Hyperglycemic clamp and oral glucose tolerance test for 3-year prediction of clinical onset in persistently autoantibody-positive offspring and siblings of type 1 diabetic patients.

Context And Objective: In preparation of future prevention trials, we aimed to identify predictors of 3-year diabetes onset among oral glucose tolerance test (OGTT)- and hyperglycemic clamp-derived metabolic markers in persistently islet autoantibody positive (autoAb(+)) offspring and siblings of patients with type 1 diabetes (T1D).

Design: The design is a registry-based study.

Setting: Functional tests were performed in a hospital setting.

Osteoprotegerin is not a determinant of metabolic syndrome in sub-Saharan Africans after age adjustment.

Objectives: Osteoprotegerin (OPG), a soluble member of tumor necrosis factor receptor superfamily that inhibits bone resorption, has been suggested as a cardiovascular risk factor in humans. In this study, we aim to investigate the potential relationship between OPG and MetS (MetS) in a sub-Saharan African population.

Methods: Four hundred and eleven volunteers (152 men, 259 women) aged ≥18 years recruited from the general population in Douala and Edea, Cameroon participated in this study.

Early alteration of kidney function in nonuremic type 1 diabetic islet transplant recipients under tacrolimus-mycophenolate therapy.

Background: Transplant patients on tacrolimus therapy exhibit a reduced glomerular filtration rate (GFR). The type of graft and immune treatment protocol may influence the extent and reversibility of this side effect.

Methods: The present single-center study is conducted in 48 nonuremic type 1 diabetic recipients of an intraportal islet-cell graft under maintenance immunosuppression (IS) with tacrolimus and mycophenolate mofetil.

Glucose regulates rat beta cell number through age-dependent effects on beta cell survival and proliferation.

Background: Glucose effects on beta cell survival and DNA-synthesis suggest a role as regulator of beta cell mass but data on beta cell numbers are lacking. We examined outcome of these influences on the number of beta cells isolated at different growth stages in their population.

Methods: Beta cells from neonatal, young-adult and old rats were cultured serum-free for 15 days.

Clinical and biological characteristics of diabetic patients under age 40 in Cameroon: relation to autoantibody status and comparison with Belgian patients.

Aims: We investigated the prevalence of diabetes autoantibodies (Abs) in Cameroonian patients and controls, assessed their contribution in disease classification and compared results with data from Belgium.

Methods: Abs against GAD (GADA), IA-2 (IA-2A) and zinc transporter 8 (ZnT8A) were assessed in 302 recently diagnosed Cameroonian patients with diabetes and 184 control subjects without diabetes aged below 40 years.

Results: Only 27 (9%) Cameroonian patients were younger than 15 years.

Omentum is better site than kidney capsule for growth, differentiation, and vascularization of immature porcine β-cell implants in immunodeficient rats.

Background: Rapid revascularization of islet cell implants is important for engraftment and subsequent survival and function. Development of an adequate vascular network is expected to allow adaptive growth of the β-cell mass. The present study compares omentum and kidney capsule as sites for growth and differentiation of immature β-cell grafts.

Functional characteristics of neonatal rat β cells with distinct markers.

Neonatal β cells are considered developmentally immature and hence less glucose responsive. To study the acquisition of mature glucose responsiveness, we compared glucose-regulated redox state, insulin synthesis, and secretion of β cells purified from neonatal or 10-week-old rats with their transcriptomes and proteomes measured by oligonucleotide and LC-MS/MS profiling. Lower glucose responsiveness of neonatal β cells was explained by two distinct properties: higher activity at low glucose and lower activity at high glucose.

In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

Aims/hypothesis: Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia.

HLA-A*24 is an independent predictor of 5-year progression to diabetes in autoantibody-positive first-degree relatives of type 1 diabetic patients.

We investigated whether HLA-A*24 typing complements screening for HLA-DQ and for antibodies (Abs) against insulin, GAD, IA-2 (IA-2A), and zinc transporter-8 (ZnT8A) for prediction of rapid progression to type 1 diabetes (T1D). Persistently Ab(+) siblings/offspring (n = 288; aged 0-39 years) of T1D patients were genotyped for HLA-DQA1-DQB1 and HLA-A*24 and monitored for development of diabetes within 5 years of first Ab(+). HLA-A*24 (P = 0.

