Knud Bonnet Yderstræde

Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype: Action LADA 7

OBJECTIVE Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes. RESEARCH DESIGN AND METHODS We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3). CONCLUSIONS Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype Action LADA 7

OBJECTIVE Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes. RESEARCH DESIGN AND METHODS We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3). CONCLUSIONS Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

Diabetes classification: grey zones, sound and smoke: Action LADA 1

Diseases gain identity from clinical phenotype as well as genetic and environmental aetiology. The definition of type 1 diabetes is clinically exclusive, comprising patients who are considered insulin dependent at diagnosis, whilst the definition of type 2 diabetes is inclusive, only excluding those who are initially insulin dependent. Ketosis‐prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these major types of diabetes.

Pharmacological Treatment of the Pathogenetic Defects in Type 2 Diabetes The randomized multicenter South Danish Diabetes Study

OBJECTIVE To determine the effect of treatment with insulin aspart compared with NPH insulin, together with metformin/placebo and rosiglitazone/placebo. The hypothesis was that combined correction of major pathogenetic defects in type 2 diabetes would result in optimal glycemic control. RESEARCH DESIGN AND METHODS This study was a 2-year investigator-driven randomized partly placebo-controlled multicenter trial in 371 patients with type 2 diabetes on at least oral antiglycemic treatment. Patients were assigned to one of eight treatment groups in a factorial design with insulin aspart at mealtimes versus NPH insulin once daily at bedtime, metformin twice daily versus placebo, and rosiglitazone twice daily versus placebo. The main outcome measurement was change in A1C. RESULTS A1C decreased more in patients treated with insulin aspart compared with NPH (−0.41 ± 0.10%, P < 0.001). Metformin decreased A1C compared with placebo (−0.60 ± 0.10%, P < 0.001), as did rosiglitazone (−0.55 ± 0.10%, P < 0.001). Triple therapy (rosiglitazone, metformin, and any insulin) resulted in a greater reduction in A1C than rosiglitazone plus insulin (−0.50 ± 0.14%, P < 0.001) and metformin plus insulin (−0.45 ± 0.14%, P < 0.001). Aspart was associated with a higher increase in body weight (1.6 ± 0.6 kg, P < 0.01) and higher incidence of mild daytime hypoglycemia (4.9 ± 7.5 vs. 1.7 ± 5.4 number/person/year, P < 0.001) compared with NPH. CONCLUSIONS Insulin treatment of postprandial hyperglycemia results in lower A1C than treatment of fasting hyperglycemia, at the expense of higher body weight and hypoglycemic episodes. However, insulin therapy has to be combined with treatment of both peripheral and liver insulin resistance to normalize blood glucose, and in this case, the insulin regimen is less important.

A qualitative study of the key factors in implementing telemedical monitoring of diabetic foot ulcer patients

INTRODUCTION The implementation of telemedicine often introduces major organizational changes in the affected healthcare sector. The objective of this study was to examine the organizational changes through the perception of the healthcare professionals regarding the implementation of a telemedical intervention. We posed the following research question: What are the key organizational factors in the implementation of telemedicine in wound care? METHODS In connection with a randomized controlled trial of telemedical intervention for patients with diabetic foot ulcers in the region of Southern Denmark, we conducted an organizational analysis. The trial was designed as a multidisciplinary assessment of outcomes using the Model of ASsessment of Telemedicine (MAST). We conducted eight semi-structured interviews including individual interviews with leaders, and an IT specialist as well as focus group interviews with the clinical staff. A qualitative data analysis of the interviews was performed in order to analyze the healthcare professionals and leaders perception of the organizational changes caused by the implementation of the intervention. RESULTS The telemedical setup enhanced confidence among collaborators and improved the wound care skills of the visiting nurses from the municipality. The effect was related to the direct communication between visiting nurses and specialist doctors. Focus on the training of the visiting nurses was highlighted as a key factor in the success to securing implementation. Concerns regarding lack of multidisciplinary wound care teams, patient responsibility and lack of patient interaction with the physician were raised. Furthermore, the need for clinical guidelines in future implementation was underlined. CONCLUSIONS Several influential factors were demonstrated in the analysis including visiting nurses wound care training, focus on management, economy, periods with absence from work and clinical care. However, the technology used here could provide an additional option to offer patients after an individual assessment of their health condition.

