Honghe Prefecture, China

Kuwait Adult Diabetes Epidemiological Multidisciplinary (KADEM) Program

The rapid increase of obesity and the detrimental complications associated with it, particularly insulin resistance, Type 2 diabetes (T2D), hypertension and cardiovascular disorders, represent a major threat to public health. Epidemiological data from Arabian Gulf countries warned of the high prevalence of obesity and T2D 1-4. According to the International Diabetes Federation (IDF), Gulf States such as Bahrain, Kuwait, Oman, Saudi Arabia, and United Arab Emirates ranked amongst the 10 countries in the world with highest prevalence of T2D 2,4. It is also known that the effect of obesity on the risk of developing these disorders differs by ethnicity 5 for example, South Asians have a higher risk for hypertension, T2D, cholesterol profiles and cardiovascular disease 6. In Arab populations, high familial aggregation of diabetes and related disorders have been observed. The population is characterised by consanguineous marriages and large family size. The large number of T2DM genetic loci identified globally to date were derived using unrelated subjects as study cohorts and explains only a relatively small proportion of observed heritability (familial clustering) of T2DM 7. Possible explanations for the "missing heritability" may originate from the role of rare variants, copy number variants, and more complex rearrangements, gene-environment interactions and epigenetics 8,9. Family-based designs allow the segregation of rare variants in a pedigree; multiple copies of such rare variants facilitate the detection of their effects. Family-based studies require fewer samples than population-based studies and offer advantages in terms of quality control, robustness to population stratification, and uniformity in exposure to environmental factors (gene-environment interactions and epigenetics) or lineage-specific diseases that have pleiotropic effect on diabetes. They also offer the potential to combine linkage and association data. Arab populations, which often have a high rate of consanguinity 10, offer a large potential for family-based designs as they show familial gene clustering for diabetes and metabolic traits 11-13. However, except for few studies, such as the "Oman Family Study" 14 and a study on an extended family from the UAE, no notable familial study for diabetes risk loci has been reported for the Arab population. Both the above-mentioned studies confirmed well-established gene loci but failed to identify any novel "rare" variants. Paralleling this world-wide increase in obesity is the increase in the incidence and prevalence of non-alcoholic fatty liver disease (NAFLD). The global prevalence of NAFLD is about 24% whereas its prevalence in the Middle East Region is more than 30% 15. Given the high percentage of obesity in a country like Kuwait, the prevalence of NAFLD would be expected to be much higher as well. Hepatic steatosis is the underlying manifestation of NAFLD and is clinically defined as a hepatic triglyceride content that exceeds 5%. Even though NAFLD was considered a benign manifestation, it is currently clear that it is linked to the development of steatohepatitis, fibrosis, cirrhosis and eventually the development of hepatocellular carcinoma 16. Liver lipid content is regulated by an intricate equilibrium between lipid uptake and secretion. The main sources for hepatic lipids are adipose tissue lipolysis (which is the source of about 60% of liver triglyceride), dietary intake and de novo lipogenesis. On the other hand, hepatic lipid content can be reduced by lipid secretion (primarily VLDL secretion) and mitochondrial fatty acid oxidation. High-fat and glucose diets as well as obesity and insulin resistance lead to increased influx of fat into the liver and the accumulation of intracellular triglyceride in hepatic tissues and ultimately to the development of nonalcoholic steatohepatitis (NASH). Kuwait and the Gulf Region lack large longitudinal studies to identify risk factors for the progression of metabolic dysfunction that leads to the transition from prediabetes to diabetes. The Kuwait Diabetes Epidemiology Program (KDEP) (RA-2010-004) was designed to develop a research dataset which offers a full characterization of the