Karena L. Swan

Is an automatic pump suspension feature safe for children with type 1 diabetes? An exploratory analysis with a closed-loop system.

OBJECTIVES It has been proposed that the first step towards a closed-loop artificial pancreas might be to use a continuous glucose sensor to automatically suspend the basal insulin delivery based on projected low sensor glucose values. METHODS We reviewed our recent experience with an artificial pancreas system, utilizing a proportional-integrative-derivative (PID) algorithm, in 17 adolescents with type 1 diabetes (T1D) to assess the safety and efficacy of this maneuver. RESULTS During 34 h of closed-loop automated insulin delivery, 18 pump suspensions > or =60 min (90 +/- 18 min) occurred in eight subjects. Sensor glucose levels fell from 159 +/- 42 mg/dL to a nadir of 72 +/- 13 mg/dL. Corresponding plasma glucose levels fell from 168 +/- 51 to 72 +/- 16 mg/dL, with values <60 mg/dL recorded in only four of the 18 events. CONCLUSIONS These data suggest that automatic pump suspension using the PID algorithm may be an effective means to prevent hypoglycemia in youth with T1D.

Effect of Age of Infusion Site and Type of Rapid-Acting Analog on Pharmacodynamic Parameters of Insulin Boluses in Youth With Type 1 Diabetes Receiving Insulin Pump Therapy

OBJECTIVE—The purpose of this study was to examine the effect of type of insulin analog and age of insertion site on the pharmacodynamic characteristics of a standard insulin bolus in youth with type 1 diabetes receiving insulin pump therapy. RESEARCH DESIGN AND METHODS—Seventeen insulin pump–treated adolescents with type 1 diabetes underwent two euglycemic clamp procedures after a 0.2 unit/kg bolus of either insulin aspart or lispro on day 1 and day 4 of insulin pump site insertion. The glucose infusion rate (GIR) required to maintain euglycemia was the primary pharmacodynamic measure. RESULTS—There were no statistically significant differences in any of the pharmacodynamic parameters between aspart and lispro during day 1 and day 4. However, when the two groups were combined, time to discontinuation of exogenous glucose infusion, and time to half-maximal onset and offset of insulin action were observed significantly earlier during day 4 compared with day 1 (P = 0.03–0.0004), but the overall area under the GIR curve was similar on day 1 and day 4. CONCLUSIONS—With both insulin aspart and lispro, there is an earlier peak and shorter duration of action with increasing duration of infusion site use, but overall insulin action is not affected.

Emerging evidence for the use of insulin pump therapy in infants, toddlers, and preschool‐aged children with type 1 diabetes

Abstract:  Insulin pump therapy has, within the last 10 years, emerged as an increasingly popular modality of treatment to achieve intensive glycemic targets in type 1 diabetes (T1D). The evidence for the benefits of pump therapy has been demonstrated in adults and adolescents; however, until recently there has been a paucity of studies examining the efficacy and safety in pump therapy in very young children. The purpose of this article is to discuss the rationale for insulin pump therapy in infants and toddlers, review the available studies of pump therapy in this population, and show that the data support the use of insulin pumps in our very youngest of patients.

The Alteration of Aspart Insulin Pharmacodynamics When Mixed With Detemir Insulin

OBJECTIVE Mixing rapid acting insulin analogs with detemir insulin to minimize daily injections has been adopted as a common regimen, especially for some children with type 1 diabetes, despite the manufacturing company’s caution against mixing these analogs in the same syringe. The effect of this practice on the pharmacodynamics (PD) of rapid-acting insulin has not been widely studied. This crossover, randomized study was undertaken to determine whether mixing aspart with detemir insulin has an adverse effect on the early glucodynamic action of rapid-acting insulin analog in humans. RESEARCH DESIGN AND METHODS Eight adolescents with type 1 diabetes (age 17.3 ± 0.6 years and A1C 7.3 ± 0.3%) had two euglycemic glucose clamps during which 0.2 units/kg aspart and 0.4 units/kg detemir insulin were injected either as a separate or single mixed injection in random order. RESULTS Mixing the two insulins diminished the peak and overall early aspart insulin action with significantly lower maximum glucose infusion rate (GIRmax separate 6.1 ± 0.7 mg/kg/min vs. mix 4.5 ± 0.5 mg/kg/min; P = 0.03) values and the area under curve for GIR during the first 3 h of the insulin action study (separate 757 ± 105 mg/kg vs. mix 491 ± 66 mg/kg; P = 0.04). CONCLUSIONS These data demonstrate that mixing aspart with detemir insulin markedly lowers the early PD action of aspart and prolongs its time-action profile as compared with the separate injection of these analogs. These changes in insulin PD should be weighed against the added convenience of mixing when considering such unlicensed use of these insulins in youth with type 1 diabetes.

