Poorly controlled type 2 diabetes mellitus is associated with a decreased risk of incident gout: a population-based case-control study

OBJECTIVE The aim of this study was to explore the risk of incident gout in patients with type 2 diabetes mellitus (T2DM) in association with diabetes duration, diabetes severity and antidiabetic drug treatment. METHODS We conducted a case-control study in patients with T2DM using the UK-based Clinical Practice Research Datalink (CPRD). We identified case patients aged ≥18 years with an incident diagnosis of gout between 1990 and 2012. We matched to each case patient one gout-free control patient. We used conditional logistic regression analysis to calculate adjusted ORs (adj. ORs) with 95% CIs and adjusted our analyses for important potential confounders. RESULTS The study encompassed 7536 T2DM cases with a first-time diagnosis of gout. Compared to a diabetes duration <1 year, prolonged diabetes duration (1-3, 3-6, 7-9 and ≥10 years) was associated with decreased adj. ORs of 0.91 (95% CI 0.79 to 1.04), 0.76 (95% CI 0.67 to 0.86), 0.70 (95% CI 0.61 to 0.86), and 0.58 (95% CI 0.51 to 0.66), respectively. Compared to a reference A1C level of <7%, the risk estimates of increasing A1C levels (7.0-7.9, 8.0-8.9 and ≥9%) steadily decreased with adj. ORs of 0.79 (95% CI 0.72 to 0.86), 0.63 (95% CI 0.55 to 0.72), and 0.46 (95% CI 0.40 to 0.53), respectively. Neither use of insulin, metformin, nor sulfonylureas was associated with an altered risk of incident gout. CONCLUSIONS Increased A1C levels, but not use of antidiabetic drugs, was associated with a decreased risk of incident gout among patients with T2DM.

Prevalence of vascular disease in systemic lupus erythematosus compared with type-1 diabetes mellitus: a cross-sectional study of two cohorts.

OBJECTIVES Systemic lupus erythematosus (SLE) is associated with considerable cardiovascular morbidity that has not yet been directly compared with other diseases with known cardiovascular risk. METHODS Two hundred and forty-one patients of the multicentre Swiss SLE cohort study (SSCS) were cross-sectionally assessed for coronary heart disease (CHD), cerebrovascular disease (CVD) and peripheral artery disease (PAD). SLE patients were compared with a cohort of 193 patients with type-1 diabetes mellitus being followed at the University Hospital Basel. A subgroup analysis of 50 age- and sex-matched patients from the University Hospital Basel was performed. RESULTS Of patients within the SSCS 13.3% had one or more vascular events: 8.3% CHD, 5% CVD and 1.2% PAD. In type-1 diabetes mellitus patients, 15% had vascular events: 9.3% CHD, 3.1% CVD and 5.6% PAD. In the matched subgroup, 26% of SLE patients had vascular events (14% CHD) compared with 12% in type-1 DM patients (2% CHD). Cardiovascular risk factors were similar in both groups. Vascular events in SLE patients were associated with age, longer disease duration, dyslipidaemia, and hypertension. CONCLUSION Cardiovascular morbidity in SLE is at least as frequent as in age- and sex-matched type-1 diabetes mellitus patients. Therefore, aggressive screening and management of cardiovascular risk factors should be performed.

Effect of large doses of parenteral vitamin D on glycaemic control and calcium/phosphate metabolism in patients with stable type 2 diabetes mellitus: a randomised, placebo-controlled, prospective pilot study.

OBJECTIVE Vitamin D (D₃) status is reported to correlate negatively with insulin production and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). However, few placebo-controlled intervention data are available. We aimed to assess the effect of large doses of parenteral D3 on glycosylated haemoglobin (HbA(₁c)) and estimates of insulin action (homeostasis model assessment insulin resistance: HOMA-IR) in patients with stable T2DM. MATERIALS AND METHODS We performed a prospective, randomised, double-blind, placebo-controlled pilot study at a single university care setting in Switzerland. Fifty-five patients of both genders with T2DM of more than 10 years were enrolled and randomised to either 300,000 IU D₃ or placebo, intramuscularly. The primary endpoint was the intergroup difference in HbA(₁c) levels. Secondary endpoints were: changes in insulin sensitivity, albuminuria, calcium/phosphate metabolism, activity of the renin-aldosterone axis and changes in 24-hour ambulatory blood pressure values. RESULTS After 6 months of D₃ supply, there was a significant intergroup difference in the change in HbA(₁c) levels (relative change [mean ± standard deviation] +2.9% ± 1.5% in the D₃ group vs +6.9% ± 2.1% the in placebo group, p = 0.041) as HOMA-IR decreased by 12.8% ± 5.6% in the D₃ group and increased by 10% ± 5.4% in the placebo group (intergroup difference, p = 0.032). Twenty-four-hour urinary albumin excretion decreased in the D₃ group from 200 ± 41 to 126 ± 39, p = 0.021). There was no significant intergroup difference for the other secondary endpoints. CONCLUSIONS D₃ improved insulin sensitivity (based on HOMA-IR) and affected the course of HbA(₁c) positively compared with placebo in patients with T2DM.

Exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus.

PURPOSE OF REVIEW The primary focus of this review is threefold: first, to summarize available knowledge on exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus (T1DM); second, to elucidate physiological mechanisms predisposing to glycemic variations in patients in T1DM; and third, to describe novel approaches derived from physiological perceptions applicable to stabilize exercise-related glycemia in individuals with T1DM. RECENT FINDINGS Recent studies corroborate the concept that despite partial differences in counter-regulatory mechanisms individuals with T1DM do not fundamentally differ in their glucose response to exercise when compared with healthy individuals if studies are performed under standardized conditions with insulin and glucose levels held close to physiological ranges. Novel approaches derived from a better understanding of exercise-associated glucose metabolism (e.g., the concept of intermittent high-intensity exercise) may provide alternative ways to master the challenges imposed by exercise to individuals with T1DM. SUMMARY Exercise still imposes high demands on patients with T1DM and increases risks for hypoglycemia and hyperglycemia. Deeper insight into the associated metabolic pathways has revealed novel options to stabilize exercise-associated glucose levels in these patients.

Carbohydrate Estimation by a Mobile Phone-Based System Versus Self-Estimations of Individuals With Type 1 Diabetes Mellitus: A Comparative Study

Background: Diabetes mellitus is spreading throughout the world and diabetic individuals have been shown to often assess their food intake inaccurately; therefore, it is a matter of urgency to develop automated diet assessment tools. The recent availability of mobile phones with enhanced capabilities, together with the advances in computer vision, have permitted the development of image analysis apps for the automated assessment of meals. GoCARB is a mobile phone-based system designed to support individuals with type 1 diabetes during daily carbohydrate estimation. In a typical scenario, the user places a reference card next to the dish and acquires two images using a mobile phone. A series of computer vision modules detect the plate and automatically segment and recognize the different food items, while their 3D shape is reconstructed. Finally, the carbohydrate content is calculated by combining the volume of each food item with the nutritional information provided by the USDA Nutrient Database for Standard Reference. Objective: The main objective of this study is to assess the accuracy of the GoCARB prototype when used by individuals with type 1 diabetes and to compare it to their own performance in carbohydrate counting. In addition, the user experience and usability of the system is evaluated by questionnaires. Methods: The study was conducted at the Bern University Hospital, “Inselspital” (Bern, Switzerland) and involved 19 adult volunteers with type 1 diabetes, each participating once. Each study day, a total of six meals of broad diversity were taken from the hospital’s restaurant and presented to the participants. The food items were weighed on a standard balance and the true amount of carbohydrate was calculated from the USDA nutrient database. Participants were asked to count the carbohydrate content of each meal independently and then by using GoCARB. At the end of each session, a questionnaire was completed to assess the user’s experience with GoCARB. Results: The mean absolute error was 27.89 (SD 38.20) grams of carbohydrate for the estimation of participants, whereas the corresponding value for the GoCARB system was 12.28 (SD 9.56) grams of carbohydrate, which was a significantly better performance ( P=.001). In 75.4% (86/114) of the meals, the GoCARB automatic segmentation was successful and 85.1% (291/342) of individual food items were successfully recognized. Most participants found GoCARB easy to use. Conclusions: This study indicates that the system is able to estimate, on average, the carbohydrate content of meals with higher accuracy than individuals with type 1 diabetes can. The participants thought the app was useful and easy to use. GoCARB seems to be a well-accepted supportive mHealth tool for the assessment of served-on-a-plate meals.

