Melissa Meredith

Threshold-Based Insulin-Pump Interruption for Reduction of Hypoglycemia

BACKGROUND The threshold-suspend feature of sensor-augmented insulin pumps is designed to minimize the risk of hypoglycemia by interrupting insulin delivery at a preset sensor glucose value. We evaluated sensor-augmented insulin-pump therapy with and without the threshold-suspend feature in patients with nocturnal hypoglycemia. METHODS We randomly assigned patients with type 1 diabetes and documented nocturnal hypoglycemia to receive sensor-augmented insulin-pump therapy with or without the threshold-suspend feature for 3 months. The primary safety outcome was the change in the glycated hemoglobin level. The primary efficacy outcome was the area under the curve (AUC) for nocturnal hypoglycemic events. Two-hour threshold-suspend events were analyzed with respect to subsequent sensor glucose values. RESULTS A total of 247 patients were randomly assigned to receive sensor-augmented insulin-pump therapy with the threshold-suspend feature (threshold-suspend group, 121 patients) or standard sensor-augmented insulin-pump therapy (control group, 126 patients). The changes in glycated hemoglobin values were similar in the two groups. The mean AUC for nocturnal hypoglycemic events was 37.5% lower in the threshold-suspend group than in the control group (980 ± 1200 mg per deciliter [54.4 ± 66.6 mmol per liter] × minutes vs. 1568 ± 1995 mg per deciliter [87.0 ± 110.7 mmol per liter] × minutes, P<0.001). Nocturnal hypoglycemic events occurred 31.8% less frequently in the threshold-suspend group than in the control group (1.5 ± 1.0 vs. 2.2 ± 1.3 per patient-week, P<0.001). The percentages of nocturnal sensor glucose values of less than 50 mg per deciliter (2.8 mmol per liter), 50 to less than 60 mg per deciliter (3.3 mmol per liter), and 60 to less than 70 mg per deciliter (3.9 mmol per liter) were significantly reduced in the threshold-suspend group (P<0.001 for each range). After 1438 instances at night in which the pump was stopped for 2 hours, the mean sensor glucose value was 92.6 ± 40.7 mg per deciliter (5.1 ± 2.3 mmol per liter). Four patients (all in the control group) had a severe hypoglycemic event; no patients had diabetic ketoacidosis. CONCLUSIONS This study showed that over a 3-month period the use of sensor-augmented insulin-pump therapy with the threshold-suspend feature reduced nocturnal hypoglycemia, without increasing glycated hemoglobin values. (Funded by Medtronic MiniMed; ASPIRE ClinicalTrials.gov number, NCT01497938.).

Evidence of a role for GTP in the potentiation of Ca(2+)-induced insulin secretion by glucose in intact rat islets.

Glucose initiates insulin secretion by closing K(+)-ATP channels, leading to Ca2+ influx (E1); it also potentiates Ca(2+)-induced secretion (E2) when the K(+)-ATP channel is kept open using diazoxide and depolarizing concentrations of K+ are provided. To examine the roles of purine nucleotides in E2, we compared the effects of glucose to those of the mitochondrial fuel monomethylsuccinate. Either agonist could induce E2 accompanied by significant increases in ATP, ATP/ADP ratio, and GTP/GDP ratio; GTP increased significantly only with glucose. Mycophenolic acid (MPA), an inhibitor of cytosolic GTP synthesis, markedly inhibited glucose-induced E2 (either in perifusions or in static incubations) and decreased GTP and the GTP/GDP ratio, but did not alter the ATP/ADP ratio. Provision of guanine (but not adenine) reversed these changes pari passu. In contrast, MPA had no effect on succinate-induced E2, despite generally similar changes in nucleotides. A similar lack of effect of MPA on E2 was seen with a second mitochondrial fuel, alpha-ketoisocaproic acid (KIC). However, in the absence of diazoxide and K+, MPA blunted the secretory effects of either glucose, succinate, or KIC. These studies suggest that GTP plays a role in both glucose and succinate or KIC-induced insulin secretion at a step dependent on mitochondrial metabolism and the K(+)-ATP channel. In addition to mitochondrial effects, glucose appears to have extramitochondrial effects important to its potentiation of Ca(2+)-induced insulin secretion that are also dependent on GTP.