Beta cell count instead of beta cell mass to assess and localize growth in beta cell population following pancreatic duct ligation in mice.

Background: Pancreatic-tail duct ligation (PDL) in adult rodents has been reported to induce beta cell generation and increase beta cell mass but increases in beta cell number have not been demonstrated. This study examines whether PDL increases beta cell number and whether this is caused by neogenesis of small clusters and/or their growth to larger aggregates.

Methodology: Total beta cell number and its distribution over small (<50 µm), medium, large (>100 µm) clusters was determined in pancreatic tails of 10-week-old mice, 2 weeks after PDL or sham.

Protein markers for insulin-producing beta cells with higher glucose sensitivity.

Background And Methodology: Pancreatic beta cells show intercellular differences in their metabolic glucose sensitivity and associated activation of insulin production. To identify protein markers for these variations in functional glucose sensitivity, rat beta cell subpopulations were flow-sorted for their level of glucose-induced NAD(P)H and their proteomes were quantified by label-free data independent alternate scanning LC-MS. Beta cell-selective proteins were also identified through comparison with rat brain and liver tissue and with purified islet alpha cells, after geometrical normalization using 6 stably expressed reference proteins.

Interaction of glibenclamide and metformin at the level of translation in pancreatic β cells.

Sulfonylurea and metformin are used in the treatment of diabetes. Their chronic effects on β cells are not well known. We have shown that sustained exposure of rat β cells to glibenclamide increased their protein synthesis activity, while metformin caused an inhibition.

Contribution of postnatally formed small beta cell aggregates to functional beta cell mass in adult rat pancreas.

Aims/hypothesis: Neogenesis of beta cells and their clustering to small aggregates is a key process in prenatal development of beta cell mass. We investigated the contribution of postnatally formed small aggregates to functional beta cell mass in adult rats.

Methods: Conditions were defined for (1) counting total beta cell number in pancreases with relative error of <10% and (2) determining their distribution over aggregates of different size and over functionally different subpopulations.

Human islet cell implants in a nude rat model of diabetes survive better in omentum than in liver with a positive influence of beta cell number and purity.

Aims/hypothesis: Intraportal human islet cell grafts do not consistently and sustainably induce insulin-independency in type 1 diabetic patients. The reasons for losses in donor cells are difficult to assess in patients. This study in streptozotocin-diabetic nude rats examines whether outcome is better in an extra-hepatic site such as omentum.

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass.

Aims/hypothesis: The aim of the study was to examine the 48 month outcome of treating recent-onset type 1 diabetic patients for 6 days with humanised CD3-antibody, ChAglyCD3.

Methods: Eighty patients, aged 12-39 years, were recruited for a phase 2 multicentre trial and randomised to placebo (n=40) or ChAglyCD3 (n=40) treatment by a third party member; participants and care-givers were blinded. The change in insulin dose (U kg(-1)day(-1)) over 48 months was chosen as primary endpoint and compared in 31 placebo-and 33 ChAglyCD3-treated patients.

Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2beta) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: implications for prevention trials.

Aims/hypothesis: We investigated whether screening for insulinoma-associated protein (IA-2) beta (IA-2beta) autoantibodies (IA-2betaA) and zinc transporter-8 (ZnT8) autoantibodies (ZnT8A) improves identification of first-degree relatives of type 1 diabetic patients with a high 5-year disease risk, which to date has been based on assays for insulin autoantibodies (IAA), GAD autoantibodies (GADA) and IA-2 autoantibodies (IA-2A).

Methods: IA-2betaA and ZnT8A (using a ZnT8 carboxy-terminal hybrid construct, CW-CR, carrying 325Arg and 325Trp) were determined by radiobinding assay in 409 IAA(+), GADA(+) and/or IA-2A(+) siblings or offspring (<40 years) of type 1 diabetic patients consecutively recruited by the Belgian Diabetes Registry. The median (interquartile range) age of the first-degree relatives was 12 (6-19) years.