Rosiglitazone Decreases Plasma Levels of Osteoprotegerin in a Randomized Clinical Trial with Type 2 Diabetes Patients

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). We suggested that plasma osteoprotegerin (OPG), a strong, independent predictor of cardiovascular disease, could discriminate between anti-diabetic treatments depending on their benefits regarding cardiovascular disease. The South Danish Diabetes Study, an investigator-driven, randomized, controlled clinical trial lasting 2 years, was used to test this hypothesis in patient groups with different medication strategies (insulin aspart or NPH insulin, added either metformin/placebo or rosiglitazone/placebo). A total of 371 individuals were eligible for the study. Basic variables were analysed along with measurement of plasma OPG and HbA(1c) at the beginning and end of the study. Only rosiglitazone treatment caused a significant decrease in plasma OPG concentrations (p = 0.003), while no significant change was seen in the other treatment groups. The effect of rosiglitazone on plasma OPG remained significant in a univariate analysis adjusted for change in HbA(1c) (p = 0.013). Of note, the change in plasma OPG significantly correlated with HbA(1c) improvement in rosiglitazone-treated patients (R = 0.29, p = 0.0002), while this correlation was poor in those not receiving rosiglitazone (R = 0.06, p =0.48). Treatment with rosiglitazone among patients with T2DM reduces the concentration of plasma OPG. This is not seen with metformin despite similar reductions in HbA(1c) . Alteration in the OPG/RANKL pathway by glitazones may have implications for the understanding of both cardiovascular effects and bone side effects of the drug.

Similar weight-adjusted insulin secretion and insulin sensitivity in short-duration late autoimmune diabetes of adulthood (LADA) and Type 2 diabetes: Action LADA 8

To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with Type 2 diabetes.

Functional and Immunohistochemical Evaluation of Porcine Neonatal Islet-Like Cell Clusters

Porcine neonatal islet-like cell clusters (NICCs) may be an attractive source of insulin-producing tissue for xenotransplantation in type I diabetic patients. We examined the functional and immunohistochemical outcome of the islet grafts in vitro during long-term culture and in vivo after transplantation to athymic nude mice. On average we obtained 29,000 NICCs from each pancreas. In a perifusion system, NICCs responded poorly to a glucose challenge alone, but 10 mmol/L arginine elicited a fourfold increase in insulin secretion and 16.7 mmol/L glucose + 10 mmol/L arginine caused a sevenfold increase in insulin secretion, indicating some sensitivity towards glucose. Hormone content as well as the number of hormone-containing cells increased for the first 14 days of culture. When NICCs were stained for hormones, proliferation (Ki67), and duct cells (CK7), some insulin- and glucagon-positive cells co-stained for proliferation. However no co-staining was observed between insulin- and glucagon-positive cells or between hormone- and CK7-positive cells. Following transplantation of 2000 NICCs under the renal capsule of diabetic nude mice, BG levels were normalized within an average of 13 weeks. Oral and IP glucose tolerance tests revealed a normal or even faster clearance of a glucose load compared with normal controls. Immunohistochemical examination of the grafts revealed primarily insulin-positive cells. In summary, in vitro, NICCs responded to a challenge including glucose and arginine. There was a potential for expansion of the β-cell mass of NICCs in vitro as well as in vivo where NICCs eventually may normalize blood glucose of diabetic mice.

A Novel −192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4α Gene (HNF4A) Associates With Late-Onset Diabetes

Recently, it has been shown that mutations in the P2 promoter of the hepatocyte nuclear factor (HNF)-4α gene (HNF4A) cause maturity-onset diabetes of the young (MODY), while single nucleotide polymorphisms in this locus are associated with type 2 diabetes. In this study, we examined 1,189 bp of the P2 promoter and the associated exon 1D of HNF4A for variations associated with diabetes in 114 patients with type 2 diabetes, 72 MODYX probands, and 85 women with previous gestational diabetes mellitus. A −192c/g mutation was found in five patients. We screened 1,587 diabetic subjects and 4,812 glucose-tolerant subjects for the −192c/g mutation and identified 5 diabetic and 1 glucose-tolerant mutation carriers (P = 0.004). Examination of the families showed that carriers of the −192c/g mutation had a significantly impaired glucose-stimulated insulin release and lower levels of serum total cholesterol compared with matched control subjects. Furthermore, the mutation disrupted the binding of an unidentified sequence-specific DNA binding complex present in human islet extracts. Also, two novel linked polymorphisms in the P2 promoter at positions −1107g/t and −858c/t were identified. These variants were not significantly associated with type 2 diabetes or any pre-diabetic traits. In conclusion, a rare, novel mutation that disrupts a protein binding site in the pancreatic HNF4A promoter associates with late-onset diabetes.

Validation of a new imaging device for telemedical ulcer monitoring

To clarify whether a new portable imaging device (PID) providing 3D images for telemedical use constitutes a more correct expression of the clinical situation compared to standard telemedical equipment in this case iPhone 4s.