Sustained efficacy of dapagliflozin when added to metformin in type 2 diabetes inadequately controlled by metformin monotherapy

Background and aims: The selective SGLT2 inhibitor dapagliflozin (DAPA) reduces hyperglycaemia independently of insulin secretion or action by inhibiting renal glucose reabsorption. This study (MB102014) is a randomised double-blind, placebo (PBO)-controlled trial of DAPA added to metformin (MET) in T2DM (n=546) inadequately controlled with MET alone. Previously reported short-term data at week 24 showed significant mean reductions in the primary [HbA1c] and secondary [fasting plasma glucose (FPG) and weight] endpoints with DAPA compared to PBO. Here we report efficacy and safety results at week 102 of the long-term extension. Materials and methods: Patients aged 18-77 years with HbA1c 7-10% received DAPA 2.5 mg, 5 mg, 10 mg or PBO, plus open-label MET (≥1500mg/d). Exploratory endpoints at week 102 included changes from baseline in HbA1c, FPG and weight, and were analyzed by longitudinal repeated measures analysis. Results: Overall 71.2% of patients completed 102 weeks of the study; fewer on PBO (63.5%) than on DAPA 2.5 mg, 5 mg, and 10 mg (68.3%, 73.0%, 79.8%), due mainly to more patients on PBO discontinuing for lack of efficacy. At week 102, all DAPA groups showed greater mean reductions from baseline in HbA1c, FPG and weight compared to PBO (table), effects that were similar to those observed at week 24 and maintained throughout the trial. More patients at week 102 also achieved a therapeutic response of HbA1c<7% with DAPA 2.5 mg, 5 mg, and 10 mg (20.7%, 26.4%, 31.5%) than with PBO (15.4%). Adverse events (AEs), serious AEs and AEs leading to discontinuation were balanced across all groups. Signs and symptoms suggestive of genital infection (GenInf) were reported in 11.7%, 14.6%, 12.6% (DAPA 2.5 mg, 5 mg, 10 mg) and 5.1% (PBO) of patients, with 1 discontinuation due to GenInf. Signs and symptoms suggestive of urinary tract infection (UTI) were reported in 8.0%, 8.8%, 13.3% (DAPA 2.5 mg, 5 mg, 10 mg) and 8.0% (PBO), with 1 discontinuation due to UTI. No event of pyelonephritis was reported. Conclusion: In comparison to PBO, DAPA added to MET over 102 weeks demonstrated greater and sustained improvements in glycaemic control, clinically meaningful reduction in weight, and no increased risk of hypoglycaemia in patients with T2DM inadequately controlled with MET alone.

Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss

We investigated the effect of different exercise modalities on high sensitivity-C reactive protein (hs-CRP) and other inflammatory markers in patients with type 2 diabetes and the metabolic syndrome. Eighty-two patients were randomized into 4 groups: sedentary control (A); receiving counseling to perform low-intensity physical activity (B); performing prescribed and supervised high-intensity aerobic (C) or aerobic + resistance (D) exercise (with the same caloric expenditure) for 12 months. Evaluation of leisure-time physical activity and assessment of physical fitness, cardiovascular risk factors and inflammatory biomarkers was performed at baseline and every 3 months. Volume of physical activity increased and HbA1c decreased in Groups B–D. VO2max, HOMA-IR index, HDL-cholesterol, waist circumference and albuminuria improved in Groups C and D, whereas strength and flexibility improved only in Group D. Levels of hs-CRP decreased in all three exercising groups, but the reduction was significant only in Groups C and D, and particularly in Group D. Changes in VO2max and the exercise modalities were strong predictors of hs-CRP reduction, independent of body weight. Leptin, resistin and interleukin-6 decreased, whereas adiponectin increased in Groups C and D. Interleukin-1β, tumor necrosis factor-α and interferon-γ decreased, whereas anti-inflammatory interleukin-4 and 10 increased only in Group D. In conclusion, physical exercise in type 2 diabetic patients with the metabolic syndrome is associated with a significant reduction of hs-CRP and other inflammatory and insulin resistance biomarkers, independent of weight loss. Long-term high-intensity (preferably mixed) training, in addition to daytime physical activity, is required to obtain a significant anti-inflammatory effect.