Kuwaiti population and contains detailed clinical, genetic, immunological, physiological, biochemical and environmental data which can serve as a resource for future research and prevention programs to fight against obesity, diabetes, and metabolic syndrome. A number of papers have been published from the original cross-sectional study reporting data regarding the studied population such as the prevalence of cardiovascular disease risk factors in South Asian expatriates in Kuwait 17, the association between adipokines and hsCRP and the Metabolic Syndrome in Arabs as well as ghrelin and adiponectin in Arabs 18-20. Another paper looked at vitamin D levels in Arab and Asians 21. Two additional studies performed genome-wide genotyping of the study cohort, resulting in papers that reported genetic risk loci for metabolic traits 22,23. An eighth paper characterizes a novel biomarker called betatrophin, showing that betatrophin levels in T2D was increased compared to non-diabetic participants. Betatrophin levels showed significant increase in subjects with longer duration of T2D 24. A major limitation of these studies is the cross-sectional design that could not support relationships between the cause and effect. In the current study, the investigators aim to do a follow up on the KDEP to provide datasets to support development of evidence-based optimal prevention strategies for the control and management of obesity and its complications, including diabetes and cardiovascular disease. Data collected in the KDEP Follow-up study will also support policy and decision-makers in implementing comprehensive health promotion programs to control these diseases at the national level and to establish their appropriateness and cost effectiveness for the whole population. The outcome of this effort will immediately serve as a database for genetic and biochemical risk factors as well as it will provide data that can be used to potentially establish risk scoring based on regional data that is applicable to the Arab population and other people living in Kuwait. It will also support efforts that implement comprehensive health promotion programs to prevent and manage these diseases at the national level. Given the magnitude of the human and the economic burden of diabetes on the Kuwaiti population, longitudinal data from the KDEP Follow-up study should contribute to reducing the impact of diabetes and related metabolic complications on the population as well as expanding the original cohort. It will also act as a guide to assist health policy and decision makers in their planning strategies for adapting appropriate preventive measures. Study Rationale The primary aim of the present study is to recall all 3970 non-diabetic participants in KDEP as well as other high risk individuals and determine the incidence of prediabetes and new onset T2DM using a 75-gram OGTT according to the ADA criteria. the investigators also will determine the incidence of microvascular (i.e. retinopathy, nephropathy, and neuropathy) and macrovascular complications in subjects who converted to T2DM and those with prediabetes compared to NGT subjects. the investigators also will perform detailed biochemical/molecular workup to identify risk factors associated with the progression to prediabetes/T2DM and associated with the development of vascular (micro- and macrovascular) complications. the investigators will also do OGTT/ Hyperglycemia CLAMP (H-CLAMP) and Euglycemic Clamp for a subset of (250) participant. Objectives The primary objective of the study is to determine the incidence of T2DM and its complications in Kuwaiti population. the investigators also will identify risk factors associated with the development of T2DM and/or its vascular complications. Therefore, the investigators propose the following SPECIFIC AIMS: Specific Aim 1: Determine the 4-7 year incidence rate of T2DM in KDEP cohort according to the ADA criteria. Specific Aim 2: Determine the incidence rate of microvascular (retinopathy, nephropathy and neuropathy) and macrovascular diabetic complications in subjects with prediabetes and new onset diabetes in KDEP cohort. Specific Aim 3: Identify metabolic/biochemical/molecular factors associated with the development of diabetes and its vascular complications in KDEP cohort.