Transient Epstein-Barr virus reactivation in CD3 monoclonal antibody-treated patients.

Here we report a unique situation in which an early and synchronized Epstein-Barr virus (EBV) reactivation was induced by a 6-day course of treatment with a humanized CD3-specific monoclonal antibody in patients with recent onset of type 1 diabetes. The virologic and immunologic analysis demonstrated that this reactivation was transient, self-limited, and isolated, associated with the rapid advent of an EBV-specific T-cell response. The anti-CD3 antibody administration induced short-lasting immunosuppression and minor yet clear-cut signs of T-cell activation that preceded viral reactivation.

Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients.

Aims/hypothesis: The aim of the study was to investigate the use of hyperglycaemic clamp tests to identify individuals who will develop diabetes among insulinoma-associated protein-2 antibody (IA-2A)-positive first-degree relatives (IA-2A(+) FDRs) of type 1 diabetic patients.

Methods: Hyperglycaemic clamps were performed in 17 non-diabetic IA-2A(+) FDRs aged 14 to 33 years and in 21 matched healthy volunteers (HVs). Insulin and C-peptide responses were measured during the first (5-10 min) and second (120-150 min) release phase, and after glucagon injection (150-160 min).

Susceptibility of pancreatic beta cells to fatty acids is regulated by LXR/PPARalpha-dependent stearoyl-coenzyme A desaturase.

Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties.

Successful Primary Treatment of a Hydatidiform Mole with Methotrexate and EMA/CO.

Background. The preferred treatment method of most hydatidiform moles is suction aspiration. In rare circumstances uterine abnormalities may preclude surgical treatment.

The beta cell population in type 1 diabetes.

Type 1 diabetes is often considered as a disease where more than 90% of the beta cells have been destroyed at clinical onset and where beta cell antigen-driven autoimmune reactivities progressively destroy remaining beta cells as well as newly formed or implanted beta cells. This view will be evaluated in light of histological observations in the pancreas of type 1 diabetic patients and of antibody-positive non-diabetic organ donors.

Functional beta-cell mass and insulin sensitivity is decreased in insulin-independent pancreas-kidney recipients.

Background: To compare functional beta-cell mass and insulin sensitivity in insulin-independent pancreas-kidney recipients with that in age- and body mass index-matched nondiabetic kidney recipients and normal controls.

Methods: All transplant recipients were on maintenance immunosuppression with mycophenolate mofetil and tacrolimus since more than 2.7 years (2.

Restoring a functional beta-cell mass in diabetes.

Type 1 and type 2 diabetes have often been presented as disease forms that profoundly differ in the presence and pathogenic significance of a reduced beta-cell mass. We review evidence indicating that the beta-cell mass in type 1 diabetes is usually not decreased by at least 90% at clinical onset, and remains often detectable for years after diagnosis at age above 15 years. Clinical and experimental evidence also exists for a reduced beta-cell mass in type 2 diabetes where it can be the cause for and/or the consequence of dysregulated beta-cell functions.

Peroxisome proliferator-activated receptor alpha-retinoid X receptor agonists induce beta-cell protection against palmitate toxicity.

Fatty acids can stimulate the secretory activity of insulin-producing beta-cells. At elevated concentrations, they can also be toxic to isolated beta-cells. This toxicity varies inversely with the cellular ability to accumulate neutral lipids in the cytoplasm.

Adiponectin levels do not predict clinical onset of type 1 diabetes in antibody-positive relatives.

Aims/hypothesis: Insulin resistance has been proposed as a risk factor for type 1 diabetes. We investigated whether adiponectin, an insulin sensitiser, can serve as an additional predictive marker for type 1 diabetes in first-degree relatives of known patients.

Methods: Adiponectin was followed in 211 persistently islet antibody-positive (Ab+) first-degree relatives of type 1 diabetic patients and in 211 age- and sex-matched persistently antibody-negative relatives, and correlated with antibody status, random proinsulin:C-peptide ratio and HLA-DQ genotype.