The blue side of diabetes: assessing the impact of depression in people with type 2 diabetes using real-world data

The aim of the thesis is to assess the impact of depression in people with type 2 diabetes. Using Healthcare Utilization Databases, I estimated in a large population-based cohort with type 2 diabetes the incidence of depression over 10 year-period, identified the demographic and clinical predictors of depression, and determined the extent to which depression is a risk factor for acute and long-term complications and mortality. In the context of COVID-19 pandemic, I evaluated whether the presence of a history of depression in type 2 diabetes increased the Emergency Department (ED) access rate for diabetes-related complications, and I investigated changes in the incidence of depression during the first year of the pandemic. Findings from the first study indicated that developing depression was associated with being a woman, being over 65 years, living in rural areas, having insulin as initial diabetes medication and having comorbid conditions; the study also confirmed that depression was associated with an increased risk for acute and long-term diabetes complications and all-cause mortality. The second observational study showed a higher rate of ED access for diabetes-related complications during the pandemic in people with type 2 diabetes and a history of depression than in those without a history of depression, similar to what was observed in a pre-pandemic period. As shown in the third population-based study, the incidence of depression decreased in 2020 compared to 2019, mainly during the first and the second waves of the COVID-19 pandemic, when people probably had difficulty reaching healthcare services. This new real-world evidence will help healthcare professionals identify timely patients at high risk of developing depression. Lastly, policymakers and physicians will benefit from new evidence of the effects of the COVID-19 pandemic on depression in people with type 2 diabetes to ensure a high level of care during crisis periods.

Metabolic origin of insulin resistance in obesity with and without type 2 (non-insulin-dependent) diabetes mellitus.

A metabolic hypothesis is presented for insulin resistance in obesity, in the presence or absence of Type 2 (non-insulin-dependent) diabetes mellitus. It is based on physiological mechanisms including a series of negative feed-back mechanisms, with the inhibition of the function of the glycogen cycle in skeletal muscle as a consequence of decreased glucose utilization resulting from increased lipid oxidation in the obese. It considers the inhibition of glycogen synthase activity together with inhibition of glucose storage and impaired glucose tolerance. The prolonged duration of increased lipid oxidation, considered as the initial cause, may lead to Type 2 diabetes. This hypothesis is compatible with others based on the inhibition of insulin receptor kinase and of glucose transporter activities.

Short-term stability in refractive status despite large fluctuations in glucose levels in diabetes mellitus type 1 and 2

Purpose: This work investigates how short-term changes in blood glucose concentration affect the refractive components of the diabetic eye in patients with long-term Type 1 and Type 2 diabetes. Methods: Blood glucose concentration, refractive error components (mean spherical equivalent MSE, J0, J45), central corneal thickness (CCT), anterior chamber depth (ACD), crystalline lens thickness (LT), axial length (AL) and ocular aberrations were monitored at two-hourly intervals over a 12-hour period in: 20 T1DM patients (mean age ± SD) 38±14 years, baseline HbA1c 8.6±1.9%; 21 T2DM patients (mean age ± SD) 56±11 years, HbA1c 7.5±1.8%; and in 20 control subjects (mean age ± SD) 49±23 years, HbA1c 5.5±0.5%. The refractive and biometric results were compared with the corresponding changes in blood glucose concentration. Results: Blood glucose concentration at different times was found to vary significantly within (p<0.0005) and between groups (p<0.0005). However, the refractive error components and ocular aberrations were not found to alter significantly over the day in either the diabetic patients or the control subjects (p>0.05). Minor changes of marginal statistical or optical significance were observed in some biometric parameters. Similarly there were some marginally significant differences between the baseline biometric parameters of well-controlled and poorly-controlled diabetic subjects. Conclusion: This work suggests that normal, short-term fluctuations (of up to about 6 mM/l on a timescale of a few hours) in the blood glucose levels of diabetics are not usually associated with acute changes in refractive error or ocular wavefront aberrations. It is therefore possible that factors other than refractive error fluctuations are sometimes responsible for the transient visual problems often reported by diabetic patients. © 2012 Huntjens et al.