The impact of nutrition intervention on glycemic control in a pediatric type 1 diabetes mellitus population

Aim: The goal of this study was to evaluate the change in hemoglobin A1C and glycemic control after nutrition intervention among a population of type 1 diabetic pediatric patients. Methods: Data was collected from all type 1 diabetic patients who were scheduled for a consultation with the diabetes/endocrine RD from January 2006 through December 2006. Two groups were compared, those who kept their RD appointment and those who did not keep their appointment. The main outcome measure was HgbA1C. An independent samples t-test compared the two groups with respect to change in HbgA1C before and after the most recent scheduled appointment with the RD. Baseline characteristics were used as covariates and analyzed and controlled for using analysis of covariance (ANCOVA). Results: There was no difference in HgbA1c after either attending an RD appointment or not having attended an RD appointment. Those who arrived for and attended their RD appointment and those who did not arrive for and attend their RD appointment, had statistically different HgbA1C's before their scheduled appointment as well as after the RD appointment. However, the two groups were not equal at the beginning of the study period. Discussion: A study design with inclusion criteria of a specified range of HgbA1C values within which the study subjects needed to fall, would have potentially eliminated the difference between the two groups at the beginning of the study period. Conducting either another retrospective study that controlled for the initial HgbA1C value or conducting a prospective study that designated a range of HgbA1C values would be worth investigating to evaluate the impact of medical nutrition therapy intervention and the role of the RD in diabetes management. It is an interesting finding that there was a significant difference in the initial HgbA1c for those who came to the RD appointment compared to those who did not come. The fact that in this study those who did not arrive for their RD appointment had worse control of their diabetes suggests that this is a high-risk group. Targeting diabetes education toward this group of patients may prove to be beneficial. ^

The performance of interferon-gamma release assays in tuberculosis patients with type II diabetes

The sensitivity of Interferon-γ release assays for detection of Mycobacterium tuberculosis (MTB) infection or disease is affected by conditions that depress host immunity (such as HIV). It is critical to determine whether these assays are affected by diabetes and related conditions (i.e. hyperglycemia, chronic hyperglycemia, or being overweight/obese) given that immune impairment is thought to underline susceptibility to tuberculosis (TB) in people with diabetes. This is important for tuberculosis control due to the millions of type 2 diabetes patients at risk for tuberculosis worldwide.^ The objective of this study was to identify host characteristics, including diabetes, that may affect the sensitivity of two commercially available Interferon-γ (IFN-γ) release assays (IGRA), the QuantiFERON®-TB Gold (QFT-G) and the T-SPOT®.TB in active TB patients. We further explored whether IFN-γ secretion in response to MTB antigens (ESAT-6 and CFP-10) is associated with diabetes and its defining characteristics (high blood glucose, high HbA1c, high BMI). To achieve these objectives, the sensitivity of QFT-G and T-SPOT. TB assays were evaluated in newly diagnosed, tuberculosis confirmed (by positive smear for acid fast bacilli and/or positive culture for MTB) adults enrolled at Texas and Mexico study sites between March 2006 and April 2009. Univariate and multivariate models were constructed to identify host characteristics associated with IGRA result and level of IFN-γ secretion.^ QFT-G was positive in 68% of tuberculosis patients. Those with diabetes, chronic hyperglycemia or obesity were more likely to have a positive QFT-G result, and to secrete higher levels of IFN-γ in response to the mycobacterial antigens (p<0.05). Previous history of BCG vaccination was the only other host characteristic associated with QFT-G result, whereby a higher proportion of non-BCG vaccinated persons were QFT-G positive, in comparison to vaccinated persons. In a separate group of patients, the T-SPOT.TB was 94% sensitive, with similar performance in all tuberculosis patients, regardless of host characteristics.^ In summary, we have demonstrated the validity of QFT-G and T-SPOT. TB to support the diagnosis of TB in patients with a range of host characteristics, but most notably in patients with diabetes. We also confirmed that TB patients with diabetes and associated characteristics (chronic hyperglycemia or BMI) secreted higher titers of IFN-γ when stimulated with MTB specific antigens, in comparison to patients without these characteristics. Together, these findings suggest that the mechanism by which diabetes increases risk to TB may not be explained by the inability to secrete IFN-γ, a key cytokine for TB control.^

Micronutrient intakes and their associations with markers of inflammation, subclinical atherosclerosis, cardiovascular disease, type II diabetes and metabolic syndrome

