes is also associated with diet composition, particularly with: (1) low fibre intake; (2) a high trans fatty acid intake and a low unsaturated:saturated fat intake ratio; (3) absence of or excess alcohol consumption. All these factors are extremely common in Western populations and therefore the potential impact of any intervention on them is large: indeed, >90% of the general population has one or more of these risk factors. The ability to correct these behaviours in the population is estimated to reduce the incidence of diabetes by as much as 87%. Recent intervention studies have shown that type 2 diabetes can be prevented by lifestyle changes aimed at body-weight reduction, increased physical activity and multiple changes in the composition of the diet. Within this context, the average amount of weight loss needed is not large, about 5% initial weight, which is much less than the weight loss traditionally considered to be clinically significant for prevention of type 2 diabetes. In conclusion, new emphasis on prevention by multiple lifestyle modifications, including moderate changes in the composition of the habitual diet, might limit the dramatic increase in incidence of type 2 diabetes envisaged worldwide.

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Incident type 2 diabetes and risk of fracture: a comparative cohort analysis using UK primary care records

10.2337/figshare.13034150.v1 ◽

2020 ◽

Author(s):

Gabrielle S Davie ◽

Kingshuk Pal ◽

Elizabeth Orton ◽

Edward G Tyrrell ◽

Irene Petersen

Keyword(s):

Type 2 Diabetes ◽

Primary Care ◽

Lifestyle Changes ◽

Health Improvement ◽

Prevalence Rates ◽

Risk Of Fracture ◽

Incident Type ◽

Increased Risk ◽

Incident Type 2 Diabetes

Objective To estimate risk of fracture in men and women with recent diagnosis of type 2 diabetes compared to individuals without diabetes. Research Design and Methods In this cohort study we used routinely-collected UK primary care data from The Health Improvement Network. In adults (>35 years) diagnosed with type 2 diabetes between 2004-2013 fractures sustained until 2019 were identified and compared to fractures sustained in individuals without diabetes. Multivariable models estimated time to first fracture following diagnosis of diabetes. Annual prevalence rates included at least one fracture in a given year. Results Among 174,244 individuals with incident type 2 diabetes and 747,290 without diabetes, there was no increased risk of fracture among males with diabetes (adjusted hazards ratio (aHR) 0.97 (95%CI 0.94, 1.00)) and a small reduced risk among females (aHR 0.94, (95%CI 0.92, 0.96)). In those aged 85 years and over those in the diabetes cohort were at significantly lower risk of incident fracture (Males: aHR 0.85, 95%CI 0.71, 1.00; Females: aHR 0.85, 95%CI 0.78, 0.94). For those in the most deprived areas, aHRs were 0.90 (95%CI 0.83, 0.98) for males and 0.91 (95%CI 0.85, 0.97) for females. Annual fracture prevalence rates, by sex, were similar for those with and without type 2 diabetes. Conclusion We found no evidence to suggest a higher risk of fracture following diagnosis of type 2 diabetes. After a diagnosis of type 2 diabetes individuals should be encouraged to make positive lifestyle changes, including undertaking weight-bearing physical activities that improve bone health.

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Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09397-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Jan Philipp Delling ◽

Tobias M. Boeckers

Keyword(s):

Animal Models ◽

Treatment Options ◽

Regulation Of Gene Expression ◽

Treatment Strategies ◽

Fetal Brain ◽

Autism Spectrum ◽

Therapeutic Strategies ◽

Clinical Severity ◽

Comprehensive Overview ◽

Increased Risk

Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. Main text This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Conclusions Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.

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Blood pressure variability and risk of heart failure in ACCORD and the VADT

10.2337/figshare.12059250.v1 ◽

2020 ◽

Author(s):

Daniel S. Nuyujukian ◽

Juraj Koska ◽

Gideon Bahn ◽

Peter D. Reaven ◽

Jin J. Zhou ◽

...

Keyword(s):

Heart Failure ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Risk Factor ◽

Blood Pressure Variability ◽

Treatment Strategies ◽

Risk Factor Management ◽

Increased Risk ◽

Blood Pressure Treatment

Objective: Although blood pressure variability is increasingly appreciated as a risk factor for cardiovascular disease, its relationship with heart failure is less clear. We examined the relationship between blood pressure variability and risk of heart failure (HF) in two cohorts of type 2 diabetes participating in trials of glucose and/or other risk factor management. Research Design and Methods: Data were drawn from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the Veterans Affairs Diabetes Trial (VADT). Coefficient of variation (CV) and average real variability (ARV) were calculated for systolic (SBP) and diastolic blood pressure (DBP) along with maximum and cumulative mean SBP and DBP during both trials. Results: In ACCORD, CV and ARV of SBP and DBP were associated with increased risk of HF, even after adjusting for other risk factors and mean blood pressure (e.g., CV-SBP: HR=1.15, p = 0.01; CV-DBP: HR=1.18, p = 0.003). In the VADT, DBP variability was associated with increased risk of HF (ARV-DBP: HR=1.16, p = 0.001; CV-DBP: HR=1.09, p = 0.04). Further, in ACCORD, those with progressively lower baseline blood pressure demonstrated a stepwise increase in risk of HF with higher CV-SBP, ARV-SBP, and CV-DBP. Effects of blood pressure variability were related to dips, not elevations, in blood pressure. Conclusions: Blood pressure variability is associated with HF risk in individuals with type 2 diabetes, possibly a consequence of periods of ischemia during diastole. These results may have implications for optimizing blood pressure treatment strategies in those with type 2 diabetes.

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Associations between Aquaglyceroporin Gene Polymorphisms and Risk of Type 2 Diabetes Mellitus

BioMed Research International ◽

10.1155/2018/8167538 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Yijun Wang ◽

Gang Chen ◽

Qingyun Tu ◽

Junxia Wu ◽

Yu Qin ◽

...

Keyword(s):

Type 2 Diabetes ◽

Metabolic Diseases ◽

Proteinase K ◽

Nucleotide Polymorphisms ◽

Chinese Han ◽

Single Nucleotide ◽

Increased Risk ◽

Polymerase Chain ◽

And Gender

Objectives. AQP7 and AQP9 represent glycerol channel in adipose tissue and liver and have been associated with metabolic diseases. We aimed to investigate the associations between genetic variants in AQP7 and AQP9 genes and the risk of type 2 diabetes (T2DM) in Chinese population. Methods. Blood samples were drawn from 400 T2DM patients and 400 age- and gender-matched controls. Genomic DNA was extracted by proteinase K digestion and phenol–chloroform extraction. Genotyping of 5 single nucleotide polymorphisms (SNPs) in AQP7 (rs2989924, rs3758269, and rs62542743) and AQP9 (rs57139208, rs16939881) was performed by the polymerase chain reaction assay with TaqMan probes. Results. The subjects with rs2989924 GA+AA genotypes had 1.47-fold increased risk of T2DM (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.06-2.04), compared to those with GG genotype, and this association remained significant after adjustment for covariates (OR 1.66, 95% CI 1.07-2.57). When compared with rs3758269 CC genotype, the subjects with CT+TT genotypes had 45% decreased T2DM risk after multivariate adjustment (OR 0.55, 95% CI 0.35-0.85). The associations were evident in elder and overweight subjects and those with central obesity. No association was observed between AQP9 SNPs and T2DM risk. Conclusions. AQP7 SNP rs2989924 and rs3758269 were associated with T2DM risk in Chinese Han population.

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