Associação entre polimorfismo inserção/delecção da enzima conversora da angiotensina na diabetes mellitus tipo 2: estudo da população portuguesa

A Diabetes mellitus tipo 2 (DM2) é uma patologia de etiologia múltipla à qual estão associados vários factores genéticos. A Enzima Conversora da Angiotensina (ECA) tem sido alvo de vários estudos pela sua relação com factores pró-inflamatórios, pró-oxidantes e pró-fibrose, sendo o polimorfismo de Inserção/Delecção o mais estudado. Neste contexto, o objectivo deste estudo é assim verificar a distribuição deste polimorfismo numa amostra de indivíduos de nacionalidade portuguesa e verificar a sua possível associação com a DM2. Para tal, foram analisadas 87 amostras (controlos n =24 e diabéticos n =63) de indivíduos de nacionalidade portuguesa. As amostras foram submetidas a um processo de extracção de ADN, sendo posteriormente amplificadas por Polymerase Chain Reaction e analisadas por eletroforese em gel de agarose a 1%. Observou-se uma prevalência de 8% (n=7) com genótipo I/I, 38% (n=33) com genótipo I/D e 54% (n=47) com genótipo D/D. A amostra em estudo demonstrou assim estar sob o equilíbrio Hardy-Weinberg. Observou-se também uma associação entre níveis mais elevados de glicemia e o genótipo I/I (p=0,019). Na análise da utilização de insulina no controlo dos níveis de glicemia na DM2, observou-se uma maior proporção de indivíduos com genótipo D/D. Este estudo demonstra a importância do investimento da caracterização genética em patologias metabólicas multifactoriais como a DM2.

Evaluation of long term persistence of Diabetes Mellitus Type II treatment newly diagnosed patients in Lisbon and Tagus health administration region : a three year follow up study