Protocol for Alpha MSH Infusion Study in Patients With Type 2 Diabetes

Pre-clinical studies in mice have shown improved glucose clearance with α-MSH infusion, particularly in skeletal muscle. Research has demonstrated that α-MSH improves glucose tolerance in healthy humans by promoting glucose uptake in skeletal muscle cells. Therefore this study seeks to answer the question of whether alpha-MSH improves glucose tolerance in patients with T2DM. This will be addressed through measuring the impact of α-MSH infusion in patients with T2DM. The research involves a double-blinded, randomized, placebo-controlled crossover study.

Timing of Resistance Exercise in Type 1 Diabetes

Resistance Exercise and Cognition in People With Type 1 Diabetes

Vitamin K2 and Muscle Weakness in Type 2 Diabetes

Krill Oil and Muscle Weakness in Type 2 Diabetes

What do Patients Expect After Scaphoid Fractures?

Using Trauma expectation factor and trauma outcome measure questionnaire. At fracture time and at one year post fracture Analyse according to age, sex, fracture pattern, type of intervention

Time-Restricted Feeding on Glucose Homeostasis and Quality of Life

Experimental Design 12-week parallel randomised control trial Recruitment We will recruit via advertisements outside Dasman using social media and local ads in addition to screening of Dasman Registry for any potential participants. Opportunistic recruitment will also occur by DDI dietitians. Following telephone screening to ensure the potential participant meets initial screening criteria we will carry out a medical screening to ensure the person can take part. Environment All screening, dietary counselling visits, and placement of the CGM will take place at the Dasman Diabetes Institute (DDI). The institute has extensive space for interventional studies, including screening rooms, body composition assessment and clinical rooms for placement of the CGM monitor. STUDY INTERVENTIONS For both groups all participants will be guided towards a 5% weight loss based on individualised energy requirements. The difference will be the hours during which the participants consume their required calories. - Time restricted feeding group: Will consume their calories between 12pm and 6pm. - Continuous energy restriction group: Will consume their calories between 8am and 11pm. Participants will be guided towards their weight loss during one-to-one visits at baseline and every 2 weeks for 12 weeks. Procedures - At baseline and follow-up all participants will undergo an oral glucose tolerance test. - A blood sample will also be taken for HbA1c, lipid profile, fasting insulin, inflammatory factors and a sample for Biobank. The biobank sample will be stored to enable us, with other researchers at DDI to understand the heterogeneity of type 2 diabetes; whether certain people respond to dietary interventions based on their genetic, epigenetic or metabolomic background; and ultimately will help guide clinical care. - Participants will wear Flash Glucose monitoring or other continuous glucose monitoring device to measure their 24-hour blood glucose concentrations during the seven days preceding the start of the dietary intervention, seven days of the second month, and the final seven days of the third month. - Participants will also measure their capillary ketones during the first three days of the first month, three days of the second month, and final three days of the third month. - Medication changes: prandial medications (insulin or sulphonylurea) will be altered to the timing of meal intake. Any reduction in medication due to changes in glucose will be carried out by the patient's doctor. - A quality of life questionnaire: PAID. - A 3 day food diary with meal times to check compliance. Statistical Methods This is a pilot study. We will recruit 25 people per group. This is based on recommendations for sample sizes for feasibility and pilot studies.