We investigated cross-sectional associations between intakes of zinc, magnesium, heme- and non heme iron, beta-carotene, vitamin C and vitamin E and inflammation and subclinical atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). We also investigated prospective associations between those micronutrients and incident MetS, T2D and CVD. Participants between 45-84 years of age at baseline were followed between 2000 and 2007. Dietary intake was assessed at baseline using a 120-item food frequency questionnaire. Multivariable linear regression and Cox proportional hazard regression models were used to evaluate associations of interest. Dietary intakes of non-heme iron and Mg were inversely associated with tHcy concentrations (geometric means across quintiles: 9.11, 8.86, 8.74, 8.71, and 8.50 µmol/L for non-heme iron, and 9.20, 9.00, 8.65, 8.76, and 8.33 µmol/L for Mg; ptrends <0.001). Mg intake was inversely associated with high CC-IMT; odds ratio (95% CI) for extreme quintiles 0.76 (0.58, 1.01), ptrend: 0.002. Dietary Zn and heme-iron were positively associated with CRP (geometric means: 1.73, 1.75, 1.78, 1.88, and 1.96 mg/L for Zn and 1.72, 1.76, 1.83, 1.86, and 1.94 mg/L for heme-iron). In the prospective analysis, dietary vitamin E intake was inversely associated with incident MetS and with incident CVD (HR [CI] for extreme quintiles - MetS: 0.78 [0.62-0.97] ptrend=0.01; CVD: 0.69 [0.46-1.03]; ptrend =0.04). Intake of heme-iron from red meat and Zn from red meat, but not from other sources, were each positively associated with risk of CVD (HR [CI] - heme-iron from red meat: 1.65 [1.10-2.47] ptrend = 0.01; Zn from red meat: 1.51 [1.02 - 2.24] ptrend =0.01) and MetS (HR [CI] - heme-iron from red meat: 1.25 [0.99-1.56] ptrend =0.03; Zn from red meat: 1.29 [1.03-1.61]; ptrend = 0.04). All associations evaluated were similar across different strata of gender, race-ethnicity and alcohol intake. Most of the micronutrients investigated were not associated with the outcomes of interest in this multi-ethnic cohort. These observations do not provide consistent support for the hypothesized association of individual nutrients with inflammatory markers, MetS, T2D, or CVD. However, nutrients consumed in red meat, or consumption of red meat as a whole, may increase risk of MetS and CVD.^

Assessing the relationship between obesity and type II diabetes among South Asian Indians in Houston A population based study

Objective: My study aimed at determining the association between obesity and diabetes prevalence in South Asian Indian immigrants in Houston, Texas. To also compare the prevalence odds of diabetes given obesity, using WHO-BMI criteria and recommended Asian ethnic-specific BMI criteria for obesity, as well as using WHO-standard waist circumference criteria and ethnic-specific criteria for abdominal obesity, across gender and age, in this population. ^ Methods: My study was a secondary data analysis based on a cross-sectional study carried out on adult South Asian Indians who attended a local community health fair in Houston, in 2007. They recruited 213 voluntary, eligible, South Asian Indian participants aged between 18 to 79 years. Self reported history of Diabetes was obtained and height, weight, waist and hip circumference were measured. I classified BMI based on WHO-standard and ethnic-specific criteria, according to gender and age groups of 18–35 years, 36–64 years and 65 years and over. Waist circumference was also classified based on WHO-standard NCEP criteria and currently recommended ethnic-specific IDF criteria and analysis was done stratifying by gender and age groups. ^ Results: The prevalence of diabetes in this population was 14.6%, significantly higher in older age groups (25.8%) and males (19.2%). The prevalence of DM was statistically similar in individuals who were overweight/obese compared to those not overweight/obese, however in overweight/obese individuals, there was a statistically significant difference in the prevalence of DM between WHO and ethnic-specific criteria for both BMI and waist circumference. In older adults and in males, ethnic-specific criteria identified significantly more as overweight/obese compared to WHO-standard criteria. ^ Conclusions: Ethnic-specific criteria for both BMI and waist circumference give a better estimate for obesity in this South Asian Indian population. Diabetes is highly prevalent in migrant South Asian Indians even at low BMI or waist circumference levels and significantly more in males and older age groups, hence adequate awareness should be created for early prevention and intervention.^

