Recovery of hypoglycemia awareness in long-standing type 1 diabetes: a multicenter 2 × 2 factorial randomized controlled trial comparing insulin pump with multiple daily injections and continuous with conventional glucose self-monitoring (HypoCOMPaSS)

To determine whether impaired awareness of hypoglycemia (IAH) can be improved and severe hypoglycemia (SH) prevented in type 1 diabetes, we compared an insulin pump (continuous subcutaneous insulin infusion [CSII]) with multiple daily injections (MDIs) and adjuvant real-time continuous glucose monitoring (RT) with conventional self-monitoring of blood glucose (SMBG).

Restoration of self-awareness of hypoglycemia in adults with long-standing type 1 diabetes: hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS trial.

OBJECTIVE: Impaired awareness of hypoglycemia (IAH) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes (T1D). We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH (Gold score ≥4) participating in the U.K.-based multicenter HypoCOMPaSS randomized controlled trial. RESEARCH DESIGN AND METHODS: Eighteen subjects with T1D and IAH (mean ± SD age 50 ± 9 years, T1D duration 35 ± 10 years, HbA1c 8.1 ± 1.0% [65 ± 10.9 mmol/mol]) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention. The intervention comprised the HypoCOMPaSS education tool in all and randomized allocation, in a 2 × 2 factorial study design, to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring. Symptoms, cognitive function, and counterregulatory hormones were measured at each glucose plateau (5.0, 3.8, 3.4, 2.8, and 2.4 mmol/L), with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies. RESULTS: After intervention, glucose concentrations at which subjects first felt hypoglycemic increased (mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L, P = 0.02), and symptom and plasma metanephrine responses to hypoglycemia were higher (median area under curve for symptoms, 580 [interquartile range {IQR} 420-780] vs. 710 [460-1,260], P = 0.02; metanephrine, 2,412 [-3,026 to 7,279] vs. 5,180 [-771 to 11,513], P = 0.01). Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged, while the color-word Stroop test showed a degree of adaptation. CONCLUSIONS: Even in long-standing T1D, IAH and defective counterregulation may be improved by a clinical strategy aimed at hypoglycemia avoidance.

Structured type 1 diabetes education delivered in routine care in Australia reduces diabetes-related emergencies and severe diabetes-related distress: the OzDAFNE program

AIMS: To evaluate structured type 1 diabetes education delivered in routine practice throughout Australia.

METHODS: Participants attended a five-day training program in insulin dose adjustment and carbohydrate counting between April 2007 and February 2012. Using an uncontrolled before-and-after study design, we investigated: HbA1c (% and mmol/mol); severe hypoglycaemia; diabetes ketoacidosis (DKA) requiring hospitalisation, and diabetes-related distress (Problem Areas in Diabetes scale; PAID), weight (kg); body mass index. Data were collected pre-training and 6-18 months post-training. Change in outcome scores were examined overall as well as between groups stratified by baseline HbA1c quartiles. Data are mean±SD or % (n).

RESULTS: 506 participants had data eligible for analysis. From baseline to follow-up, significant reductions were observed in the proportion of participants reporting at least one severe hypoglycaemic event (24.7% (n=123) vs 12.1% (n=59), p<0.001); and severe diabetes-related distress (29.3% (n=145) vs 12.6% (n=60), p<0.001). DKA requiring hospitalisation in the past year reduced from 4.1% (n=20) to 1.2% (n=6). For those with above target baseline HbA1c there was a small, statistically significant improvement (n=418, 8.4±1.1% (69±12mmol/mol) to 8.2±1.1% (66±12mmol/mol). HbA1c improvement was clinically significant among those in the highest baseline quartile (n=122, 9.7±1.1% (82±11mmol/mol) to 9.0±1.2% (75±13mmol/mol), p<0.001).

CONCLUSIONS: The proportion of participants reporting severe hypoglycaemia, DKA and severe diabetes-related distress was at least halved, and HbA1c reduced by 0.7% (7mmol/mol) among those with highest baseline levels. Structured type 1 diabetes education delivered in routine practice offers clinically important benefits for those with greatest clinical need.