Dapagliflozin Plus Pioglitazone in T1DM

Insulin deficiency, due to autoimmune destruction of beta cells, is the primary factor responsible for the development of T1DM, and insulin replacement therapy is the mainstay for the management of hyperglycemia. However, insulin therapy often is associated with adverse events, including weight gain which promotes insulin resistance leading to an increase in insulin demand. This results in a self-perpetuating vicious cycle whereby the increase in insulin dose causes weight gain that worsens insulin sensitivity, and further enhances insulin requirement. Hyperinsulinemia per se also induces insulin resistance. To break this cycle, adjunctive therapies have been added to insulin in T1DM patients to lower the plasma glucose concentration. However, the addition of metformin, pioglitazone, and GLP-1 agonists to insulin in T1DM patients have not provided convincing evidence for a clinically meaningful reduction in the HbA1c or significant reduction in daily insulin dose. SGLT2 inhibitors (SGLT2i) are a novel class of antidiabetic agents which reduce the plasma glucose concentration by inhibiting renal glucose reuptake and producing glucosuria. Because of this unique mechanism of action, which is independent of insulin secretion and insulin action, SGLT2i have proven to be very effective in lowering the plasma glucose concentration in T1DM. Initial proof of concept studies have demonstrated that, compared to placebo, all members of this class (dapagliflozin, empagliflozin, canagliflozin and sotagliflozin) effectively lower the plasma glucose concentration, HbA1c and daily insulin dose in T1DM without increased risk of hypoglycemia. Further, SGLT2i improved cardiovascular risk factors in T1DM by promoting weight loss and decreasing blood pressure. Despite the promising potential for SGLT2i as adjunctive therapy to insulin in T1DM, recent large clinical trials have demonstrated two important limitations to this therapeutic strategy: First, although the decrease in HbA1c caused by SGLT2i in T1DM patients was statistically significant, the absolute decrease was relatively modest (0.30-0.45%). The investigators, previously have shown that SGLT2i stimulate an increase in the basal rate of hepatic glucose production (HGP) in T2DM patients. This SGLT2i-induced increase in HGP offsets by approximately one half the amount of glucose lost in the urine. Therefore, the investigators have hypothesize that, similar to what they have observed in T2DM patients, the addition of SGLT2i to insulin in T1DM patients stimulates HGP thereby attenuating the decrease in HbA1c. Further, the decrease in daily insulin dose after initiating therapy with SGLT2i in T1DM patients would be expected to enhance the increase in HGP and diminish the decrease in HbA1c. Thus, preventing the increase in HGP caused by SGLT2i in T1DM can be expected to markedly amplify the clinical efficacy of SGLT2i and enhance the reduction in HbA1c. A second limitation of the use of SGLT2i an adjunct therapy to insulin in T1DM patients is the increase in diabetic ketoacidosis (DKA) risk. In three large clinical trials , the addition of SGLT2i to insulin in T1DM patients was associated with a 3-6% increase in DKA risk (see Table 1 below). Because of the significant morbidity and mortality associated with DKA, the increased DKA risk in T1DM has raised concerns about the use of SGLT2i as an adjunct therapy to insulin in T1DM patients despite their multiple metabolic benefits. The Investigators previously have demonstrated that SGLT2i cause a significant increase in plasma FFA concentration, fat oxidation and subsequent increase in plasma ketone concentration in T2DM patients (27). Therefore, they hypothesize that in T1DM, SGLT2i cause a similar increase in plasma FFA concentration, fat oxidation and plasma ketone concentration which in certain clinical conditions (e.g. acute illness) can increase the production of ketones and result in the development of DKA. Further, prevention of the increase in plasma FFA concentration will inhibit the increase in plasma ketone concentration and reduce DKA risk associated with SGLT2i use in T1DM patients. Pioglitazone inhibits lipolysis and markedly decreases the plasma FFA concentration. Further, pioglitazone is a potent inhibitor of HGP. These actions of pioglitazone are due to direct actions of the drug on adipocytes and liver, respectively, are mediated by PPAR gama, and are independent of the plasma insulin and glucagon concentrations. In fact, pioglitazone inhibits lipolysis and HGP in type 2 diabetic patients despite a decrease in plasma insulin concentration. Therefore, the investigators hypothesize that the addition of pioglitazone to SGLT2i in T1DM patients will prevent the rise in HGP caused by SGLT2i and, thereby, augment the decrease in HbA1c. Further, combination therapy with pioglitazone plus SGLT2i will prevent the increase in plasma FFA concentration and subsequent increase in plasma ketone concentration, thus reducing the risk of DKA.

The International ITP Registry

This is an observational disease registry database for recently-diagnosed adult patients with primary ITP that aims to understand the natural history of this rare disease and disease management. Participating investigators will prospectively enter real-world patient data on their enrolled patients with a minimum of 2 years follow up. Data from this registry will be used to generate descriptive statistics on demographics, clinical characteristics including prevalence and incidence of co-morbidities, treatment patterns, and adverse outcomes (resulting from treatment or disease) on ITP patients on an annual basis. The information will be generated at the national or combined-country level. Furthermore, each institution will have an access to its data and may choose to generate descriptive statistics for its specific institution on a more frequent, ad-hoc basis. New research questions or questions addressing a subset of registry patients to take advantage of combined registry data will require a separate protocol and review by independent committees The focus of this protocol is on adults with primary ITP, however, in future there may be interest to expand the population to explore secondary ITP patients as well. Hence, this registry is built to allow for some optional preliminary information related to secondary ITP to be captured. Multi-site participation of this registry project will be rolled out in stages, and will be offered to centres with appropriate expertise. Pilot countries included Australia, Korea, Taiwan, Singapore, Malaysia, Japan, Thailand and Turkey and sites will be selected based on their potential research (interest, resources, and expected patient volume). Additional sites may be added in the future from countries in Asia Pacific, Middle East and Latin America. Japan has an independent national ITP registry run by the government, however voluntary participation of interested Japanese investigators in this database will be welcomed, therefore allowing comparison of data between Japanese and non-Japanese patients.