THE MOLECULAR INTERACTION BETWEEN TYPE II DIABETES AND ALZHEIMER’S DISEASE THROUGH CROSS-SEEDING OF PROTEIN MISFOLDING

With the population of the world aging, the prominence of diseases such as Type II Diabetes (T2D) and Alzheimer’s disease (AD) are on the rise. In addition, patients with T2D have an increased risk of developing AD compared to age-matched individuals, and the number of AD patients with T2D is higher than among aged-matched non-AD patients. AD is a chronic and progressive dementia characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), neuronal loss, brain inflammation, and cognitive impairment. T2D involves the dysfunctional use of pancreatic insulin by the body resulting in insulin resistance, hyperglycemia, hyperinsulinemia, pancreatic beta cell (β-cell) death, and other complications. T2D and AD are considered protein misfolding disorders (PMDs). PMDs are characterized by the presence of misfolded protein aggregates, such as in T2D pancreas (islet amyloid polypeptide - IAPP) and in AD brain (amyloid– Aβ) of affected individuals. The misfolding and accumulation of these proteins follows a seeding-nucleation model where misfolded soluble oligomers act as nuclei to propagate misfolding by recruiting other native proteins. Cross-seeding occurs when oligomers composed by one protein seed the aggregation of a different protein. Our hypothesis is that the pathological interactions between T2D and AD may in part occur through cross-seeding of protein misfolding. To test this hypothesis, we examined how each respective aggregate (Aβ or IAPP) affects the disparate disease pathology through in vitro and in vivo studies. Assaying Aβ aggregates influence on T2D pathology, IAPP+/+/APPSwe+/- double transgenic (DTg) mice exhibited exacerbated T2D-like pathology as seen in elevated hyperglycemia compared to controls; in addition, IAPP levels in the pancreas are highest compared to controls. Moreover, IAPP+/+/APPSwe+/- animals demonstrate abundant plaque formation and greater plaque density in cortical and hippocampal areas in comparison to controls. Indeed, IAPP+/+/APPSwe+/- exhibit a colocalization of both misfolded proteins in cerebral plaques suggesting IAPP may directly interact with Aβ and aggravate AD pathology. In conclusion, these studies suggest that cross-seeding between IAPP and Aβ may occur, and that these protein aggregates exacerbate and accelerate disease pathology, respectively. Further mechanistic studies are necessary to determine how these two proteins interact and aggravate both pancreatic and brain pathologies.

Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur.

Mice that carry the lethal yellow (Ay) or viable yellow (Avy) mutation, two dominant mutations of the agouti (a) gene in mouse chromosome 2, exhibit a phenotype that includes yellow fur, marked obesity, a form of type II diabetes associated with insulin resistance, and an increased susceptibility to tumor development. Molecular analyses of these and several other dominant "obese yellow" a-locus mutations suggested that ectopic expression of the normal agouti protein gives rise to this complex pleiotropic phenotype. We have now tested this hypothesis directly by generating transgenic mice that ectopically express an agouti cDNA clone encoding the normal agouti protein in all tissues examined. Transgenic mice of both sexes have yellow fur, become obese, and develop hyperinsulinemia. In addition, male transgenic mice develop hyperglycemia by 12-20 weeks of age. These results demonstrate conclusively that the ectopic agouti expression is responsible for most, if not all, of the phenotypic traits of the dominant, obese yellow mutants.

The relative benefits of endurance and strength training on the metabolic factors and muscle function of people with type 2 diabetes mellitus

Objective: To compare the effects of a 4-month strength training (ST) versus aerobic endurance training (ET) program on metabolic control, muscle strength, and cardiovascular endurance in subjects with type 2 diabetes mellitus (T2D). Design: Randomized controlled trial. Setting: Large public tertiary hospital. Participants: Twenty-two T21) participants (I I men, I I women; mean age +/- standard error, 56.2 +/- 1.1 y; diabetes duration, 8.8 +/- 3.5y) were randomized into a 4-month ST program and 17 T2D participants (9 men, 8 women; mean age, 57.9 +/- 1.4y; diabetes duration, 9.2 +/- 1.7y) into a 4-month ET program. Interventions: ST (up to 6 sets per muscle group per week) and ET (with an intensity of maximal oxygen consumption of 60% and a volume beginning at 15min and advancing to a maximum of 30min 3X/wk) for 4 months. Main Outcome Measures: Laboratory tests included determinations of blood glucose, glycosylated hemoglobin (Hb A(1c)), insulin, and lipid assays. Results: A significant decline in Hb A, was only observed in the ST group (8.3% +/- 1.7% to 7.1% +/- 0.2%, P=.001). Blood glucose (204 +/- 16mg/dL to 147 +/- 8mg/dL, P <.001) and insulin resistance (9.11 +/- 1.51 to 7.15 +/- 1.15, P=.04) improved significantly in the ST group, whereas no significant changes were observed in the ET group. Baseline levels of total cholesterol (207 +/- 8mg/dL to 184 +/- 7mg/dL, P <.001), low-density lipoprotein cholesterol (120 +/- 8mg/dL to 106 +/- 8mg/dL, P=.001), and triglyceride levels (229 +/- 25mg/dL to 150 +/- 15mg/dL, P=.001) were significantly reduced and high-density lipoprotein cholesterol (43 +/- 3mg/dL to 48 +/- 2mg/dL, P=.004) was significantly increased in the ST group; in contrast, no such changes were seen in the ET group. Conclusions: ST was more effective than ET in improving glycemic control. With the added advantage of an improved lipid profile, we conclude that ST may play an important role in the treatment of T2D.