Ling Hinshaw

Diurnal pattern of insulin action in type 1 diabetes: implications for a closed-loop system.

We recently demonstrated a diurnal pattern to insulin action (i.e., insulin sensitivity [SI]) in healthy individuals with higher SI at breakfast than at dinner. To determine whether such a pattern exists in type 1 diabetes, we studied 19 subjects with C-peptide–negative diabetes (HbA1c 7.1 ± 0.6%) on insulin pump therapy with normal gastric emptying. Identical mixed meals were ingested during breakfast, lunch, and dinner at 0700, 1300, and 1900 h in randomized Latin square of order on 3 consecutive days when measured daily physical activity was equal. The triple tracer technique enabled measurement of glucose fluxes. Insulin was administered according to the customary insulin:carbohydrate ratio for each participant. Although postprandial glucose excursions did not differ among meals, insulin concentration was higher (P < 0.01) and endogenous glucose production less suppressed (P < 0.049) at breakfast than at lunch. There were no differences in meal glucose appearance or in glucose disappearance between meals. Although there was no statistical difference (P = 0.34) in SI between meals in type 1 diabetic subjects, the diurnal pattern of SI taken across the three meals in its entirety differed (P = 0.016) from that of healthy subjects. Although the pattern in healthy subjects showed decreasing SI between breakfast and lunch, the reverse SI pattern was observed in type 1 diabetic subjects. The results suggest that in contrast to healthy subjects, SI diurnal pattern in type 1 diabetes is specific to the individual and cannot be extrapolated to the type 1 diabetic population as a whole, implying that artificial pancreas algorithms may need to be personalized.

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

CONTEXTnClosed-loop control (CLC) relies on an individuals open-loop insulin pump settings to initialize the system. Optimizing open-loop settings before using CLC usually requires significant time and effort.nnnOBJECTIVEnThe 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.nnnDESIGNnThis study reports a multicenter, outpatient, randomized, crossover clinical trial.nnnPATIENTSnThirty-seven adults with type 1 diabetes were enrolled at three clinical sites.nnnINTERVENTIONSnEach subjects 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. Subjects followed their usual meal-plan and had an unannounced exercise session.nnnMAIN OUTCOMES AND MEASURESnTime in the glucose range was 80-140 mg/dL, compared between both arms.nnnRESULTSnThirty-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.nnnCONCLUSIONSnA 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.

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 subjects 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.

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.

Effects of delayed gastric emptying on postprandial glucose kinetics, insulin sensitivity, and β-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 β-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 β-cell function, insulin sensitivity, and β-cell responsivity simultaneously. Delayed gastric emptying induced by pramlintide improved total insulin sensitivity and decreased total β-cell responsivity. However, β-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.

Recommendations for Managing Patients With Diabetes Mellitus in Cardiopulmonary Rehabilitation AN AMERICAN ASSOCIATION OF CARDIOVASCULAR AND PULMONARY REHABILITATION STATEMENT

Diabetes mellitus is a highly prevalent condition in patients participating in cardiopulmonary rehabilitation. However, research and subsequent guidelines specifically applicable to patients with diabetes, participating in cardiopulmonary rehabilitation, are limited. Recognizing this limitation, the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) initiated this statement, with the goal of developing a template that incorporated recommendations provided in the AACVPR Core Components and the American Association of Diabetes Educators 7 Self-Care Behaviors. This statement describes key processes regarding evaluation, interventions, and expected outcomes in each of the core components for the management of patients with diabetes in a cardiopulmonary rehabilitation program.

Effect of Pramlintide on Postprandial Glucose Fluxes in Type 1 Diabetes

CONTEXTnEarly postprandial hyperglycemia and delayed hypoglycemia remain major problems in current management of type 1 diabetes (T1D).nnnOBJECTIVEnOur objective was to investigate the effects of pramlintide, known to suppress glucagon and delay gastric emptying, on postprandial glucose fluxes in T1D.nnnDESIGNnThis was a single-center, inpatient, randomized, crossover study.nnnPATIENTSnTwelve patients with T1D who completed the study were analyzed.nnnINTERVENTIONSnSubjects 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.nnnMAIN OUTCOME MEASUREnGlucose turnover and SI were the main outcome measures.nnnRESULTSnWith 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).nnnCONCLUSIONSnInhibition of glucagon and gastric emptying delaying reduced 2-hour prandial glucose excursions in T1D by delaying meal rate of glucose appearance.