RESUMO: Raional: A persistência à terapêutica é o tempo em qualquer antidiabético oral, desde o seu início até à descontinuação de todas as medicações ou até ao fim do período do estudo. Os objetivos deste estudo foi a análise da persistência à terapêutica no segundo e terceiro anos após início do tratamento em doentes adultos diagnosticados na região de Lisboa e Vale do Tejo e determinar o efeito de determinadas variáveis na persistência a longo prazo. Métodos: Um estudo retrospetivo não interventivo foi desenhado com base nos dados a obter do SIARS (prescrições e aquisições na farmácia) e Pordata. A persistência foi quantificada como a percentagem de doentes que continuam a adquirir pelo menos um antidiabético oral ao segundo e terceiro anos após a compra da primeira receita. A associação entre a persistência e o segundo e terceiro anos com cada uma das co-variáveis foi aferido pelo teste qui-quadrado e os odd ratios foram calculados com recurso a um modelo de regressão logística. Resultados: A persistência à terapêutica obtida foi de 80% e 62% para o segundo e terceiro anos após início da terapêutica. Odd ratios para primeiro e segundo ano: número de grupos farmacoterapêuticos diferentes (OR = 2.167, 1.807 – 2.598, p = 0.000 / OR = 1.863, 1.621 – 2.142, p = 0.000); idade (OR = 0.914, 0.772 – 1.081, p = 0.294 / OR = 0.875, 0.764 – 1.002, p = 0.054); sexo (OR = 1.163, 0.983 – 1.377, p = 0.079); número de diferentes prescritores (OR = 3.594, 3.030 – 4.262, p = 0.000 / OR = 2.167, 1.886 – 2.491, p = 0.000); instituição de prescrição (OR = 0.725, 0.698 – 0.753, p = 0.000 / OR = 0.683, 0.650 – 0.717, p = 0.000); grupo farmacoterapêutico (OR = 1.056, 1.043 – 1.069, p = 0.000 / OR = 1.077, 1.060 – 1.095, p = 0.000); relação com o médico (OR = 0.834, 0.816 – 0.852, p = 0.000 / OR = 0.799, 0.777 – 0.821, p = 0.000) e custo médio mensal por grupo farmacoterapêutico (OR = 0.954, 0.942 – 0.968, p = 0.000 / OR = 0.930, 0.914 – 0.947, p = 0.000). Conclusões: O valor da persistência à terapêutica no segundo ano é ligeiramente acima do que é mencionado na literatura e não existem dados para comparar os resultados do terceiro ano. Relativamente ao efeito das co-variáveis no segundo e terceiro anos após o início do tratamento, os resultados são sobreponíveis, sendo que o sexo não está associado à persistência ao terceiro ano.----------------------------------ABSTRACT: Background: Therapy persistence is the time on any antidiabetic medication, from initiation of therapy to discontinuation of all medications or the end of the study period. The aim of the study was to analyse the therapy persistence in the second and third years after treatment initiation in newly diagnosed adult patients in the Lisbon and Tagus Valley region and to determine the effect of several co-variables in the long term persistence. Methods: A retrospective non-interventional study based on SIARS data (drug prescriptions and acquisitions) and Pordata was designed. Persistence was quantified as the percentage of patients that continued to purchase at least one type of antidiabetic at year 2 and 3 after the date of first prescription acquisition. Association between persistence at second and third years with each of the other co-variables were verified by using the Chi-Square test and odds ratio were calculated using a regression logistic model. Results: Therapy persistence obtained was 80% and 62% for the second and third years after treatment initiation. Odd ratios for second and third years: number of different pharmacotherapeutic groups (OR = 2.167, 1.807 – 2.598, p = 0.000 / OR = 1.863, 1.621 – 2.142, p = 0.000); age (OR = 0.914, 0.772 – 1.081, p = 0.294 / OR = 0.875, 0.764 – 1.002, p = 0.054); gender (OR = 1.163, 0.983 – 1.377, p = 0.079); number of different prescribers (OR = 3.594, 3.030 – 4.262, p = 0.000 / OR = 2.167, 1.886 – 2.491, p = 0.000); institution of prescription (OR = 0.725, 0.698 – 0.753, p = 0.000 / OR = 0.683, 0.650 – 0.717, p = 0.000); pharmacotherapeutic group (OR = 1.056, 1.043 – 1.069, p = 0.000 / OR = 1.077, 1.060 – 1.095, p = 0.000); relationship with the physician (OR = 0.834, 0.816 – 0.852, p = 0.000 / OR = 0.799, 0.777 – 0.821, p = 0.000) and average cost per month and per pharmacotherapeutic group (OR = 0.954, 0.942 – 0.968, p = 0.000 / OR = 0.930, 0.914 – 0.947, p = 0.000). Conclusions: Second year therapy persistence value is slightly above of what is referenced in literature and no data was found to compare the third year value. Regarding the effect of the co-variables analysed at second and third years after treatment initiation, the results were overlapping with gender being not associated with persistence at the third year.

Asociación entre psoriasis y el control de diabetes mellitus tipo 2

La psoriasis es una enfermedad que se caracteriza por un proceso inflamatorio crónico y exagerado local y sistémico. Se ha encontrado en la literatura una relación entre la psoriasis y el desarrollo de patologías como diabetes mellitus tipo 2 y el mal control de estas patologías, lo cual aumenta la morbimortalidad de estos pacientes. El presente estudio mostró que no se encontró asociación entre psoriasis y el control de la DM2 , y que la variable mas significativa sobre el control es la adherencia al tratamiento hipoglicemiante.

