Citations

Abstract Context: Early postprandial hyperglycemia and delayed hypoglycemia remain major problems in current management of type 1 diabetes (T1D). Objective: Our objective was to investigate the effects of pramlintide, known to suppress glucagon and delay gastric emptying, on postprandial glucose fluxes in T1D. Design: This was a single-center, inpatient, randomized, crossover study. Patients: Twelve patients with T1D who completed the study were analyzed. Interventions: Subjects were studied on two occasions with or without pramlintide. Triple tracer mixed-meal method and oral minimal model were used to estimate postprandial glucose turnover and insulin sensitivity (SI). Integrated liver insulin sensitivity was calculated based on glucose turnover. Plasma glucagon and insulin were measured. Main Outcome Measure: Glucose turnover and SI were the main outcome measures. Results: With pramlintide, 2-hour postprandial glucose, insulin, glucagon, glucose turnover, and SI indices showed: plasma glucose excursions were reduced (difference in incremental area under the curve [iAUC], 444.0 mMmin, P = .0003); plasma insulin concentrations were lower (difference in iAUC, 7642.0 pMmin; P = .0099); plasma glucagon excursions were lower (difference in iAUC, 1730.6 pg/mlmin; P = .0147); meal rate of glucose appearance was lower (difference in iAUC: 1196.2 μM/kg fat free mass [FFM]; P = .0316), endogenous glucose production was not different (difference in iAUC: −105.5 μM/kg FFM; P = .5842), rate of glucose disappearance was lower (difference in iAUC: 1494.2 μM/kg FFM; P = .0083). SI and liver insulin sensitivity were not different between study visits (P > .05). Conclusions: Inhibition of glucagon and gastric emptying delaying reduced 2-hour prandial glucose excursions in T1D by delaying meal rate of glucose appearance.

AbstractBackgroundWhile simultaneous pancreas kidney transplant (SPKTx) is a therapeutic option for patients with type 1 diabetes (T1DM) and renal failure, few centers offer SPKTx to “select” non‐T1DM patients. To address concerns that existing insulin resistance may limit the benefits of the pancreas allograft among non‐T1DM, we compared several indices of glucose homeostasis, in “select” non‐T1DM and T1DM patients who received SPKTx.MethodsCriteria for “select” non‐T1DM included the following: positive C‐peptide, BMI <30 kg/m2, treatment with oral agents before insulin initiation, and insulin at <1 unit/kg/d. We compared several indices of glucose homeostasis within 1 yr post‐SPKTx among seven “select” patients with non‐T1DM and nine patients with T1DM with similar age, BMI, and immunosuppression. Measurements of insulin resistance included the following: homeostatic model, insulin sensitivity index, and insulin–glucose ratio; insulin secretion measures included the following: corrected insulin response.ResultsNon‐T1DM had similar pre‐transplant metabolic (fasting glucose, HbA1c, blood pressure, and lipid) parameters to the T1DM cohort. There were no significant differences in the various measures of insulin resistance and secretion between T1DM and “select” non‐T1DM patients.ConclusionOur results suggest SPKTx should be considered in the therapeutic armamentarium among carefully select non‐T1DM with features of minimal insulin resistance; however, a larger cohort with longer follow‐up is needed to confirm our results.

Physical activity is an important determinant of glucose variability in type 1 diabetes (T1D). It has been incorporated as a nonglucose input into closed-loop control (CLC) protocols for T1D during the last 4 years mainly by 3 research groups in single center based controlled clinical trials involving a maximum of 18 subjects in any 1 study. Although physical activity data capture may have clinical benefit in patients with T1D by impacting cardiovascular fitness and optimal body weight achievement and maintenance, limited number of such studies have been conducted to date. Clinical trial registries provide information about a single small sample size 2 center prospective study incorporating physical activity data input to modulate closed-loop control in T1D that are seeking to build on prior studies. We expect an increase in such studies especially since the NIH has expanded support of this type of research with additional grants starting in the second half of 2015. Studies (1) involving patients with other disorders that have lasted 12 weeks or longer and tracked physical activity and (2) including both aerobic and resistance activity may offer insights about the user experience and device optimization even as single input CLC heads into real-world clinical trials over the next few years and nonglucose input is introduced as the next advance.

Background: Quantitative assessment of the dynamic relationship between plasma and interstitial fluid (ISF) glucose and the estimation of the plasma-to-ISF delay are of major importance to determine the accuracy of subcutaneous glucose sensors, an essential component of open- and closed-loop therapeutic systems for type 1 diabetes mellitus (T1DM). The goal of this work is to develop a model of plasma-to-ISF glucose kinetics from multitracer plasma and interstitium data, obtained by microdialysis, in healthy and T1DM subjects, under fasting conditions. Materials and Methods: A specific experimental design, combining administration of multiple tracers with the microdialysis technique, was used to simultaneously frequently collect plasma and ISF data. Linear time-invariant compartmental modeling was used to describe glucose kinetics from the tracer data because the system is in steady state. Results: A two-compartment model was shown accurate and was identified from both plasma and ISF data. An “equilibration time” between plasma and ISF of 9.1 and 11.0 min (median) in healthy and T1DM subjects, respectively, was calculated. Conclusions: We have demonstrated that, in steady-state condition, the glucose plasma-to-ISF kinetics can be modeled with a linear two-compartment model and that the “equilibration time” between the two compartments can be estimated with precision. Future studies will assess plasma-to-interstitium glucose kinetics during glucose and insulin perturbations in both healthy and T1DM subjects.

