Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments.

Glucagon use in artificial pancreas for type 1 diabetes (T1D) is being explored for prevention and rescue from hypoglycemia. However, the relationship between glucagon stimulation of endogenous glucose production (EGP) viz., hepatic glucagon sensitivity, and prevailing glucose concentrations has not been examined. To test the hypothesis that glucagon sensitivity is increased at hypoglycemia vs. euglycemia, we studied 29 subjects with T1D randomized to a hypoglycemia or euglycemia clamp. Each subject was studied at three glucagon doses at euglycemia or hypoglycemia, with EGP measured by isotope dilution technique. The peak EGP increments and the integrated EGP response increased with increasing glucagon dose during euglycemia and hypoglycemia. However, the difference in dose response based on glycemia was not significant despite higher catecholamine concentrations in the hypoglycemia group. Knowledge of glucagon's effects on EGP was used to develop an in silico glucagon action model. The model-derived output fitted the obtained data at both euglycemia and hypoglycemia for all glucagon doses tested. Glucagon clearance did not differ between glucagon doses studied in both groups. Therefore, the glucagon controller of a dual hormone control system may not need to adjust glucagon sensitivity, and hence glucagon dosing, based on glucose concentrations during euglycemia and hypoglycemia.

Exercise effects on postprandial glucose metabolism in type 1 diabetes: a triple-tracer approach.

To determine the effects of exercise on postprandial glucose metabolism and insulin action in type 1 diabetes (T1D), we applied the triple tracer technique to study 16 T1D subjects on insulin pump therapy before, during, and after 75 min of moderate-intensity exercise (50% V̇o2max) that started 120 min after a mixed meal containing 75 g of labeled glucose. Prandial insulin bolus was administered as per each subject's customary insulin/carbohydrate ratio adjusted for meal time meter glucose and the level of physical activity. Basal insulin infusion rates were not altered. There were no episodes of hypoglycemia during the study. Plasma dopamine and norepinephrine concentrations rose during exercise. During exercise, rates of endogenous glucose production rose rapidly to baseline levels despite high circulating insulin and glucose concentrations. Interestingly, plasma insulin concentrations increased during exercise despite no changes in insulin pump infusion rates, implying increased mobilization of insulin from subcutaneous depots. Glucagon concentrations rose before and during exercise. Therapeutic approaches for T1D management during exercise will need to account for its effects on glucose turnover, insulin mobilization, glucagon, and sympathetic response and possibly other blood-borne feedback and afferent reflex mechanisms to improve both hypoglycemia and hyperglycemia.

Effects of delayed gastric emptying on postprandial glucose kinetics, insulin sensitivity, and ß-cell function.

Controlling meal-related glucose excursions continues to be a therapeutic challenge in diabetes mellitus. Mechanistic reasons for this need to be understood better to develop appropriate therapies. To investigate delayed gastric emptying effects on postprandial glucose turnover, insulin sensitivity, and ß-cell responsivity and function, as a feasibility study prior to studying patients with type 1 diabetes, we used the triple tracer technique C-peptide and oral minimal model approach in healthy subjects. A single dose of 30 µg of pramlintide administered at the start of a mixed meal was used to delay gastric emptying rates. With delayed gastric emptying rates, peak rate of meal glucose appearance was delayed, and rate of endogenous glucose production (EGP) was lower. C-peptide and oral minimal models enabled the assessments of ß-cell function, insulin sensitivity, and ß-cell responsivity simultaneously. Delayed gastric emptying induced by pramlintide improved total insulin sensitivity and decreased total ß-cell responsivity. However, ß-cell function as measured by total disposition index did not change. The improved whole body insulin sensitivity coupled with lower rate of appearance of EGP with delayed gastric emptying provides experimental proof of the importance of evaluating pramlintide in artificial endocrine pancreas approaches to reduce postprandial blood glucose variability in patients with type 1 diabetes.

Postprandial glucose fluxes and insulin sensitivity during exercise: a study in healthy individuals.