The renaissance of insulin pump treatment in childhood type 1 diabetes

Current goals for the treatment of children and adolescents with type 1 diabetes mellitus include achieving near-normal blood sugar levels, minimizing the risk of hypoglycemia, optimizing quality of life, and preventing or delaying long-term microvascular and macrovascular complications. Continuous subcutaneous insulin infusion (CSII), or insulin pump therapy, provides a treatment option that can assist in the attainment of all of these goals in all ages of children. In pediatric patients, CSII has been demonstrated to reduce both glycosylated hemoglobin levels and frequency of severe hypoglycemia, without sacrifices in safety, quality of life, or weight gain, particularly in conjunction with the use of new insulin analogs and improvements in pump technology. Clinical studies of safety and efficacy of CSII in children are reviewed, as well as criteria for patient selection and practical considerations using pump therapy in youth with T1DM.

Calcium-Sensing Receptor Promotes Breast Cancer by Stimulating Intracrine Actions of Parathyroid Hormone–Related Protein

Parathyroid hormone-related protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, tumor growth, and osteolytic bone metastases, but it is not known how PTHrP is upregulated in breast tumors. Here we report a central role in this process for the calcium-sensing receptor, CaSR, which enables cellular responses to changes in extracellular calcium, through studies of CaSR-PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo Tissue-specific disruption of the casr gene in mammary epithelial cells in MMTV-PymT mice reduced tumor PTHrP expression and inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. The actions of the CaSR appeared to be mediated by nuclear actions of PTHrP that decreased p27(kip1) levels and prevented nuclear accumulation of the proapoptotic factor apoptosis inducing factor. Taken together, our findings suggest that CaSR-PTHrP interactions might be a promising target for the development of therapeutic agents to limit tumor cell growth in bone metastases and in other microenvironments in which elevated calcium and/or PTHrP levels contribute to breast cancer progression. Cancer Res; 76(18); 5348-60. ©2016 AACR.

Hypoglycemia in childhood type 1 diabetes mellitus: Understanding and managing the dark side of intensive insulin therapy

Abstract Background: Despite the availability of advanced insulin delivery systems, blood glucose-monitoring equipment, and insulin analogue formulations, hypoglycemia remains a significant concern in the treatment of children and adolescents with type 1 diabetes mellitus (DM). Furthermore, patients who manage their blood glucose levels most effectively may also be the ones at greatest risk for hypoglycemia. Objective: The aim of this article was to review current issues surrounding the pathophysiology and frequency of hypoglycemia in children and adolescents with type 1 DM. Methods: Relevant articles for this review were identified through a search of MEDLINE (1992–2007; English-language articles only). The search terms used were children, adolescents, hypoglycemia, diabetes, insulin, and continuous subcutaneous insulin infusion . Results: The threat of severe hypoglycemia remains a major obstacle to the effective treatment of type 1 DM. Basalbolus therapy, using continuous subcutaneous insulin infusion or multiple daily injections, is the most effective and flexible method available for maintaining good glycemic control in children as well as in adults. Insulin analogues can be used effectively in these regimens and may be helpful toward addressing risks for hypoglycemia. Patient education should also be given a high priority in addressing the risk of hypoglycemia in children and adolescents with type 1 DM. The development of continuous glucose-monitoring systems offers the potential for an even brighter future for this group of patients. Conclusions: Recent advances in DM technology reduce but do not eliminate the risk of hypoglycemia in youth with type 1 DM. These observations underscore the need for a closed-loop insulin delivery system in which the rate of insulin infusion is regulated by real-time changes in glucose concentrations. ( Insulin. 2007;2:157–165) Key words: type 1 diabetes mellitus; hypoglycemia; children; adolescents; insulin analogue; continuous subcutaneous insulin infusion; multiple daily injections; basal-bolus therapy. Accepted for publication 09052007