Human islet amyloid polypeptide (IAPP) is a 37-residue peptide that is co-secreted with insulin by the β-cell and might be involved in the pathogenesis of non-insulin-dependent diabetes mellitus. We developed an improved assay in vitrobased on the fluorescence of bound thioflavin T to study factors affecting amyloidogenesis. Monomeric IAPP formed amyloid fibrils, as detected by increased fluorescence and by electron microscopy. Fluorimetric analysis revealed that the initial rate of amyloid formation was: (1) proportional to the peptide monomer concentration, (2) maximal at pH 9.5, (3) maximal at 200 mM KCl, and (4) proportional to temperature from 4 to 37 °C. We found that 5-fold and 10-fold molar excesses of proinsulin inhibited fibril formation by 39% and 59% respectively. Insulin was somewhat more potent with 5-fold and 10-fold molar excesses inhibiting fibril formation by 69% and 73% respectively, whereas C-peptide had no effect at these concentrations. Thus at physiological ratios of IAPP to insulin, insulin and proinsulin, but not C-peptide, can retard amyloidogenesis. Because insulin resistance or hyperglycaemia increase the IAPP-to-insulin ratio, increased intracellular IAPP compared with insulin expression in genetically predisposed individuals might contribute to intracellular amyloid formation, β-cell death and the genesis of non-insulin-dependent diabetes mellitus.

Background: Understanding the effect size, variability, and underlying physiology of the dawn phenomenon is important for next-generation closed-loop control algorithms for type 1 diabetes (T1D). Subjects and Methods: We used an iterative protocol design to study 16 subjects with T1D on individualized insulin pump therapy for two successive nights. Endogenous glucose production (EGP) rates at 3 a.m. and 7 a.m. were measured with [6,6- 2 H 2 ]glucose as a single tracer, infused from midnight to 7 a.m. in all subjects. To explore possibility of tracer recycling due to prolonged [6,6- 2 H 2 ]glucose infusion, which was highly probable after preplanned interim data analyses, we infused a second tracer, [6- 3 H]glucose, from 4 a.m. to 7 a.m. in the last seven subjects to measure EGP at 7 a.m. Results: Cortisol concentrations increased during both nights, but changes in glucagon and insulin concentration were inconsistent. Although the plasma glucose concentrations rose from midnight to 7 a.m. during both nights, EGP measured with [6,6- 2 H 2 ]glucose between 3 a.m. and 7 a.m. did not differ during Night 1 but fell in Night 2. However, EGP measured with [6- 3 H]glucose at 7 a.m. was higher than that measured with [6,6- 2 H 2 ]glucose during both nights, thereby suggesting tracer recycling probably underestimating EGP calculated at 7 a.m. with [6,6- 2 H 2 ]glucose. Likewise, EGP was higher at 7 a.m. with [6- 3 H]glucose than at 3 a.m. with [6,6- 2 H 2 ]glucose during both nights. Conclusions: The data demonstrate a consistent overnight rise in glucose concentrations through increased EGP, mediated likely by rising cortisol concentrations. The observations with the dual tracer approach imply significant tracer recycling leading to underestimation of EGP measured by longer-duration tracer infusion.

ObjectiveTo report the impact of bariatric surgery on metabolic outcomes in patients with type 1 diabetes (DM1) versus insulin‐requiring type 2 diabetes mellitus (IRDM2).MethodsTen subjects with DM1 were compared with 118 subjects with IRDM2 at baseline and at 1 and 2 years post‐bariatric surgery for: anthropometric measures, HbA1c, and number of medications (anti‐hyperglycemic, anti‐hypertensive, lipid‐lowering).ResultsDM1 and IRDM2 groups lost similar amounts of weight 2 years post‐bariatric surgery (39.5 ± 14.7 kg vs. 40.3 ± 24.4 kg). IRDM2 subjects had significant improvements in HbA1c (7.8% ± 1.4% vs. 6.8% ± 1.4%, P value <0.0001) and decreases in number of anti‐hyperglycemic (2.4 ± 0.8 vs. 0.7 ± 0.8, P value <0.0001), anti‐hypertensive (2.2 ± 1.3 vs. 1.3 ± 1.2, P value <0.0001), and lipid‐lowering (1.1 ± 0.8 vs. 0.6 ± 0.6, P value <0.0001) medications. DM1 subjects had no improvement in HbA1c (8.2% ± 1.6% vs. 7.8% ± 0.9%) or use of anti‐hypertensive medications (2.1 ± 1.4 vs. 2.3 ± 1.5). Their use of lipid‐lowering medications improved (1.0 ± 0.5 vs. 0.5 ± 0.8, P value 0.04).ConclusionsOur study suggests that improved glycemic control may not be an expected outcome when considering bariatric surgery in patients with DM1; however, additional investigation is warranted.