Quantifying the effect size of acute exercise on insulin sensitivity (SI(exercise)) and simultaneous measurement of glucose disappearance (R(d)), endogenous glucose production (EGP), and meal glucose appearance in the postprandial state has not been developed in humans. To do so, we studied 12 healthy subjects [5 men, age 37.1 ± 3.1 yr, body mass index 24.1 ± 1.1 kg/m², fat-free mass (FFM) 50.9 ± 3.9 kg] during moderate exercise at 50% V(O2max) for 75 min, 120-195 min after a triple-tracer mixed meal consumed at time 0. Tracer infusion rates were adjusted to achieve constant tracer-to-tracee ratio and minimize non-steady-state errors. Glucose turnover was estimated by accounting for the nonstationary kinetics introduced by exercise. Insulin sensitivity index was calculated in each subject both in the absence [time (t) = 0-120 min, SI(rest)] and presence (t = 0-360 min, SI(exercise)) of physical activity. EGP at t = 0 min (13.4 ± 1.1 µM·kg FFM⁻¹·min⁻¹) fell at t = 120 min (2.4 ± 0.4 µM·kg FFM⁻¹·min⁻¹) and then rapidly rose almost eightfold at t = 180 min (18.2 ± 2.6 µM·kg FFM⁻¹·min⁻¹) before gradually falling at t = 360 min (10.6 ± 0.9 µM·kg FFM⁻¹·min⁻¹). R(d) rapidly peaked at t = 120 min at the start of exercise (89.5 ± 11.6 µM·kg FFM⁻¹·min⁻¹) and then gradually declined at t = 195 min (26.4 ± 3.3 µM·kg FFM⁻¹·min⁻¹) before returning to baseline at t = 360 min. SI(exercise) was significantly higher than SI(rest) (21.6 ± 3.7 vs. 12.5 ± 2.0 10⁻4 dl·kg⁻¹·min⁻¹ per µU/ml, P < 0.0005). Glucose turnover was estimated for the first time during exercise with the triple-tracer technique. Our results, applying state-of-the-art techniques, show that moderate exercise almost doubles postprandial insulin sensitivity index in healthy subjects.

Epidemiology of vancomycin-resistant Enterococcus faecalis: a case-case-control study.

Although much is known about vancomycin-resistant (VR) Enterococcus faecium, little is known about the epidemiology of VR Enterococcus faecalis. The predilection of VR E. faecalis to transfer the vancomycin resistance determinant to Staphylococcus aureus is much greater than that of VR E. faecium. The epidemiology of VR E. faecalis has important implications regarding the emergence of vancomycin-resistant S. aureus (VRSA); 8 of 13 reported VRSA cases have been from Michigan. A retrospective case-case-control study was conducted at the Detroit Medical Center, located in southeastern Michigan. Unique patients with VR E. faecalis infection were matched to patients with strains of vancomycin-susceptible (VS) E. faecalis and to uninfected controls at a 1:1:1 ratio. Five hundred thirty-two VR E. faecalis cases were identified and were matched to 532 VS E. faecalis cases and 532 uninfected controls. The overall mean age of the study cohort (n = 1,596) was 63.0 ± 17.4 years, and 747 (46.8%) individuals were male. Independent predictors for the isolation of VR E. faecalis (but not VS E. faecalis) compared to uninfected controls were an age of ≥65 years, nonhome residence, diabetes mellitus, peripheral vascular disease, exposure to cephalosporins and fluoroquinolones in the prior 3 months, and immunosuppressive status. Invasive procedures and/or surgery, chronic skin ulcers, and indwelling devices were risk factors for both VR E. faecalis and VS E. faecalis isolation. Cephalosporin and fluoroquinolone exposures were unique, independent predictors for isolation of VR E. faecalis. A majority of case patients had VR E. faecalis present at the time of admission. Control of VR E. faecalis, and ultimately VRSA, will likely require regional efforts focusing on infection prevention and antimicrobial stewardship.

Effect of Pramlintide on Postprandial Glucose Fluxes in Type 1 Diabetes.

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.

Nocturnal Glucose Metabolism in Type 1 Diabetes: A Study Comparing Single Versus Dual Tracer Approaches.

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.

Adjustment of Open-Loop Settings to Improve Closed-Loop Results in Type 1 Diabetes: A Multicenter Randomized Trial.

CONTEXT: Closed-loop control (CLC) relies on an individual's open-loop insulin pump settings to initialize the system. Optimizing open-loop settings before using CLC usually requires significant time and effort. OBJECTIVE: The objective was to investigate the effects of a one-time algorithmic adjustment of basal rate and insulin to carbohydrate ratio open-loop settings on the performance of CLC. DESIGN: This study reports a multicenter, outpatient, randomized, crossover clinical trial. PATIENTS: Thirty-seven adults with type 1 diabetes were enrolled at three clinical sites. INTERVENTIONS: Each subject's insulin pump settings were subject to a one-time algorithmic adjustment based on 1 week of open-loop (i.e., home care) data collection. Subjects then underwent two 27-hour periods of CLC in random order with either unchanged (control) or algorithmic adjusted basal rate and carbohydrate ratio settings (adjusted) used to initialize the zone-model predictive control artificial pancreas controller. Subject's followed their usual meal-plan and had an unannounced exercise session. MAIN OUTCOMES AND MEASURES: Time in the glucose range was 80-140 mg/dL, compared between both arms. RESULTS: Thirty-two subjects completed the protocol. Median time in CLC was 25.3 hours. The median time in the 80-140 mg/dl range was similar in both groups (39.7% control, 44.2% adjusted). Subjects in both arms of CLC showed minimal time spent less than 70 mg/dl (median 1.34% and 1.37%, respectively). There were no significant differences more than 140 mg/dL. CONCLUSIONS: A one-time algorithmic adjustment of open-loop settings did not alter glucose control in a relatively short duration outpatient closed-loop study. The CLC system proved very robust and adaptable, with minimal (<2%) time spent in the hypoglycemic range in either arm.