Serum titres of anti-glutamic acid decarboxylase-65 and anti-IA-2 autoantibodies are associated with different immunoregulatory milieu in newly diagnosed type 1 diabetes patients

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Farmacocinética pré-clínica e avaliação toxicológica preliminar da nova tiazolidinadiona desenvolvida para o tratamento do diabetes mellitus tipo 2: 5-(4-cloro-benzilideno)-3-(4-metil-benzil)-tiazolidina-2,4-diona (GQ-2)

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Avaliação da expressão gênica e de lesões no DNA de índividuos portadores de diabetes mellitus tipo 2, dislipidemia e periodontite crônica

Pós-graduação em Odontologia - FOAR

Metabolic control in children and adolescents with diabetes mellitus type I in Berne: a cross-sectional study.

AIMS/HYPOTHESIS In diabetes mellitus type I, good glycaemic control is crucial in preventing long-term diabetic complications. The aim of this study was to determine the current level of metabolic control in children and adolescents in our diabetes outpatient clinic at the University Children's Hospital, Berne. Furthermore, the impact of different factors such as age, pubertal stage, sex, duration of diabetes and insulin regimen on glycaemic control was studied. METHODS In a cross-sectional, prospective study 168 children and adolescents with type I diabetes mellitus (f:m = 87:81; prepubertal 48 [mean age 4.4 years, mean duration of diabetes 2.8 years]; pubertal 120 [mean age 9.4 years; mean duration of diabetes 5.2 years]) were studied for three months. Clinical data and HbA1c levels (latex immunoagglutination test) were recorded, statistically analysed and compared with the international literature. RESULTS In our type I diabetic children and adolescents the overall HbA1c was 8.07 +/- 1.15% (mean +/- SD; test-specific norm for healthy subjects: 4.1-6.1%). Glycaemic control was significantly worse in the pubertal group compared to the prepubertal (HbA1c 8.22 +/- 1.25% vs. 7.81 +/- 0.87%; p < 0.01). In addition, we found better metabolic control in patients with duration of diabetes below 2 years in children and adolescents (HbA1c prepubertal < 2 years: 7.45 +/- 0.67% vs. > 2 years: 8.05 +/- 0.93%, p < 0.05; pubertal < 2 years: 7.62 +/- 0.75% vs. > 2 years: 8.31 +/- 1.29%, p < 0.005). Importantly, sex and insulin regimen did not significantly influence glycaemic control. CONCLUSION/INTERPRETATION The current level of metabolic control in our children and adolescents with diabetes mellitus type I is comparable to the glycaemic control of the intensively treated adolescent group of the DCCT-study, in whom decreased risk of long-term diabetic complications was found. In contrast, our patients were intensively treated in terms of frequent contacts with the diabetes team, but were not necessarily on an intensified insulin regimen. The impact of biopsychosocial support from multidisciplinary diabetes team on good metabolic control in children and adolescents with type I diabetes mellitus and their families seems to be very important.

Plasma Levels of MASP-1 and MASP-2 are Elevated in Type 1 Diabetes and Correlate with Glycaemic Control

There is increasing evidence that the complement system plays an important role in diabetes and the development of diabetic vascular complications. In particular, mannan-binding lectin (MBL) levels are elevated in diabetes patients, and diabetes patients with diabetic nephropathy have higher MBL levels than diabetes patients with normal renal function. The MBL-associated serine proteases (MASPs) MASP-1, MASP-2, and MASP-3, and MBL-associated protein MAp44 have not yet been studied in diabetes patients. We therefore measured plasma levels of MASP-1, MASP-2, MASP-3, and MAp44 in 30 children with type 1 diabetes mellitus (T1DM) and 17 matched control subjects, and in 45 adults with T1DM and 31 matched control subjects. MASP-1 and MASP-2 levels were significantly higher in children and adults with T1DM than in their respective control groups, whereas MASP-3 and MAp44 levels did not differ between patients and controls. MASP-1 and MASP-2 levels correlated with HbA1c, and MASP levels decreased when glycaemic control improved. Since MASP-1 and MASP-2 have been shown to directly interact with blood coagulation, elevated levels of these proteins may play a role in the enhanced thrombotic environment and consequent vascular complications in diabetes.