Gene Expression Profiles Stratified according to Type 1 Diabetes Mellitus Susceptibility Regions

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

TNFa-e microsatellite, HLA-DRB1 and-DQB1 alleles and haplotypes in Brazilian patients presenting recently diagnosed type 1 diabetes mellitus

TNF microsatellite and HLA class II polymorphisms were studied in 28 recently diagnosed Brazilian patients presenting type 1 diabetes mellitus (T1DM) and in 120 healthy controls. TNFa-e and HLA-DRB1/DQB1 alleles were identified using sets of sequence-specific primers. Compared to controls, the DRB1* 03 and DQBI*02 allele groups, TNFa1 allele, and the TNFa4-b5-c1-d4-e3 and TNFa10-b5-c1-d4-e3 haplotypes were overrepresented in patients. TNF microsatellite together with HLA polymorphisms is associated with type 1 diabetes in Brazilian patients, corroborating the participation of the MHC genes in disease susceptibility.

Auditory evaluation in patients with type 1 diabetes

Objectives: We performed a prospective clinical study of the cochleovestibular symptoms and the risk cofactors and characteristics of hearing loss in patients with type 1 diabetes.Methods: Group I consisted of 40 patients with type I diabetes, and group 2 consisted of 20 control subjects without diabetes. All participants answered a questionnaire, and their medical records were reviewed. They also were submitted to otorhinolaryngological examinations and to auditory tests (pure tone audiometry and acoustic immitance and auditory brain stem response [ABR] tests).Results: Dyslipidemia, hypertension, retinopathy, and diabetic neuropathy were not frequent in the patients of group 1, but incipient nephropathy was present in 47.5% of them. The most frequent cochleovestibular symptoms were tinnitus and hearing loss. Sensorineural hearing loss was found in 4 patients of group I and was predominantly bilateral, symmetric, and affecting the high frequencies, coexisting with normal vocal discrimination. These patients had a longer time from diabetes diagnosis and had poor glycemia control. A delay of ABR interpeak latency I-III was observed in 11.25% of the group I ears. All patients of group 2 presented normal audiograms and ABR tests.Conclusions: In group 1, the most frequent cochleovestibular symptoms were tinnitus and hearing loss. The sensorineural hearing loss was mild, symmetric, and predominantly high-frequency. A delay of ABR interpeak latencies was detected in the patients of group I who had normal audiometric thresholds.

Sequential IL-23 and IL-17 and increased Mmp8 and Mmp14 expression characterize the progression of an experimental model of periodontal disease in type 1 diabetes

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

Temporal trends in incidence of Type 1 diabetes between 1986 and 2006 in Brazil

Background: Scarce information is available about the variation in the incidence of Type 1 diabetes in the Brazilian population in the last decades. Aim: The objective of this study was to assess the long-term trends (1986-2006) in the incidence of Type 1 diabetes in Bauru, São Paulo State, Brazil. Subjects and methods: The annual incidence of Type 1 diabetes (per 100,000 per yr) from 1986 to 2006 was determined in children yr of age, using the capture and recapture method. Results: A total of 176 cases were diagnosed in the study population. The overall incidence was 10.4/100,000 with a range of 2.82/100,000 in 1987 to 18.49/100,000 in 2002 representing a 6.56-fold increase within the same population. The estimated incidence, using the capture and recapture method varied from 2.82/100,000 per yr in 1987 to 27.20/100,000 per yr in 2002, representing a 9.6-fold variation. The global pattern of incidence variation was categorized as high (10-19.99/100,000 per yr), and very high (20/100,000 per yr) in 71.43% of the study-years. Incidence was slightly higher among females, Caucasians, children in the 5-9 yr of age range and belonging to lower socio-economic classes. Most diagnoses were established during the colder months and/or with higher pluviometric indexes. Conclusions: The incidence of Type 1 diabetes in children is increasing in Bauru, São Paulo State, Brazil, and the global pattern of incidence was classified as high or very high, mainly in the last 10 yr. All Brazilian regions should be involved in the study. (J. Endocrinol. Invest. 33: 373-377, 2010) (C)2010, Editrice Kurtis

