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.

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 (GIR(max) 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.

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.

Fully automated closed-loop insulin delivery versus semiautomated hybrid control in pediatric patients with type 1 diabetes using an artificial pancreas.

OBJECTIVE: The most promising beta-cell replacement therapy for children with type 1 diabetes is a closed-loop artificial pancreas incorporating continuous glucose sensors and insulin pumps. The Medtronic MiniMed external physiological insulin delivery (ePID) system combines an external pump and sensor with a variable insulin infusion rate algorithm designed to emulate the physiological characteristics of the beta-cell. However, delays in insulin absorption associated with the subcutaneous route of delivery inevitably lead to large postprandial glucose excursions. RESEARCH DESIGN AND METHODS: We studied the feasibility of the Medtronic ePID system in youth with type 1 diabetes and hypothesized that small manual premeal "priming" boluses would reduce postprandial excursions during closed-loop control. Seventeen adolescents (aged 15.9 +/- 1.6 years; A1C 7.1 +/- 0.8%) underwent 34 h of closed-loop control; 8 with full closed-loop (FCL) control and 9 with hybrid closed-loop (HCL) control (premeal priming bolus). RESULTS: Mean glucose levels were 135 +/- 45 mg/dl in the HCL group versus 141 +/- 55 mg/dl in the FCL group (P = 0.09); daytime glucose levels averaged 149 +/- 47 mg/dl in the HCL group versus 159 +/- 59 mg/dl in the FCL group (P = 0.03). Peak postprandial glucose levels averaged 194 +/- 47 mg/dl in the HCL group versus 226 +/- 51 mg/dl in the FCL group (P = 0.04). Nighttime control was similar in both groups (111 +/- 27 vs. 112 +/- 28 mg/dl). CONCLUSIONS: Closed-loop glucose control using an external sensor and insulin pump provides a means to achieve near-normal glucose concentrations in youth with type 1 diabetes during the overnight period. The addition of small manual priming bolus doses of insulin, given 15 min before meals, improves postprandial glycemic excursions.

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.

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

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.