Alterations in energy balance following exenatide administration

Exenatide is a medication similar in structure and effect to native glucagon-like peptide-1, an incretin hormone with glucose-lowering properties. The aim of the study was to measure the change in total energy expenditure (TEE) and body composition during exenatide administration and by deduction the relative contributions of energy expenditure and energy intake to exenatide-induced weight loss. Forty-five obese (body mass index, 30-40 kg·m⁻²) subjects were identified. After exclusion criteria application, 28 subjects entered into the study and 18 subjects (12 female, 6 male) completed the study, which consisted of 6 visits over 14 weeks and injection of exenatide for an average of 84 ± 5 days. Respiratory gas analysis and doubly labeled water measurements were performed before initiation of exenatide and after approximately 3 months of exenatide administration. The average weight loss from the beginning of injection period to the end of the study in completed subjects was 2.0 ± 2.8 kg (p = 0.01). Fat mass declined by 1.3 ± 1.8 kg (p = 0.01) while the fat-free mass trended downward but was not significant (0.8 ± 2.2 kg, p = 0.14). There was no change in weight-adjusted TEE (p = 0.20), resting metabolic rate (p = 0.51), or physical activity energy expenditure (p = 0.38) and no change in the unadjusted thermic effect of a meal (p = 0.37). The significant weight loss because of exenatide administration was thus the result of decreasing energy intake. In obese nondiabetic subjects, exenatide administration did not increase TEE and by deduction the significant weight loss and loss of fat mass was due to decreased energy intake.

A Retrospective Study Comparing Neutral Protamine Hagedorn Insulin with Glargine as Basal Therapy in Prednisone-Associated Diabetes Mellitus in Hospitalized Patients

OBJECTIVE To compare glycemic outcomes in hospitalized patients with or without type 2 diabetes mellitus receiving neutral protamine Hagedorn insulin (NPH) vs glargine as basal insulin for management of glucocorticoid-associated hyperglycemia. METHODS We conducted a retrospective review of electronic medical records in prednisone-treated adult patients with hyperglycemia in a university hospital. Consecutive patients were selected in both the NPH and glargine cohorts using inclusion and exclusion criteria. Baseline characteristics were assessed in each cohort. Glycemic outcomes were analyzed by comparing fasting blood glucose, mean daily blood glucose concentration, median daily blood glucose concentration, and the number of hypoglycemic episodes on a prespecified index day. RESULTS One hundred twenty patients were included: 60 patients in the NPH cohort and 60 patients in the glargine cohort. The weight-based insulin requirement was lower in the NPH cohort than in the glargine cohort (0.27 ± 0.2 units/kg vs 0.34 ± 0.2 units/kg [P = .04] for basal insulin and 0.26 ± 0.2 units/kg vs 0.36 ± 0.2 units/kg [P = .03] for bolus insulin). NPH and glargine cohorts were similar regarding age, sex, race, body mass index, hemoglobin A1c, serum creatinine, and prednisone dosage. Glycemic outcomes in the NPH cohort compared with outcomes in the glargine cohort were similar regarding mean fasting blood glucose concentration (134 ± 49 mg/dL vs 139 ± 54 mg/dL [P = .63]), mean daily blood glucose (167 ± 46 mg/dL vs 165 ± 52 mg/dL [P = .79]), median blood glucose (160 ± 49 mg/dL vs 159 ± 57 mg/dL [P = .90]), and number of hypoglycemic episodes per day (0.12 ± 0.3 vs 0.10 ± 0.3 [P = .77]). CONCLUSIONS NPH and glargine appear to be equally effective as basal insulin in the management of hyperglycemia in hospitalized patients receiving prednisone. However, the total daily insulin doses used were lower in the NPH cohort.

Dual Functional Effects of Interleukin-1β on Purine Nucleotides and Insulin Secretion in Rat Islets and INS-1 Cells

Interleukin-1β (IL-1β) has been shown to inhibit glucose-induced insulin secretion from rat islets and purified β-cells, primarily through the generation of nitric oxide (NO). However, the mechanisms by which NO exerts its effects remain unclear. To examine the role of purine nucleotides, we cultured intact rat islets or INS-1 (glucose-responsive transformed rat) β-cells for 18 h in the presence or absence of IL-1β. In islets, the exposure to IL-1β (100 pmol/l) inhibited subsequent glucose-induced insulin secretion by 91% with no significant effect on insulin content or basal insulin release. IL-1β also diminished insulin secretion induced by pure mitochondrial fuels, 40 mmol/l K+, or a phorbol ester. Concomitantly, IL-1β significantly decreased islet ATP (–45%), GTP (–33%), ATP/ADP (–54%), and GTP/GDP (–46%). These effects were totally reversed by provision of Nω-nitro-L-arginine methyl ester (NAME) in arginine-free media that inhibited NO production. In contrast, in INS-1 cells, IL-1β (10 or 100 pmol/l) reduced both basal and glucose-induced insulin secretion by 50%, but insulin content was also reduced by 35%. Therefore, the INS-1 cells were still able to respond to glucose stimulation with a 1.8–2.0–fold increase in insulin release in either the presence or absence of IL-1β. Concomitantly, in INS-1 cells, IL-1β had no effect on ATP/ADP or GTP/GDP ratios, although it modestly decreased ATP (–25%) and GTP (–22%). As in islets, all effects of IL-1β in INS-1 cells were prevented by NAME. Thus, in rat islets, IL-1β (via the generation of NO) abolishes insulin exocytosis in association with large decreases in the ATP/ADP (and GTP/GDP) ratio, implying the impairment of mitochondrial function. Furthermore, IL-1β inhibits cytosolic synthesis of new purine nucleotides (via the salvage pathway), as assessed by a decrease in their specific activity after labeling with [3H]hypoxanthine. In contrast, in INS-1 cells, IL-1β appears to impair cytosolic synthesis of purine nucleotides and insulin biosynthesis selectively (both possibly reflecting decreased glycolysis) with little direct effect on insulin exocytosis itself.