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)

Bacille Calmette-Guérin/DNAhsp65 prime-boost is protective against diabetes in non-obese diabetic mice but not in the streptozotocin model of type 1 diabetes

Type I diabetes is a disease caused by autoimmune destruction of the beta cells in the pancreas that leads to a deficiency in insulin production. The aim of this study was to evaluate the prophylactic potential of a prime-boost strategy involving bacille Calmette-Guérin (BCG) and the pVAXhsp65 vaccine (BCG/DNAhsp65) in diabetes induced by streptozotocin (STZ) in C57BL/6 mice and also in spontaneous type 1 diabetes in non-obese diabetic (NOD) mice. BCG/DNAhsp65 vaccination in NOD mice determined weight gain, protection against hyperglycaemia, decreased islet inflammation, higher levels of cytokine production by the spleen and a reduced number of regulatory T cells in the spleen compared with non-immunized NOD mice. In the STZ model, however, there was no significant difference in the clinical parameters. Although this vaccination strategy did not protect mice in the STZ model, it was very effective in NOD mice. This is the first report demonstrating that a prime-boost strategy could be explored as an immunomodulatory procedure in autoimmune diseases. © 2013 British Society for Immunology.

Heart rate variability in children with type 1 diabetes mellitus

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

Periodontal disease-associated compensatory expression of osteoprotegerin is lost in type 1 diabetes mellitus and correlates with alveolar bone destruction by regulating osteoclastogenesis

Alveolar bone resorption results from the inflammatory response to periodontal pathogens. Systemic diseases that affect the host response, such as type 1 diabetes mellitus (DM1), can potentiate the severity of periodontal disease (PD) and accelerate bone resorption. However, the biological mechanisms by which DM1 modulates PD are not fully understood. The aim of this study was to determine the influence of DM1 on alveolar bone resorption and to evaluate the role of receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) in osteoclastogenesis in rats. PD was induced by means of ligature in nondiabetic and in streptozotocyn-induced DM1 rats. Morphological and morphometric analyses, stereology and osteoclast counting were performed. RANKL and OPG mRNA levels, protein content, and location were determined. PD caused alveolar bone resorption, increased the number of osteoclasts in the alveolar bone crest and also promoted changes in RANKL/OPG mRNA expression. DM1 alone showed alveolar bone destruction and an increased number of osteoclasts at the periapical and furcal regions. DM1 exacerbated these characteristics, with a greater impact on bone structure, resulting in a low OPG content and a higher RANKL/OPG ratio, which correlated with prominent osteoclastogenesis. This work demonstrates that the effects of PD and DM1 enhance bone destruction, confirms the importance of the RANKL signaling pathway in bone destruction in DM1 in animal models and suggests the existence of alternative mechanisms potentiating bone degradation in PD.

Prevalence of adults with type 1 diabetes who meet the goals of care in daily clinical practice: A nationwide multicenter study in Brazil

Objective: To determine the prevalence of patients with type 1 diabetes mellitus who meet the glycemic and cardiovascular (CV) risk factors goals and the frequency of screening for diabetic complications in Brazil according to the American Diabetes Association guidelines. Research design and methods: This was a cross-sectional, multicenter study conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. Data were obtained from 1774 adult patients (56.8% females, 57.2% Caucasians) aged 30.3 +/- 9.8 years with diabetes duration of 14.3 +/- 8.8 years. Results: Systolic blood pressure was at goal in 40.3% and diastolic blood pressure was at goal in 26.6% of hypertensive patients. LDL cholesterol and HbA1c were at the goal in 45.2% and 13.2% of the patients, respectively. Overweight was presented in 25.6% and obesity in 6.9%. Among those with more than 5 years of disease, screening for retinopathy was performed in the preceding year in 70.1%. Nephropathy and feet complications were screened in 63.1% and 65.1%, respectively. Conclusions: The majority of patients did not meet metabolic control goals and a substantial proportion was not screened for diabetic complications. These issues may increase the risk of chronic complications and negatively impact public health. (C) 2012 Elsevier Ireland Ltd. All rights reserved.