Conversion of Mature Human β-Cells Into Glucagon-Producing α-Cells

Conversion of one terminally differentiated cell type into another (or transdifferentiation) usually requires the forced expression of key transcription factors. We examined the plasticity of human insulin-producing β-cells in a model of islet cell aggregate formation. Here, we show that primary human β-cells can undergo a conversion into glucagon-producing α-cells without introduction of any genetic modification. The process occurs within days as revealed by lentivirus-mediated β-cell lineage tracing. Converted cells are indistinguishable from native α-cells based on ultrastructural morphology and maintain their α-cell phenotype after transplantation in vivo. Transition of β-cells into α-cells occurs after β-cell degranulation and is characterized by the presence of β-cell–specific transcription factors Pdx1 and Nkx6.1 in glucagon+ cells. Finally, we show that lentivirus-mediated knockdown of Arx, a determinant of the α-cell lineage, inhibits the conversion. Our findings reveal an unknown plasticity of human adult endocrine cells that can be modulated. This endocrine cell plasticity could have implications for islet development, (patho)physiology, and regeneration

Association between person and disease related factors and the planned diabetes care in people who receive person-centered type 2 diabetes care : An implementation study

AIMS: To assess the planned diabetes care for the coming year and its associated factors in patients with Type 2 diabetes who have a person-centered annual consultation. METHODS: Implementation study of a new consultation model in 47 general practices (primary care) and 6 outpatient clinics (secondary care); 1200 patients from primary and 166 from secondary care participated. Data collection took place between November 2015 and February 2017. Outcomes: preferred monitoring frequency; referral to other health care provider(s); medication change. One measurement at the end of the consultation. We performed logistic regression analyses. Differences between primary and secondary care were analyzed. RESULTS: Many patients arranged a monitoring frequency <4 times per year (general practices 19.5%, outpatient clinics 40%, p < .001). Type of provider (physician/nurse, OR 3.83, p < .001), baseline HbA1c (OR 1.02, p = .017), glucose lowering medication; and setting treatment goals (OR .65, p = .048) were associated with the chosen frequency. Independently associated with a referral were age (OR .99, p = .039), baseline glucose lowering medication and patients' goal setting (OR 1.52, p = .016). Medication change was associated with type of provider, baseline HbA1c, blood glucose lowering medication, quality of life (OR .80, p = .037) and setting treatment goals (OR 2.64, p = .001). CONCLUSIONS: Not only disease but also person related factors, especially setting treatment goals, are independently associated with planned care use in person-centered diabetes care

Advances in β-cell replacement therapy for the treatment of type 1 diabetes

The main goal of treatment for type 1 diabetes is to control glycaemia with insulin therapy to reduce disease complications. For some patients, technological approaches to insulin delivery are inadequate, and allogeneic islet transplantation is a safe alternative for those patients who have had severe hypoglycaemia complicated by impaired hypoglycaemia awareness or glycaemic lability, or who already receive immunosuppressive drugs for a kidney transplant. Since 2000, intrahepatic islet transplantation has proven efficacious in alleviating the burden of labile diabetes and preventing complications related to diabetes, whether or not a previous kidney transplant is present. Age, body-mass index, renal status, and cardiopulmonary status affect the choice between pancreas or islet transplantation. Access to transplantation is limited by the number of deceased donors and the necessity of immunosuppression. Future approaches might include alternative sources of islets (eg, xenogeneic tissue or human stem cells), extrahepatic sites of implantation (eg, omental, subcutaneous, or intramuscular), and induction of immune tolerance or encapsulation of islets

Patient activation in individuals with type 2 diabetes mellitus : Associated factors and the role of insulin

Aim: This study explored the relationship between insulin use and patient activation (a person’s internal readiness and capabilities to undertake health-promoting actions) in individuals with type 2 diabetes mellitus and aimed to identify demographic, clinical and psychosocial factors involved in patient activation. Methods: In this cross-sectional study, baseline data from a Dutch nationwide study were analyzed. Patient activation was assessed with the Patient Activation Measure 13. A linear mixed model was used to take clustering into account. Results: In total, 1,189 persons were included (310 of whom were on insulin), enrolled via 47 general practices and six hospitals. Their mean Patient Activation Measure 13 score was 59±12. We found no association between insulin therapy and patient activation. In the multivariable analysis, individuals with a better health status, very good or very poor social support (vs good social support), individuals who felt they had greater control over their illness and those with a better subjective understanding of their illness showed higher patient activation. Individuals with a lower educational level and those who expected their illness to continue showed a lower activation level. Conclusion: Patient activation does not differ between individuals with type 2 diabetes mellitus on insulin therapy and those on other therapies