Cytosolic biosynthesis of GTP and ATP in normal rat pancreatic islets

GTP and ATP are necessary for glucose-induced insulin secretion; however, the biosynthetic pathways of purine nucleotides have not been studied in pancreatic islets. The present work examines the cytosolic pathways of purine nucleotide synthesis using intact rat islets cultured overnight in RPMI 1640 medium containing either [14C]glycine (to label the de novo pathway) or [3H]hypoxanthine (to mark the salvage pathway), with or without mycophenolic acid or L-alanosine (selective inhibitors of cytosolic GTP and ATP synthesis, respectively). Addition of mycophenolic acid decreased total GTP content (mass) by 73-81%; although the incorporation of labeled hypoxanthine into GTP also fell by 87%, the incorporation of glycine did not change. Similarly, L-alanosine decreased ATP mass by 26-33% in the presence of either label; whereas the incorporation of hypoxanthine into ATP fell 59%, the incorporation of glycine was again not significantly decreased. Thus, both the de novo and salvage purine nucleotide biosynthetic pathways are present in rat islets; however, the salvage pathway appears to be quantitatively the more important source of nucleotides. This conclusion was supported by additional studies of the effects on nucleotide content and insulin secretion of various site-specific inhibitors of purine synthesis. These findings have potential relevance to the processes of mitogenesis, cell proliferation and differentiation of islet cells, as well as for the control of insulin secretion.

ASPIRE In-Home: Rationale, Design, and Methods of a Study to Evaluate the Safety and Efficacy of Automatic Insulin Suspension for Nocturnal Hypoglycemia

Nocturnal hypoglycemia is a barrier to therapy intensification efforts in diabetes. The Paradigm® Veo™ system may mitigate nocturnal hypoglycemia by automatically suspending insulin when a prespecified sensor glucose threshold is reached. ASPIRE (Automation to Simulate Pancreatic Insulin REsponse) In-Home (NCT01497938) was a multicenter, randomized, parallel, adaptive study of subjects with type 1 diabetes. The control arm used sensor-augmented pump therapy. The treatment arm used sensor-augmented pump therapy with threshold suspend, which automatically suspends the insulin pump in response to a sensor glucose value at or below a prespecified threshold. To be randomized, subjects had to have demonstrated ≥2 episodes of nocturnal hypoglycemia, defined as >20 consecutive minutes of sensor glucose values ≤65 mg/dl starting between 10:00 PM and 8:00 AM in the 2-week run-in phase. The 3-month study phase evaluated safety by comparing changes in glycated hemoglobin (A1C) values and evaluated efficacy by comparing the mean area under the glucose concentration time curves for nocturnal hypoglycemia events in the two groups. Other outcomes included the rate of nocturnal hypoglycemia events and the distribution of sensor glucose values. Data from the ASPIRE In-Home study should provide evidence on the safety of the threshold suspend feature with respect to A1C and its efficacy with respect to severity and duration of nocturnal hypoglycemia when used at home over a 3-month period.

Threshold-based insulin-pump interruption for reduction of hypoglycemia

Continuous glucose monitoring (CGM) in the pediatric population with type 1 diabetes (T1D) was somewhat infamously described as “satisfaction without success” (1); success with CGM is strongly related to its use, and children and adolescents in some countries seem to be particularly reluctant to use CGM devices regularly as the behavioral changes these devices force on them may not be desirable. However, the SWITCH randomized clinical trial clearly demonstrated that CGM can be as successful in adolescents as in adults with T1D. Despite this fact, the reimbursement for CGM in Europe is still far from universal (2) but growing steadily as data on its benefits accumulate. The use of retrospective (professional) CGM has expanded far beyond its initial indications. Also, type 2 diabetes (T2D) is becoming an important focus for both retrospective and real-time CGM. Finally, an important study demonstrated that the home use of threshold insulin suspend based on sensor-augmented insulin pump therapy in T1D can reduce and prevent hypoglycemia.