Early postprandial glucagon concentrations are higher in type 1 diabetes (T1D) than in individuals with no diabetes (ND). To determine the cause, we infused stable [13C9, 15N1]glucagon before, during, and after a mixed meal in 16 ND and 16 T1D individuals to measure glucagon turnover. In a subcohort of 9 ND and 12 T1D individuals, we estimated [13C9, 15N1]glucagon kinetics during steady state. A linear, single-compartment model described [13C9, 15N1]glucagon kinetics and allowed precise estimation of the volume of distribution (VD) and clearance rate (CL). Model parameters were similar between groups, with the VD of [13C9, 15N1]glucagon at 42.1 ± 3.3 mL/kg, implying that [13C9, 15N1]glucagon distributes in a single compartment and with VD approximating the plasma volume and CL at 10.6 ± 0.9 mL/kg/min. Higher early (0–120 min after meal ingestion) postprandial glucagon concentrations (1,907.9 ± 373.4 vs. −93.6 ± 240.5 pg/mL · 120 min P < 0.001) observed in T1D was due to higher rates of glucagon appearance (3.39 ± 2.8 vs. −3.95 ± 2.0 ng/kg · 120 min, P < 0.04) and disappearance (2.13 ± 2.6 vs. −5.28 ± 2.1 ng/kg · 120 min, P < 0.04) compared with ND. We have determined postprandial glucagon turnover in humans and have demonstrated that changes in postprandial glucagon concentrations in T1D are due to increased rates of glucagon turnover during the early postprandial period. ARTICLE HIGHLIGHTS:This study was conducted to determine postprandial glucagon metabolism in people with and without type 1 diabetes. We wanted to determine the cause for higher early postprandial glucagon concentrations in type 1 diabetes. We found that higher early postprandial glucagon turnover is the cause of higher early postprandial glucagon concentrations in type 1 diabetes Strategies that decrease early post prandial glucagon fluxes could improve postprandial glucose concentrations in type 1 diabetes.

Introduction and Objective: We have previously shown that the diurnal pattern of glucose tolerance following simple carbohydrate meals differ in people with or without type 2 diabetes (T2D). This study aimed to further characterize the inter-individual variability of insulin sensitivity (SI), beta cell responsivity (Φ) and disposition index (DI) in people with T2D. Methods: Nineteen subjects with T2D (Age=61±10 y; BMI=32±5 kg/m2; 7F) were studied with identical mixed meals (8 kcal/kg/meal;75 g carbohydrate) at breakfast, lunch, and dinner on 3 consecutive days in a randomized latin square design. Glucose and C-peptide minimal models were used to estimate SI, Φ and DI. We identified the maximum SI, Φ and DI in each individual and used Z-test to classify the remaining as high as the maximum (H) or significantly lower (L). Based on these classifications, each individual exhibited one of the following seven patterns across breakfast, lunch, and dinner: HHH, HHL, HLH, HLL, LHH, LHL, or LLH. Results: The most frequently observed patterns for SI, Φ and DI were LHL (7/19, 37%), HLL (7/19, 37%) and HHL (6/19, 32%), respectively (Fig.1). Conclusion: We described the heterogeneity of SI, Φ and DI daily patterns in T2D. Results show that, in most individuals with T2D, DI declines during the day. Perhaps changing meal type to complex carbohydrate or adjusting the exercise regimen could help sustaining glucose tolerance though the day. Disclosure J. Bonet: None. C. Dalla Man: Other - Webinar provider; Ended; Sanofi. Other - Joint research project; Current; Sanofi-Aventis Deutschland GmbH. B. Gran: None. A. Basu: Research Support; Current; Dexcom, Inc. M. Schiavon: Research Support; Current; Sanofi. R. Basu: None. Funding MUR PRIN 2022 PNRR (P2022XSFA7), NIH (R01 DK 029953)