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 glucagons 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.

Twelve-Week 24/7 Ambulatory Artificial Pancreas With Weekly Adaptation of Insulin Delivery Settings: Effect on Hemoglobin A1c and Hypoglycemia

OBJECTIVE Artificial pancreas (AP) systems are best positioned for optimal treatment of type 1 diabetes (T1D) and are currently being tested in outpatient clinical trials. Our consortium developed and tested a novel adaptive AP in an outpatient, single-arm, uncontrolled multicenter clinical trial lasting 12 weeks. RESEARCH DESIGN AND METHODS Thirty adults with T1D completed a continuous glucose monitor (CGM)-augmented 1-week sensor-augmented pump (SAP) period. After the AP was started, basal insulin delivery settings used by the AP for initialization were adapted weekly, and carbohydrate ratios were adapted every 4 weeks by an algorithm running on a cloud-based server, with automatic data upload from devices. Adaptations were reviewed by expert study clinicians and patients. The primary end point was change in hemoglobin A1c (HbA1c). Outcomes are reported adhering to consensus recommendations on reporting of AP trials. RESULTS Twenty-nine patients completed the trial. HbA1c, 7.0 ± 0.8% at the start of AP use, improved to 6.7 ± 0.6% after 12 weeks (−0.3, 95% CI −0.5 to −0.2, P < 0.001). Compared with the SAP run-in, CGM time spent in the hypoglycemic range improved during the day from 5.0 to 1.9% (−3.1, 95% CI −4.1 to −2.1, P < 0.001) and overnight from 4.1 to 1.1% (−3.1, 95% CI −4.2 to −1.9, P < 0.001). Whereas carbohydrate ratios were adapted to a larger extent initially with minimal changes thereafter, basal insulin was adapted throughout. Approximately 10% of adaptation recommendations were manually overridden. There were no protocol-related serious adverse events. CONCLUSIONS Use of our novel adaptive AP yielded significant reductions in HbA1c and hypoglycemia.

Overnight Closed-Loop Control Improves Glycemic Control in a Multicenter Study of Adults With Type 1 Diabetes

ContextnClosed-loop control (CLC) for the management of type 1 diabetes (T1D) is a novel method for optimizing glucose control, and strategies for individualized implementation are being developed.nnnObjectivenTo analyze glycemic control in an overnight CLC system designed to reset the patient to near-normal glycemic targets every morning.nnnDesignnRandomized, crossover, multicenter clinical trial.nnnParticipantsnForty-four subjects with T1D requiring insulin pump therapy.nnnInterventionnSensor-augmented pump therapy (SAP) at home vs 5 nights of CLC (active from 23:00 to 07:00) in a supervised outpatient setting (research house or hotel), with a substudy of 5 nights of CLC subsequently at home.nnnMain Outcome MeasurenThe percentage of time spent in the target range (70 to 180 mg/dL measured using a continuous glucose monitor).nnnResultsnForty subjects (age, 45.5 ± 9.5 years; hemoglobin A1c, 7.4% ± 0.8%) completed the study. The time in the target range (70 to 180 mg/dL) significantly improved in CLC vs SAP over 24 hours (78.3% vs 71.4%; P = 0.003) and overnight (85.7% vs 67.6%; P < 0.001). The time spent in a hypoglycemic range (<70 mg/dL) decreased significantly in the CLC vs SAP group over 24 hours (2.5% vs 4.3%; P = 0.002) and overnight (0.9% vs 3.2%; P < 0.001). The mean glucose level at 07:00 was lower with CLC than with SAP (123.7 vs 145.3 mg/dL; P < 0.001). The substudy at home, involving 10 T1D subjects, showed similar trends with an increased time in target (70 to 180 mg/dL) overnight (75.2% vs 62.2%; P = 0.07) and decreased time spent in the hypoglycemic range (<70 mg/dL) overnight in CLC vs SAP (0.6% vs 3.7%; P = 0.03).nnnConclusionnOvernight-only CLC increased the time in the target range over 24 hours and decreased the time in hypoglycemic range over 24 hours in a supervised outpatient setting. A pilot extension study at home showed a similar nonsignificant trend.