COL18A1 is highly expressed during human adipocyte differentiation and the SNP c.1136C > T in its "frizzled" motif is associated with obesity in diabetes type 2 patients

Collagen XVIII can generate two fragments, NC11-728 containing a frizzled motif which possibly acts in Wnt signaling and Endostatin, which is cleaved from the NC1 and is a potent inhibitor of angiogenesis. Collagen XVIII and Wnt signaling have recently been associated with adipogenic differentiation and obesity in some animal models, but not in humans. In the present report, we have shown that COL18A1 expression increases during human adipogenic differentiation. We also tested if polymorphisms in the Frizzled (c.1136C>T; Thr379Met) and Endostatin (c.4349G>A; Asp1437Asn) regions contribute towards susceptibility to obesity in patients with type 2 diabetes (113 obese, BMI =30; 232 non-obese, BMI < 30) of European ancestry. No evidence of association was observed between the allele c.4349G>A and obesity, but we observed a significantly higher frequency of homozygotes c.1136TT in obese (19.5%) than in non-obese individuals (10.9%) [P = 0.02; OR = 2.0 (95%CI: 1.07-3.73)], suggesting that the allele c.1136T is associated to obesity in a recessive model. This genotype, after controlling for cholesterol, LDL cholesterol, and triglycerides, was independently associated with obesity (P = 0.048), and increases the chance of obesity in 2.8 times. Therefore, our data suggest the involvement of collagen XVIII in human adipogenesis and susceptibility to obesity.

Internal Pudendal Artery from Type 2 Diabetic Female Rats Demonstrate Elevated Endothelin-1-Mediated Constriction

Introduction. Diabetes is a risk factor for female sexual dysfunction (FSD). FSD has several etiologies, including a vasculogenic component that could be exacerbated in diabetes. The internal pudendal artery supplies blood to the vagina and clitoris and diabetes-associated functional abnormalities in this vascular bed may contribute to FSD. Aim. The Goto-Kakizaki (GK) rat is a non-obese model of type 2 diabetes with elevated endothelin-1 (ET-1) activity. We hypothesize that female GK rats have diminished sexual responses and that the internal pudendal arteries demonstrate increased ET-1 constrictor sensitivity. Methods. Female Wistar and GK rats were used. Apomorphine (APO)-mediated genital vasocongestive arousal (GVA) was measured. Functional contraction (ET-1 and phenylephrine) and relaxation (acetylcholine, ACh) in the presence or absence of the ETA receptor antagonist (ET(A)R; atrasentan) or Rho-kinase inhibitor (Y-27632) were assessed in the internal pudendal and mesenteric arteries. Protein expression of ET-1 and RhoA/Rho-kinase signaling pathway was determined in the internal pudendal and mesenteric arteries. Main Outcome Measure. APO-mediated GVAs; contraction and relaxation of internal pudendal and mesenteric arteries; ET-1/RhoA/Rho-kinase protein expression. Results. GK rats demonstrated no APO-induced GVAs. Internal pudendal arteries, but not mesenteric arteries, from GK rats exhibited greater contractile sensitivity to ET-1 compared with Wistar arteries. ETAR blockade reduced ET-1-mediated constriction in GK internal pudendal and mesenteric arteries. Rho-kinase inhibition reduced ET-1-mediated constriction of GK internal pudendal but not mesenteric arteries; however, it had no effect on arteries from Wistar rats. RhoA protein expression was elevated in GK internal pudendal arteries. At the highest concentrations, ACh-mediated relaxation was greater in the GK internal pudendal artery; however, no difference was observed in the mesenteric artery. Conclusions. Female GK rats demonstrate decreased sexual responses that may be because of increased constrictor sensitivity to the ET-1/RhoA/Rho-kinase signaling in the internal pudendal artery. Allahdadi KJ, Hannan JL, Ergul A, Tostes RC, and Webb RC. Internal pudendal artery from type 2 diabetic female rats demonstrate elevated endothelin-1-mediated constriction. J Sex Med 2011;8:2472-2483.