Introduction and Objective: The relative contribution of circulating glucose and insulin concentrations to glucagon secretion in healthy individuals is unknown. We therefore assessed glucagon secretion using [13C9,15N1]-glucagon tracer at varying insulin and glucose concentrations in healthy individuals. Methods: After overnight fast, twelve healthy individuals underwent three separate clamp visits (hypo-, eu-, hyper-glycemia) in random order at two insulin infusion rates. Five (3F; mean±SE: age=27.6±4.1 y; BMI=24.1±1.8 kg/m²) received insulin infusion at 0.25 and 0.75 mU/kg/min for 90 min each; the remaining (3F; age=27.6±1.8 y; BMI=26.4±1.0 kg/m²) at 0.5 and 1 mU/kg/min over the same intervals. Simultaneously, [13C9,15N1]-glucagon tracer was infused. Arterialized venous blood was collected for plasma glucose, insulin, glucagon and glucagon tracer measurements. Systemic rate of glucagon appearance (Ra) was calculated as recently described. Results: At hyperglycemia, glucagon Ra was suppressed and did not differ from 0 at any insulin concentration. At euglycemia, a negative trend in glucagon Ra was observed with rising insulin levels. During hypoglycemia, glucagon Ra was significantly higher than eu- and hyper-glycemia (p<0.001), with no apparent effects of increasing insulin concentrations. Conclusion: Glucagon secretion appears to be primarily regulated by circulating glucose and not by insulin concentrations in healthy adults. Disclosure E. Zagallo: None. M. Schiavon: Research Support; Current; Sanofi. F. Ruchi: None. C. Dalla Man: Other - Webinar provider; Ended; Sanofi. Other - Joint research project; Current; Sanofi-Aventis Deutschland GmbH. R. Basu: None. A. Basu: Research Support; Current; Dexcom, Inc. Funding National Institutes of Health (DK085516), National Institutes of Health (DK029953)

CONTEXT:Higher gluconeogenesis (GNG) contributes to higher nocturnal endogenous glucose production (EGP) in type 2 diabetes (T2D). Studies using 13C magnetic resonance spectroscopy (MRS) have confirmed lower hepatic glycogen content in subjects with T2D than in subjects with no diabetes (ND). OBJECTIVE:We determined the role of glycogen loading (GL) vs nonglycogen loading (NGL) on the contribution of GNG to nocturnal EGP in T2D. METHODS:In total, 14 subjects with T2D and 15 matched subjects with ND were studied on 2 occasions, with GL (60% carbohydrate) vs NGL (40% carbohydrate) isocaloric meals for 3 days, in random order in the overnight state. [6,6-2H2] glucose was infused to measure EGP, deuterium labelled water was used to measure GNG, and 13C MRS scans were performed in fed and fasted states to measure hepatic glycogen content. RESULTS:Hepatic glycogen content and nocturnal EGP were higher (P < .05) in GL vs NGL in both cohorts. The % GNG to EGP averaged ∼50% in subjects with ND throughout the night after both meals. In contrast, % GNG to nocturnal EGP in T2D was lower with GL vs NGL and matched the pattern observed in subjects with ND with GL lowering overnight rates of GNG in subjects with T2D. CONCLUSION:Selective targeting of GNG at night with appropriate medications could reduce nocturnal and early morning fasting hyperglycemia and hepatic insulin resistance in people with T2D.

Circulating glucagon concentrations differ between nondiabetic (ND) and type 1 diabetes (T1D) individuals. We combined isotope dilution technique using stable tracers [6,22 13C9, 15N1]-Glucagon and [6,14,19,22 13C9, 15N1]-Glucagon with splanchnic and leg catheterization in ND (n=8; age 23.1±2.9 yrs, BMI 26.6±3.5 kg/m2, HbA1c 5.0±0.2% (31±2 mmol/mol) and T1D (n=6; 29.0±8.8 yrs, BMI 26.3±5.0 kg/m2, HbA1c 7.9±0.8% (63±8 mmol/mol) participants in the overnight fasted state. After baseline period, exogenous glucagon was infused at rates designed to achieve plasma glucagon concentrations spanning the physiological ranges, to determine the effects of rising glucagon concentrations on splanchnic and leg glucagon balance. At baseline, splanchnic glucagon extraction (SGE) was similar (30.7±2.7 vs. 29.1±2.9%), but leg glucagon extraction (LGE) lower (27.0±4.2 vs. 40.6±3.1%), in T1D than ND participants. However, with increasing plasma glucagon concentrations, while SGE remained unchanged within and between groups, LGE fell in ND (41 vs. 31 vs. 24%) but did not change in T1D participants. Despite a numerically lower net splanchnic glucagon production in T1D than ND participants, no changes were observed with increasing glucagon concentrations within the physiological range in both groups. This is the first human study, applying novel glucagon isotopes, that describes regional glucagon metabolism in ND and T1D participants. Our observations provide translational relevance for dual hormone closed loop systems as well as provide tools for probing the effects of GLP-1, dual and triple receptor agonists on pancreatic a-cell functions.

Circulating glucagon concentrations differ between individuals with no diabetes (ND) and those with type 1 diabetes (T1D). We combined an isotope dilution technique using stable tracers [6,22-13C9,15N1]glucagon and [6,14,19,22-13C9,15N1]glucagon with splanchnic and leg catheterization in participants with ND (n = 8; age 23.1 ± 2.9 years, BMI 26.6 ± 3.5 kg/m2, HbA1c 5.0 ± 0.2% [31 ± 2 mmol/mol]) and T1D (n = 6; 29.0 ± 8.8 years, BMI 26.3 ± 5.0 kg/m2, HbA1c 7.9 ± 0.8% [63 ± 8 mmol/mol]) in the overnight fasted state. After baseline period, exogenous glucagon was infused at rates designed to achieve plasma glucagon concentrations spanning the physiological ranges, to determine the effects of rising glucagon concentrations on splanchnic and leg glucagon balance. At baseline, splanchnic glucagon extraction (SGE) was similar (30.7 ± 2.7 vs. 29.1 ± 2.9%) but leg glucagon extraction (LGE) was lower (27.0 ± 4.2 vs. 40.6 ± 3.1%) in participants with T1D versus those with ND. However, with increasing plasma glucagon concentrations, while SGE remained unchanged within and between groups, LGE fell in participants with ND (41 vs. 31 vs. 24%) but did not change in those with T1D. Despite a numerically lower net splanchnic glucagon production in participants with T1D than in those with ND, no changes were observed with increasing glucagon concentrations within the physiological range in both groups. This is the first human study applying novel glucagon isotopes that describes regional glucagon metabolism in participants with ND and T1D. Our observations provide translational relevance for dual hormone closed-loop systems and provide tools for probing the effects of GLP-1, dual, and triple receptor agonists on pancreatic α-cell functions. ARTICLE HIGHLIGHTS:This study was conducted to assess splanchnic and leg glucagon metabolism in humans using stable glucagon isotopes. We wanted to evaluate whether splanchnic and leg glucagon metabolism differed between participants with no diabetes (ND) and those with type 1 diabetes (T1D) at glucagon concentrations spanning the physiological range. Whereas splanchnic glucagon extraction did not differ between participants with ND and those with T1D, leg glucagon extraction fell in those with ND but did not change in those with T1D as glucagon concentrations increased. Net splanchnic glucagon production did not change with exogenous glucagon infusion. Our study has implications for dual hormone closed-loop control in T1D where glucagon is infused for prevention of hypoglycemia and for investigating the effects of emerging GLP-1, glucose-dependent insulinotropic polypeptide, and glucagon receptor agonists on endogenous glucagon secretion and clearance.

Introduction and Objective: A novel tracer method using natural [13C]-enrichment of polysaccharides in commercially available grains was developed previously to measure postprandial insulin sensitivity and β-cell function, using Minimal Model analysis. This study was conducted to determine whether complex carbohydrate-based meals can improve insulin resistance in Type 2 diabetes (T2D). Methods: Seven T2D were studied twice following isocaloric mixed meals with identical macronutrient compositions (50% carb, 20% protein, 30% fat). The carbohydrate was either glucose (simple carb, SC) or sorghum (complex carb, CC). Oral antidiabetes medications were withheld prior to meal study. We estimated Si, a marker of whole-body insulin sensitivity, and beta cell responsiveness (Phitotal) in response to meal stimuli. Disposition index (DI; beta cell responsivity appropriate to the degree of insulin resistance) was computed as well. Results: Results are shown in Figure 1. Post meal glucose concentrations were lower with CC than SC meal. Si and DI were significantly higher (p<0.05) with CC vs SC meal while Phitotal increased but was not statistically different (p=0.21). Conclusion: Results suggest that CC meals significantly improve insulin resistance in people with T2D. We provide mechanistic insights as to why glucose tolerance improves with CC meals and should be preferred over SC meals in T2D. S. Perazzolo: Consultant; Abbott Diagnostics. U.S. Unni: None. C. Lane: None. B. Gran: None. A. Basu: None. R. Basu: Advisory Panel; Novo Nordisk, Boehringer-Ingelheim. National Institute of Health (R01 DK029953, R01 DK085516, DK059637 (MMPC)) and (DK020593 (DRTC))

The development of automated insulin delivery systems has seen tremendous improvements from individual components to interoperable system combinations of devices and new drugs besides insulin. The components have become progressively smaller, more accurate, and more user friendly. This article summarizes the history of the artificial pancreas from the earliest concepts to fully functional systems to research into further improvements in the future. The authors include many of the developers of this technology who received research support from the National Institute of Diabetes and Digestive and Kidney Diseases at various stages to develop these systems.

To date, few studies have quantified glucagon kinetics in humans with and without diabetes, with results often varying due to differences in experimental designs and glucagon assay methodologies. This has limited the ability to study glucagon secretion in vivo using methods such as deconvolution. To overcome these limitations, a novel stable glucagon tracer, [13C15N]-glucagon, along with high-resolution mass spectrometry, has been used to study glucagon kinetics and turnover in humans.In this work, we present a nonlinear mixed effects modeling approach to describe glucagon kinetics in healthy subjects and individuals with type 1 diabetes (T1D). To do so, data from a novel stable isotope-labeled glucagon tracer ([13C15N]-glucagon), collected in 9 healthy controls (HC) and 12 individuals with T1D following an intravenous bolus injection under basal steady-state, post-absorptive conditions, were used. Models of increasing complexity were developed and tested against the data, with model selection guided by standard criteria such as the ability of the model to describe the data, precision and physiological plausibility of parameter estimates and parsimony.A one-compartment model effectively describes typical population kinetics (TPK) of glucagon, along with the between-subject variability (BSV) and inter-occasion variability (IOV), linking individual differences to easily accessible subject characteristics. In particular, model-predicted outcome highlights that variability in glucagon kinetics is predominantly explained by individual-specific factors, like age and body weight, rather than by group-specific factors, like HC vs. T1D.Future work will focus on integrating this model into simulation platforms to enable the evaluation of advanced artificial pancreas systems, further enhancing diabetes care.Clinical Relevance— This model is crucial for assessing glucagon turnover in the post-absorptive state and represents a significant step toward the quantification of glucagon secretion in humans.

Introduction and Objective: In Type 2 Diabetes (T2D) higher nocturnal glucose production (EGP) results from higher glycogenolysis (GGL) and gluconeogenesis (GNG). Appropriate medications are needed to restore nocturnal EGP. We hypothesized that Dorzagliatin (DG) IND-159103-Glucokinase activator), insulin glargine (IG) (inhibitor of GGL) and metformin (M) (inhibitor of GNG) may lower GGL and GNG thereby lowering EGP in T2D. Methods: Twenty-three T2D subjects (age ~62 yrs, BMI ~32.0Kg/m2, FPG ~7.0mmol/L, HbA1C ~7.0%, ~9 years average diabetes duration) insulin or long acting GLP-1 agonist naive received 6-week monotherapy with either DG=7 (75mg bid), IG=9 (once daily) or M=7 (1.5-2gm daily). All other antidiabetes medications were washed out. Studies were conducted overnight at baseline (BL) and post treatment (PT). EGP, GNG and GGL were estimated at 1,4,7 AM using infusion of [6,6-2H2] glucose (10 PM-7 AM) following ingestion of deuterium labeled water (2H2O) as previously established. Results: The trial is ongoing. EGP was lower with DG (BL vs PT:18.7±9.8vs.15.6±12.5 at 1am;15.4±4.9 vs 14.6±7.0 µmol/KgFFM/min at 7am) primarily due to lower GGL (BL vs PT:10.3±4.2 vs 9.1±7.5 at 1am; 10.4±3.4 vs 7.9±3.5 µmol/kgFFM/min at 7am with similar values at 4am). Similarly, EGP was lower with IG (BL vs PT:19.1±8.0 vs 18.5±10.4 at 1am, 17.9±5.6 vs 16.4±7.3 at 4am and 18.9±5.5 vs 17.1±8.1 µmol/kgFFM/min at 7am). Decrease in EGP was due to lower GGL overnight as hypothesized (9.8±4.2 vs 8.6±3.7 at 4am and 10.2±4.4 vs 9.3± 4.4 µmol/kgFFM/min at 7am). On the contrary, M therapy with the prescribed standard dose was insufficient to lower EGP overnight (BL vs PT: 14.3±8.8 vs 17.5±4.1 at 1am;18.0±5.0 vs 18.2±6.0 at 4am;12.2±4.6 vs 15.6±5.5 µmol/kgFFM/min at 7am). Conclusion: Both DG and IG lowered nocturnal EGP by reducing rates of GGL overnight with a smaller contribution of GNG. M used as monotherapy did not provide adequate lowering of nocturnal EGP. These drugs used in combination may target GGL and GNG overnight thereby reducing nighttime EGP. A. Hodhod: None. U.S. Unni: None. B. Gran: None. A. Basu: None. R. Basu: Advisory Panel; Novo Nordisk, Boehringer-Ingelheim. National Institutes of Health (R01 DK029953, R01 DK085516DK059637 (MMPC), and DK020593 (DRTC))

Artificial pancreas (AP) systems, also called automated insulin delivery systems, have improved the time in range of glucose levels, reduced the daily burden of the user for glucose regulation, and improved their quality of life. Several commercially available AP systems operate in hybrid closed-loop mode that requires manual information from the user for meals and exercise. This article summarizes the progress on mathematical models of glucose-insulin dynamics, continuous glucose monitoring systems, and insulin pumps that form the building blocks of AP systems, the shift from animal studies to in silico clinical trials that accelerated the rate of progress in AP technologies and the efforts for developing the next-generation AP systems, and the fully automated AP that eliminates manual inputs and mitigates the effects of disturbances to glucose homeostasis-meals, physical activities, acute stress, and variations in sleep characteristics. A section is devoted to discuss the unique glycemic management challenges faced by women with diabetes across the lifespan (menstrual cycle, menopause, pregnancy) and summarize progress made to reduce their impact on glycemic management.

Context: Insulin sensitivity (SI) varies with age in type 1 diabetes (T1D). Objective: To compare postprandial glucose turnover and SI between adolescents and adults with T1D. Design: This cross-sectional comparison at a clinical research unit included 21 early adolescents with T1D (T1D-adol) (12 F; age, 11.5 +/- 0.5 years; BMI 19 +/- 2 kg/m(2)), 13 adults with T1D (T1D-adult) (5 F; 37.8 +/- 9.1 years; BMI 27 +/- 2 kg/m(2)), and 14 anthropometrically matched adults without diabetes (ND) (7 F; 26.9 +/- 7.0 years; BMI 25 +/- 2.5 kg/m(2)). Using triple tracer mixed meal and oral glucose models, SI in T1D-adol and T1D-adult was compared. Results: Postprandial glucose excursions were not different in T1D-adol vs T1D-adult (P = .111) but higher than in ND (P < .01). Insulin excursions were also similar in T1D-adol vs T1D-adult (P = .600) and they were both lower (P < .05) compared to ND, while glucagon excursions were lower (P < .01) in T1D-adol than in T1D-adult and ND. Integrated rates of endogenous glucose production and glucose disappearance were lower in T1D-adol than in T1D-adult and in ND vs T1D-adult but did not differ between T1D-adol and ND. Meal glucose appearance did not differ between groups. While SI in T1D-adol vs ND was similar (P = .299), it was higher in T1D-adol and ND vs T1D-adult (P < .01). Conclusion: We report differences in parameters of postprandial glucose turnover and insulin sensitivity between adults and early adolescents with T1D that could, at least in part, be due to the shorter duration of diabetes among T1D-adol. These data support the concept that over time with T1D, endogenous glucose production increases and SI deteriorates.

CONTEXT:Circulating lactate concentration is an important determinant of exercise tolerance. OBJECTIVE:This work aimed to determine the role of hyperglycemia on lactate metabolism during exercise in individuals with type 1 diabetes (T1D). METHODS:The protocol at the University of Virginia compared 7 T1D participants and 7 participants without diabetes (ND) at euglycemia (5.5 mM) or hyperglycemia (9.2 mM) in random order in T1D and at euglycemia in ND. Intervention included [1-13C] lactate infusion, exercise at 65% maximal oxygen uptake (VO2max), euglycemia, and hyperglycemia visits. The main outcome measure was lactate turnover before, during, and after 60 minutes of exercise at 65% VO2max. RESULTS:A 2-compartment model with loss only from the peripheral compartment described lactate kinetics. Volume of distribution of the accessible compartment was similar between T1D and ND individuals (P = .76) and concordant with plasma volume (∼40 mL/kg). Circulating lactate concentrations were higher (P < .001) in T1D participants during exercise at hyperglycemia than euglycemia. Exercise-induced lactate appearance did not differ (P = .13) between hyperglycemia and euglycemia. However, lactate clearance (CL) was lower (P = .03) during hyperglycemia than euglycemia in T1D participants. There were no differences in any of the aforementioned parameters between T1D and ND participants during euglycemia. CONCLUSION:Hyperglycemia modulates lactate metabolism during exercise by lowering CL, leading to higher circulating lactate concentrations in T1D individuals. This novel observation implies that exercise during hyperglycemia can lead to higher circulating lactate concentrations thus increasing the likelihood of reaching the lactate threshold sooner in T1D, and has high translational relevance both for providers and recreationally active people with T1D.