Increased Insulin Requirements During Exercise at Very High Altitude in Type 1 Diabetes

Item does not contain fulltextOBJECTIVE: Safe, very high altitude trekking in subjects with type 1 diabetes requires understanding of glucose regulation at high altitude. We investigated insulin requirements, energy expenditure, and glucose levels at very high altitude in relation to acute mountain sickness (AMS) symptoms in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: Eight individuals with complication-free type 1 diabetes took part in a 14-day expedition to Mount Meru (4,562 m) and Mount Kilimanjaro (5,895 m) in Tanzania. Daily insulin doses, glucose levels, energy expenditure, and AMS symptoms were determined. Also, energy expenditure and AMS symptoms were compared with a healthy control group. RESULTS: We found a positive relation between AMS symptoms and insulin requirements (r = 0.78; P = 0.041) and AMS symptoms and glucose levels (r = 0.86; P = 0.014) for Mount Kilimanjaro. Compared with sea level, insulin doses tended to decrease by 14.2% (19.7) (median [interquartile range]) (P = 0.41), whereas glucose levels remained stable up to 5,000 m altitude. However, at altitudes >5,000 m, insulin dose was unchanged (36.8 +/- 17 vs. 37.6 +/- 19.1 international units [mean +/- SD] P = 0.75), but glucose levels (7.5 +/- 0.6 vs. 9.5 +/- 0.8 mmol/L [mean +/- SD] P = 0.067) and AMS scores (1.3 +/- 1.6 vs. 4.4 +/- 4 points [mean +/- SD] P = 0.091) tended to increase. Energy expenditure and AMS symptoms were comparable in both groups (P = 0.84). CONCLUSIONS: Our data indicate that in complication-free individuals with type 1 diabetes, insulin requirements tend to increase during altitudes above 5,000 m despite high energy expenditure. This change may be explained, at least partly, by AMS

Erfelijke ouderdomsdiabetes bij jongeren

Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes mellitus, estimated to account for approximately 1-4% of patients with diabetes. The predicted prevalence is, therefore, 20,000 patients in The Netherlands. Unfortunately less than 5% of these patients are confirmed by molecular genetic analysis. MODY is a clinically heterogeneous group of disorders caused by β-cell dysfunction, which is caused by mutations in multiple genes. MODY is characterized by an early onset of diabetes (often before the age of 30 years) and autosomal dominant inheritance. Patients do not usually require insulin at diagnosis. To emphasize the importance of genetic analysis we describe a 7-year-old boy and his siblings with MODY type 2. Molecular genetic testing is essential for individual patient care, as treatment options differ between the various forms of MODY; it also provides an opportunity to screen relatives

Pancreatic islet macroencapsulation using microwell porous membranes

Allogeneic islet transplantation into the liver in combination with immune suppressive drug therapy is widely regarded as a potential cure for type 1 diabetes. However, the intrahepatic system is suboptimal as the concentration of drugs and nutrients there is higher compared to pancreas, which negatively affects islet function. Islet encapsulation within semipermeable membranes is a promising strategy that allows for the islet transplantation outside the suboptimal liver portal system and provides environment, where islets can perform their endocrine function. In this study, we develop a macroencapsulation device based on thin microwell membranes. The islets are seeded in separate microwells to avoid aggregation, whereas the membrane porosity is tailored to achieve sufficient transport of nutrients, glucose and insulin. The non-degradable, microwell membranes are composed of poly (ether sulfone)/polyvinylpyrrolidone and manufactured via phase separation micro molding. Our results show that the device prevents aggregation and preserves the islet's native morphology. Moreover, the encapsulated islets maintain their glucose responsiveness and function after 7 days of culture (stimulation index above 2 for high glucose stimulation), demonstrating the potential of this novel device for islet transplantation

Genome-wide association study on the early-phase insulin response to a liquid mixed meal : Results from the NEO study

Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm-transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (β: -6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10-8]) located in the ABO gene reached genome-wide significant level (P < 531028) and was also replicated successfully (β: 27.8% [MAF 0.32, P = 7.2 × 10-5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion

Genome-wide association study on the early-phase insulin response to a liquid mixed meal : Results from the NEO study

Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm-transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (β: -6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10-8]) located in the ABO gene reached genome-wide significant level (P < 531028) and was also replicated successfully (β: 27.8% [MAF 0.32, P = 7.2 × 10-5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion