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Treatments for diabetic kidney disease (DKD) mainly focus on managing hyperglycemia and hypertension, but emerging evidence suggests that inflammation also plays a role in the pathogenesis of DKD. This 10-week study evaluated the efficacy of daily oral nanoparticulate-curcumin (nCUR) together with long-acting insulin (INS) to treat DKD in a rodent model. Diabetic rats were dosed with unformulated CUR alone, nCUR alone or together with INS, or INS alone. The progression of diabetes was reflected by increases in plasma fructosamine, blood urea nitrogen, creatinine, bilirubin, ALP, and decrease in albumin and globulins. These aberrancies were remedied by nCUR+INS or INS but not by CUR or nCUR. Kidney histopathological results revealed additional abnormalities characteristic of DKD, such as basement membrane thickening, tubular atrophy, and podocyte cytoskeletal impairment. nCUR and nCUR+INS mitigated these lesions, while CUR and INS alone were far less effective, if not ineffective. To elucidate how our treatments modulated inflammatory signaling in the liver and kidney, we identified hyperactivation of P38 (MAPK) and P53 with INS and CUR, whereas nCUR and nCUR+INS deactivated both targets. Similarly, the latter interventions led to significant downregulation of renal NLRP3, IL-1β, NF-ĸB, Casp3, and MAPK8 mRNA, indicating a normalization of inflammasome and apoptotic pathways. Thus, we show therapies that reduce both hyperglycemia and inflammation may offer better management of diabetes and its complications.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the United States and worldwide. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is a leading indication for liver transplant. Comorbidities associated with NAFLD development and NASH include type 2 diabetes, obesity, metabolic syndrome, and dyslipidemia. Extrahepatic morbidity and mortality are considerable as NAFLD is associated with an increased risk of cardiovascular disease and chronic kidney disease. Once NAFLD is diagnosed, the presence of liver fibrosis is the central determinant of hepatic prognosis. Severe liver fibrosis requires aggressive clinical management. No pharmacologic agents have regulatory approval in the United States for the treatment of NAFLD or NASH. Management is centered on efforts to reduce underlying obesity (lifestyle, medications, surgical or endoscopic interventions) and metabolic derangements (prediabetes, type 2 diabetes, hypertension, hyperlipidemia, and others). Current pharmacologic therapy for NAFLD is limited mainly to the use of vitamin E and pioglitazone, although other agents are being investigated in clinical trials. Cardiovascular and metabolic risk factors must also be assessed and managed. Here, NAFLD evaluation, diagnosis, and management are considered in the primary care setting and endocrinology clinics.

To evaluate whether short-term treatment with a selective 11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, AZD4017, would block hepatic cortisol production and thereby decrease hepatic fat in patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type 2 diabetes (T2D).This was a randomized, double-blind, placebo-controlled, phase 2 study conducted at two sites. Key inclusion criteria were the presence of NAFLD or NASH on magnetic resonance imaging (MRI) or recent biopsy positive for NASH. Enrolled patients were randomly assigned (1:1) to AZD4017 or placebo for 12 weeks. Primary outcomes were between-group differences in mean change from baseline to week 12 in liver fat fraction (LFF) and conversion ofA total of 93 patients were randomized; 85 patients completed treatment. The mean (standard deviation [SD]) change in LFF was -0.667 (5.246) and 0.139 (4.323) in the AZD4017 and placebo groups (P = 0.441). For patients with NASH and T2D, the mean (SD) change in LFF was significantly improved in the AZD4017 versus the placebo group (-1.087 [5.374] vs. 1.675 [3.318]; P = 0.033). Conversion ofAlthough the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of

To assess the diurnal patterns of postprandial glucose tolerance and insulin sensitivity, 19 subjects with type 2 diabetes (8 women; 60 ± 11 years; BMI 32 ± 5 kg/m2) and 19 anthropometrically matched subjects with no diabetes (ND; 11 women; 53 ± 12 years; BMI 29 ± 5 kg/m2) were studied during breakfast (B), lunch (L), and dinner (D) with identical mixed meals (75 g carbohydrates) on 3 consecutive days in a randomized Latin square design. Three stable isotopes of glucose were ustilized to estimate meal fluxes, and mathematical models were used in estimating indices of insulin action and β-cell function. Postmeal glucose excursions were higher at D versus B and at D versus L in type 2 diabetes (P < 0.05), while in ND they were higher at D versus B (P = 0.025) and at L versus B (P = 0.04). The insulin area under the curve was highest at B compared with L and D in type 2 diabetes, while no differences were observed in ND. Disposition index (DI) was higher at B than at L (P < 0.01) and at D (P < 0.001) in ND subjects, whereas DI was low with unchanging pattern across B-L-D in individuals with type 2 diabetes. Furthermore, between-meal differences in β-cell responsivity to glucose (F) and insulin sensitivity (SI) were concurrent with changes in the DI within groups. Fasting and postmeal glucose, insulin, and C-peptide concentrations, along with estimates of endogenous glucose production (EGP), Rd, SI, F, hepatic extraction of insulin, insulin secretion rate, extracted insulin, and DI, were altered in type 2 diabetes compared with ND (P < 0.011 for all). The data show a diurnal pattern of postprandial glucose tolerance in overweight otherwise glucose-tolerant ND individuals that differs from overweight individuals with type 2 diabetes. The results not only provide valuable insight into management strategies for better glycemic control in people with type 2 diabetes, but also improved understanding of daytime glucose metabolism in overweight individuals without impaired glucose tolerance or overt diabetes.

Diabetes mellitus (DM), a multifaceted metabolic disorder if not managed properly leads to secondary complications. Diabetic peripheral neuropathy (DPN) is one such complication caused by nerve damage that cannot be reversed but can be delayed. Recently, diabetes patients are using dietary supplements, although there remains a general skepticism about this practice. Curcumin (CUR), one such supplement can help prevent underlying low-grade inflammation in diabetes, but it is plagued by poor oral bioavailability. To better understand the role of bioavailability in clinical outcomes, we have tested double-headed nanosystems containing curcumin (nCUR) on DPN. Because CUR does not influence glucose levels, we have also tested the effects of nCUR combined with long-acting subcutaneous insulin (INS). nCUR with or without INS alleviates DPN at two times lower dose than unformulated CUR, as indicated by qualitative and quantitative analysis of the hind paw, sciatic nerve, spleen, and L4-6 spinal cord. In addition, nCUR and nCUR+INS preserve hind paw nerve axons as evident by the Bielschowsky silver stain and intraepidermal nerve fibers (IENF) density measured by immunofluorescence. The mechanistic studies further corroborated the results, where nCUR or nCUR+INS showed a significant decrease in TUNEL positive cells, mRNA expression of NLRP3, IL-1β, and macrophage infiltration while preserving nestin and NF200 expression in the sciatic nerve. Together, the data confirms that CUR bioavailability is proportional to clinical outcomes and INS alone may not be one of the solutions for DM. This study highlights the potential of nCUR with or without INS in alleviating DPN and warrants further investigation.

Postprandial glucose turnover in adolescents with type 1 diabetes (T1D) has not been investigated. To do so, we studied adolescents (n=15, age 11.5±0.5 yrs, BMI 19±2.3 kg/m2, HbA1c 7.5±1%, diabetes duration 4.6±3 yrs) and adults (n=15, age 36.3±9.4 yrs, BMI 27.1±2.1 kg/m2, HbA1c 6.9±1.1%, diabetes duration 18.1±9.6 yrs) with T1D after a mixed meal. Healthy adults (n=14, age 26.9 ± 7 yrs, BMI 24.9±2.5 kg/m2, HbA1c 5.0±0.3%) served as controls. T1D subjects administered their customary insulin bolus dose at meal onset. Rates of endogenous glucose production (EGP) , meal glucose appearance (MRa) and glucose disappearance (Rd) were calculated by the triple tracer method with stable isotopes ([1-13C] glucose, [2-13C] glucose and [6, 6-2H2] glucose) . Integrated glucose excursions did not differ between adolescents and adults with T1D during early (0-120 min) and total (0-300 min) postprandial periods. While basal EGP at start of the meal was higher (p Disclosure F. Ruchi: None. D. Romeres: None. S. Gururaj: None. M. D. Deboer: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. R. Basu: Consultant; Sparrow Pharmaceuticals Inc, Research Support; Abbott Diabetes, AstraZeneca. A. Basu: Speaker's Bureau; Zealand Pharma A/S. Funding DK 124886, DK 085516, DK 029953

Use of continuous glucose monitoring (CGM) facilitates better management of type 2 diabetes (T2D) in outpatient clinics in academic medical centers. In a Quality Improvement project, we evaluated the effects of telehealth aided by CGM on HbA1c and percent time in range (TIR 70-180 mg/dl) in patients with T2D over a 6-month duration. Diabetes management advice based on intermittent CGM use was provided via phone by an academic endocrinologist to the clinical pharmacist at a rural community clinic. Inadequately controlled (HbA1c > 8%) T2D patients (n=27) on at least one antidiabetic drug were included and were monitored over a 6 month period, baseline (V1) , 3 months (V2) and 6 months (V3) . All patients received standard of care (SOC) treatment. On each visit, 12 patients (age 59 8y, BMI 36.2 3.6kg/m2, HbA1C 9.3 1.3%) received a professional CGM for 2 weeks. Thereafter, the devices were removed and analyzed. The PCP implemented medication changes based on recommendations by the endocrinologist to the clinical pharmacist. The other 15 patients (age 60 8y, BMI 32 4 kg/m2, HbA1C 9.1 1.6%) underwent the same schedule without CGM or telehealth consultations. There were no significant differences in age or HbA1c between groups at baseline. HbA1c (%) decreased (Δ -1.0 ± 1.4; p=0.03) , and CGM TIR (%) increased (Δ +24.3 ± 38.7; p=0.05) at V3 vs. V1 in the telehealth group. However, weight, CGM time below and above ranges (%) did not differ (p>0.05) statistically. In contrast, there were no significant differences in HbA1c (Δ +0.4 ± 1.7; p=0.3) between V3 and V1 in the SOC without telehealth group. Our results show that intermittent CGM use coupled with tele-consultation with diabetes expert improves glucose control and care quality in patients with T2D in community based health practice. This strategy could potentially mitigate existing health care disparities between suburban/rural-based community health practices and academic medical centers, thus closing the gaps in quality of care. Disclosure S. Gururaj: None. A. Asfa: None. L. C. Hanley: None. Y. R. Yadav: None. R. T. Bashore: None. R. Basu: Consultant; Sparrow Pharmaceuticals Inc, Research Support; Abbott Diabetes, AstraZeneca. A. Basu: Speaker’s Bureau; Zealand Pharma A/S. Funding Virginia Department of Health (GS11963)

Background Glucagon serves as an important regulatory hormone for regulating blood glucose concentration with tight feedback control exerted by insulin and glucose. There are critical gaps in our understanding of glucagon kinetics, pancreatic α cell function and intra-islet feedback network that are disrupted in type 1 diabetes. This is important for translational research applications of evolving dual-hormone (insulin + glucagon) closed-loop artificial pancreas algorithms and their usage in type 1 diabetes. Thus, it is important to accurately measure glucagon kinetics in vivo and to develop robust models of glucose-insulin-glucagon interplay that could inform next generation of artificial pancreas algorithms. Methods Here, we describe the administration of novel 13C15N heavy isotope-containing glucagon tracers—FF glucagon [(Phe 6 13C9,15N; Phe 22 13C9,15N)] and FFLA glucagon [(Phe 6 13C9,15N; Phe 22 13C9,15N; Leu 14 13C6,15N; Ala 19 13C3)] followed by anti-glucagon antibody-based enrichment and LC–MS/MS based-targeted assays using high-resolution mass spectrometry to determine levels of infused glucagon in plasma samples. The optimized assay results were applied for measurement of glucagon turnover in subjects with and without type 1 diabetes infused with isotopically labeled glucagon tracers. Results The limit of quantitation was found to be 1.56 pg/ml using stable isotope-labeled glucagon as an internal standard. Intra and inter-assay variability was Conclusions The methods described in this study for simultaneous detection and quantitation of glucagon tracers have clinical utility for investigating glucagon kinetics in vivo in humans.

Context The effect of physiological changes in night-time cortisol and glucagon on endogenous glucose production (EGP) and nocturnal glycemia are unknown. Objective To determine the effects of changes in cortisol and glucagon on EGP during the night. Design Two overnight protocols were conducted. In Protocol 1, endogenous cortisol was blocked with metyrapone and hydrocortisone infused either at constant (constant) or increasing (variable) rates to mimic basal or physiological nocturnal cortisol concentrations. In Protocol 2, endogenous glucagon was blocked with somatostatin and exogenous glucagon was infused at either basal or elevated rates to mimic nocturnal glucagon concentrations observed in nondiabetic (ND) and type 2 diabetes (T2D) individuals. EGP was measured using [3-3H] glucose and gluconeogenesis estimated with 2H2O in all studies. Setting Mayo Clinic Clinical Research Trials Unit, Rochester, MN, US. Participants In Protocol 1, 34 subjects (17 ND and 17 T2D) and in Protocol 2, 39 subjects (21 ND and 18 T2D) were studied. Main Outcome Measures Endogenous glucose production Results EGP, gluconeogenesis, and glycogenolysis were higher with variable than with constant cortisol at 7 am in T2D subjects. In contrast, nocturnal EGP did not differ in ND subjects between variable and constant cortisol. While elevated glucagon increased EGP, glycogenolysis, and gluconeogenesis in ND, the data in T2D subjects indicated that EGP and gluconeogenesis but not glycogenolysis were higher during the early part of the night. Conclusion Nocturnal hyperglucagonemia, but not physiological rise in cortisol, contributes to nocturnal hyperglycemia in T2D due to increased gluconeogenesis.

Quantification of disturbances in glucose-insulin homeostasis has been the cornerstone of appraising insulin resistance and detecting early-stage diabetes. Metabolic homeostasis arises from feedback and feed-forward interactions among (at least) all four of glucose, insulin, glucagon, and cortisol. Quantifying such tetrapartite interactions in the fasting (endogenously regulated) state overnight could elucidate very early regulatory disruption. In the present study, healthy subjects without diabetes (ND; n = 20) and patients with Type 2 diabetes (T2D; n = 21) were investigated by repeated overnight blood sampling of all four of glucose, insulin, glucagon, and cortisol concentrations. To obviate confounding by hormone-specific disappearance rates, analyses were performed at the level of production (glucose) or secretion (insulin, glucagon, and cortisol) rates estimated by regularized deconvolution analysis. Then, a novel method for quantifying the loss of homeostasis among glucose, insulin, and glucagon (and, when available, cortisol) secretion patterns was developed. Potential early stage prediabetic candidates were identified. The new methodology avoids many of the difficulties encountered in the conventional estimation of insulin-glucose sensitivity or resistance, while incorporating the dynamics of the key coregulators under fasting conditions.

CONTEXT: Chronic hyperglycemia worsens skeletal muscle insulin resistance and β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity is not clear. OBJECTIVE: To examine the effect of sustained physiologic hyperglycemia (similar to that observed in patients with type 2 diabetes) on endogenous (primarily reflecting hepatic) glucose production (EGP) in healthy individuals. DESIGN: Volunteers participated in a three-step hyperinsulinemic (10, 20, 40 mU/m(2) per minute) euglycemic clamp before and after a 48-hour glucose infusion to increase plasma glucose concentration by ∼40 mg/dL above baseline. EGP was measured with 3-(3)H-glucose before and after chronic glucose infusion. PARTICIPANTS: Sixteen persons with normal glucose tolerance [eight with and eight without a family history (FH) of diabetes] participated in the study. MAIN OUTCOME MEASURE: EGP. RESULTS: Basal EGP increased following 48 hours of glucose infusion (from a mean ± SEM of 2.04 ± 0.08 to 3.06 ± 0.29 mg/kg(ffm)⋅ min; P < 0.005). The hepatic insulin resistance index (basal EGP × fasting plasma insulin) markedly increased following glucose infusion (20.1 ± 1.8 to 51.7 ± 6.6; P < 0.005) in both FH+ and FH− subjects. CONCLUSION: Sustained physiologic hyperglycemia for as little as 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in health persons with normal glucose tolerance, providing evidence for the role of glucotoxicity in the increase in hepatic glucose production in type 2 diabetes.

People with diabetes mellitus are more vulnerable to viral infections including influenza and the ongoing COVID-19 pandemic. Fatal pneumonia and cytokine storm is a contributor to the mortality. We hypothesized that aberrant glycemic control induces an immune dysregulation, which compromises the anti-viral immunity and promotes inflammation by altering the balance of the protective T-regulatory cells (Tregs) and IL-17 responses. Indeed, comparison of the peripheral blood lymphocytes in a limited cohort of healthy controls (HC; n=4) and people with diabetes (n=9) showed profound immune dysregulation. As compared to HC (66±21 x10^3/ml), the number of circulating Tregs were significantly (p In summary, altered glycemic control, as indicated by higher HbA1c levels, significantly correlates with compromised IFNg production in the CD8 and Th1 cells, which is important for anti-viral immunity, as well as a marked proinflammatory shift shown as reduced Tregs levels and enhanced IL-17 production by both CD4 and CD8 cells. This immune-dysregulation in diabetes may thus contribute to a greater susceptibility to viral infections and infection-induced pathology. Disclosure V. Sabapathy: Stock/Shareholder; Self; 10x Genomics, Apple, AstraZeneca, Bayer U. S., Gilead Sciences, Inc. M. Dogan: None. R. Venkatadri: None. R. Arbab: None. J. Z. Ma: None. A. Basu: None. R. Basu: None. R. Sharma: Other Relationship; Self; SlateBio Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104963); University of Virginia

We have recently established a method utilizing the natural abundance of [13C] polysaccharide enabling measurement of enrichment of [13C] glucose in healthy humans. We now compare complex carb (CC) meal with a single tracer infusion of [6,6-2H2] glucose at -120 min to the established simple carb (SC) triple tracer protocol with infusion of [6,6-2H2] glucose at -120 min and [2-13C] glucose at 0 min with meal ingested at time 0. Six type 2 diabetes subjects (4M, age 65±6 y; BMI 33±4 kg/m2; HbA1c 50±10 mM/mol) were studied in random order with SC labeled with [1-13C] glucose and CC meal with sorghum grain. All meals had ~75 g carbohydrates with matched macronutrient content. Steele’s non-steady state equations were used to calculate glucose fluxes: rates of meal glucose appearance (Rameal), glucose disappearance (Rd) and endogenous glucose production (EGP) (Results in Fig1). Glucose, insulin and C-peptide concentrations achieved as well as iAUC of Rameal and Rd were significantly lower with CC than SC meal (p Disclosure Y. R. Yadav: None. A. Asfa: None. F. Ruchi: None. A. Weaver: None. C. M. Amarasekarage: None. C. Lane: None. A. Basu: None. R. Basu: None. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

Studies suggest that Indian Americans (IA) living in US have higher basal insulin resistance than other ethnic groups thereby increasing risk for T2DM. To characterize glucose metabolism between IA to Indians (I) living in India, we studied thirty-one Indians recruited at the Chellaram Hospital in Pune, India and twenty Indian Americans at Mayo Clinic, MN. All underwent a 3-hour 9-point OGTT with analyses of glucose, insulin and C-peptide. The oral minimal model was used to estimate β-cell function (φtotal) and insulin sensitivity (SI), with assessment of β-cell responsivity (Disposition Index: DI). Insulin clearance was calculated as AUC of insulin secretion rate over insulin concentrations. Both I and IA were similar with respect to age (33±7 vs. 39±13y), BMI (25.0±1.8 vs. 24.7± 3.2kg/m2) and sex (13F and 9F) respectively. Results are in fig 1. Fasting and iAUC glucose did not differ between groups (p=0.478), while integrated C-peptide and Insulin concentrations were higher in I than IA (p Disclosure V. Purandare: None. A. Galderisi: None. M. Maertino: None. A. Basu: None. C. Cobelli: None. A. Unnikrishnan: Advisory Panel; Self; Sanofi-Aventis, Other Relationship; Self; Novo Nordisk A/S, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes. R. Basu: None. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.)

The triple tracer method has enabled accurate and concurrent measurements of glucose turnover as well as indices of insulin action and beta cell function in people with diabetes. We have previously utilized the natural enrichment of 13C polysaccharide in commercially available grains, and compared indices obtained after a complex carbohydrate (CC) meal to those obtained after a simple carbohydrate (SC) mixed meal in healthy humans. We have now completed studies in 6 subjects with type 2 diabetes (4M, age 65±6 y; BMI 33±4 kg/m2; HbA1c 50±10 mM/mol) after ~75 gm of either sorghum (naturally enriched 13C) or glucose labeled with 13C mixed meals containing ~75 gm carbs and matched protein and fat in random order. Results in figure. Glucose, insulin and C-peptide concentrations achieved were significantly lower with CC meal as compared to SC meal (p Disclosure D. Romeres: None. A. Basu: None. Y. R. Yadav: None. C. Cobelli: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. R. Basu: None. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

Inappropriately elevated postprandial (PP) glucagon concentrations contribute to hyperglycemia in type 1 diabetes (T1D). To define the underlying mechanisms, we infused 13C15N glucagon tracer in healthy and T1D subjects during a mixed meal (75 gm carb, 15% fat, 35% protein; 8 kcal/kg) to estimate PP glucagon turnover. We show data from 12 healthy (age 26 ± 6 yrs, BMI 24.6±2.8 kg/m2, fasting plasma glucose 4.8±0.3 mM, HbA1c 5.0±0.3%) and 4, C-peptide negative T1D (age 37 ± 15 yrs, BMI 27.5 ± 2.3 kg/m2, fasting plasma glucose 11.1 ± 2.9 mM, HbA1c 7.7 ± 0.9%) subjects completed thus far. Arterialized venous samples were drawn periodically for measurements of 13C15N glucagon (tandem mass spectrometry), glucagon (Mercodia), and glucose (YSI) concentrations throughout the study. Systemic glucagon turnover was calculated by non-steady-state Steele’s equation after determining volume of distribution of glucagon. Integrated PP glucagon concentrations were higher (p Disclosure F. Ruchi: None. Y. R. Yadav: None. M. Schiavon: None. A. Weaver: None. C. Cobelli: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. R. Basu: None. A. Basu: None. Funding National Institutes of Health (DK085516 to A.B.), (DK029953 to R.B.); National Mouse Metabolic Phenotyping Center (DK059637); Vanderbilt Diabetes Research and Training Center (DK020593)

We recently developed a novel stable glucagon tracer, [13C15N]-glucagon, to study glucagon kinetics and turnover in humans. Here, [13C15N]-glucagon was used to model glucagon kinetics during steady-state conditions in 5 nondiabetic subjects with complete data thus far (age 27±7 y; BMI 25.3±2.4 kg/m2, Mean±SD) who underwent two separate protocols: bolus injection (1497±564 pg/kg) and stop-from-constant infusion (138±33 pg/kg/min) of [13C15N]-glucagon. Arterialized blood was frequently sampled to measure the decay of [13C15N]-glucagon concentrations using tandem mass spectrometry. A linear, single compartment model was necessary and sufficient to reliably describe [13C15N]-glucagon kinetics and estimate both glucagon volume of distribution and clearance rate. The model well predicted the data (Fig. 1) and model parameters were estimated with precision (CV = 6±3 %). Volume of glucagon distribution was 37±9 mL/kg while clearance rate was 8.1±1.5 mL/kg/min. Results suggest that glucagon distributes in a single compartment with a volume of distribution approximately equal to the plasma volume. Additional nondiabetic and subjects with type 1 diabetes are currently under study. This model will be key to study postprandial glucagon turnover. Disclosure M. Schiavon: None. F. Ruchi: None. Y. R. Yadav: None. R. Basu: None. C. Cobelli: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A. Basu: None. Funding National Institutes of Health (DK085516 to A.B.), (DK029953 to R.B.); Italian Ministry of Education, University and Research (Law 232/2016 to M.S. and C.D.M.)

Exercise effects (EE) on whole body glucose rate of disappearance (Rd) occur through insulin- independent (IIRd) and insulin-dependent (IDRd) mechanisms. Quantifying these processes in vivo would allow a better understanding of the physiology of glucose regulation. This is of particular importance in individuals with type 1 diabetes (T1D) since such a knowledge may help to improve glucose management. However, such a model is still lacking. Here, we analyzed data from 6 T1D and 6 nondiabetic (ND) subjects undergoing a labeled glucose clamp study during, before and after a 60 min exercise session at 65% VO2max on three randomized visits: euglycemia-low insulin, euglycemia-high insulin and hyperglycemia-low insulin. We tested a set of models, all sharing a single-compartment description of glucose kinetics, but differing in how exercise is assumed to modulate glucose disposal. Model selection was based on parsimony criteria. The best model assumed an exercise-induced immediate effect on IIRd and a delayed effect on IDRd. It predicted that exercise increases IIRd, compared to rest, by 66% - 82% and 67% - 97% in T1D and ND, respectively, not significantly different between the two groups. Conversely, the exercise effect on IDRd ranged between 81% - 155% in T1D and it was significantly higher than ND, which ranged between 10% - 40%. The exaggerated effect observed in IDRd can explain the higher hypoglycemia risk related to T1D individuals. This novel exercise model could help in informing safe and effective glucose management during and after exercise in T1D individuals.

Exercise effects (EE) on whole body glucose rate of disappearance (Rd) occur through insulin-independent (IIRd) and insulin-dependent (IDRd) mechanisms. Quantifying these processes in vivo would allow a better understanding of the physiology of glucose regulation. This is of particular importance in individuals with type 1 diabetes (T1D) since such a knowledge may help to improve glucose management. However, such a model is still lacking. Here, we analyzed data from six T1D and six nondiabetic (ND) subjects undergoing a labeled glucose clamp study during, before, and after a 60-min exercise session at 65% V̇o(2max) on three randomized visits: euglycemia-low insulin, euglycemia-high insulin, and hyperglycemia-low insulin. We tested a set of models, all sharing a single-compartment description of glucose kinetics, but differing in how exercise is assumed to modulate glucose disposal. Model selection was based on parsimony criteria. The best model assumed an exercise-induced immediate effect on IIRd and a delayed effect on IDRd. It predicted that exercise increases IIRd, compared with rest, by 66%–82% and 67%–97% in T1D and ND, respectively, not significantly different between the two groups. Conversely, the exercise effect on IDRd ranged between 81% and 155% in T1D and it was significantly higher than ND, which ranged between 10% and 40%. The exaggerated effect observed in IDRd can explain the higher hypoglycemia risk related to individuals with T1D. This novel exercise model could help in informing safe and effective glucose management during and after exercise in individuals with T1D. NEW & NOTEWORTHY Here, we present a new mathematical model describing the effect of moderate physical activity on insulin-mediated and noninsulin-mediated glucose disposal in subjects with and without diabetes. We believe that this represents a step-forward in the knowledge of type 1 diabetes pathophysiology, and an useful tool to design safe and effective insulin-therapies.

Quantifying the exercise effect (EE) on glucose turnover is fundamental for type 1 diabetes (T1D) management. We recently proposed a model describing EE on insulin-dependent and -independent glucose utilization in subjects with and without T1D (ND). However, to date, a model of EE on endogenous glucose production (EGP) is still lacking. To do so, we analysed existing data on 6 T1D (age 29±3 yrs, BMI 28.3±2.0 kg/m2, VO2 max 28.7±2.9 ml/kg/min, mean±SE) and 6 ND (age=28.2±4.2 yr, BMI=23.6 ±1.0 kg/m2, VO2 max 36.6±2.9 ml/kg/min) subjects studied with a glucose clamp, during, before and after a 60 min aerobic exercise session at 65% VO2max on three visits: euglycemia-low insulin (V1); euglycemia-high insulin (V2) and hyperglycemia-low insulin (V3) in random order. EGP was measured with the isotope dilution technique using [6,6-2H2]glucose. A battery of models was tested against data to assess if EE on EGP is mediated by insulin, glucose or both. The best model (Fig 1) provided a good description of the data in both groups. Results show that EE on EGP is delayed and insulin mediated. Further studies are needed to validate the model in real life conditions thus making it usable for optimization of insulin therapy. Disclosure D. Romeres: None. M. Schiavon: None. R. Visentin: None. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. C. Cobelli: None. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. Funding Italian Ministry of Education (232/2016); National Institute of Diabetes and Digestive and Kidney Diseases (DK029953 to R.B.), (DK085516 to A.B.)

We have recently developed a novel isotope dilution method using nonradioactive, stable human Glucagon (Phe 6 13C9, 15N; Phe 22 13C9, 15N) tracer to measure glucagon turnover. In this study we combined this method with organ catheterization technique to estimate the effects of increasing circulating glucagon concentrations, spanning the physiological range, on splanchnic and leg glucagon extraction. We present data from the first 6 healthy subjects (age 25±3.6 yrs; BMI 26.7±4.5 kg/m2; fasting glucose 4.6±0.5 mM; HbA1c 5.1±0.3%) completed thus far. After IRB approval and informed consent, subjects were admitted in the morning after an overnight fast to Interventional Radiology, where catheters were placed in the right femoral artery and vein under local anesthesia with aseptic precautions. Under fluoroscopic guidance, a hepatic venous catheter was positioned through the femoral vein. Glucagon tracer was infused intravenously and Indocyanine Green infused via the femoral artery sheath to measure splanchnic and femoral plasma flows. After a 90 min period for basal sampling, exogenous glucagon was infused at 0.65 ng/kg/min for 60 minutes (low) followed by 1.5 ng/kg/min (high) for another 60 minutes. Plasma samples were collected periodically from femoral artery, femoral vein and hepatic vein for concentrations of Glucagon tracer (Tandem Mass Spectrometry), glucagon, glucose and Indocyanine Green (Spectrophotometry) concentrations. Arterial glucagon concentrations were 45.2±9.6 pg/ml (basal), 56.3±13.3 pg/ml (low) and 81.4±15.5 pg/ml (high). While fractional splanchnic glucagon extraction remained relatively unchanged (24.0±12.5% vs. 27.7±15.6% vs. 23.5±10.1%: basal vs. low vs. high), fractional leg glucagon extraction tended to increase (13.5±3.8% vs. 16.0±7.2% vs. 18.5±9.4%: basal vs. low vs. high) with increasing glucagon concentrations. These initial data suggest differing mechanisms of glucagon clearance across the splanchnic and leg tissues in humans. Disclosure F. Ruchi: None. Y.R. Yadav: None. D. Romeres: None. S. Sawleh: None. L.M. Benson: None. K.L. Johnson: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. C. Cobelli: None. D.J. McCormick: None. L.R. Wilkins: None. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

Glucagon metabolism in humans is poorly understood and is currently under active investigation. We have recently developed a new isotope dilution method using nonradioactive, stable human glucagon (Phe 6 13C9, 15N; Phe 22 13C9, 15N) tracer to measure glucagon fluxes. To estimate postprandial glucagon turnover using this novel technique, we present data from the first 5 healthy subjects (3 males, age 26.2±7.9 years, BMI 25.4±2.6 kg/m2, fasting plasma glucose 4.7±0.2 mM, HbA1c 5.1±0.2 %) done thus far. After IRB approval and informed consent, subjects presented to the clinical research unit in the morning after an overnight fast. A catheter was inserted in a forearm vein for glucagon tracer infusion and another catheter placed in the contralateral hand and the hand kept in a heated box for periodic draws of arterialized venous samples for measurements of glucagon tracer (tandem mass spectrometry), glucagon and glucose concentrations during the study. A mixed meal (75 grams carb, 15% protein, 35% fat; 8 kcal/kg) was ingested at time 0 and the glucagon tracer infusion rate adjusted to mimic the anticipated changes in postprandial circulating glucagon concentrations for 6 hours. Systemic glucagon appearance rate (Ra glucagon) was calculated by the isotope dilution method. Fig 1 shows the Ra glucagon in all subjects. These initial data show that postprandial glucagon turnover can be calculated in humans applying this novel technique. Disclosure F. Ruchi: None. Y.R. Yadav: None. D. Romeres: None. S. Sawleh: None. L.M. Benson: None. K.L. Johnson: None. M. Schiavon: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. C. Cobelli: None. D.J. McCormick: None. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

We have recently demonstrated successful estimation of postprandial glucose fluxes using a novel triple tracer technique after ingestion of a mixed meal containing complex carbohydrates (CC) that is naturally enriched with 13C polysaccharide ([13C]-PS). We also reported higher insulin sensitivity (SI) with CC than simple carbohydrate (SC) containing mixed meals. The current analysis was designed to determine if [13C]-PS per se could directly measure hepatic (SIH) and disposal SI (SID) during the CC containing mixed meal. Sixteen healthy subjects (9M, age=33±2 y, BMI=23±1 kg/m2) received, in random order, either SC (labeled with [13C]-glucose) or CC (naturally containing [13C]-PS) mixed meals. All meals were isocaloric and contained 50g carbohydrates with similar macronutrient composition. Plasma glucose, [13C]-glucose and insulin were measured and the Single Tracer Oral Minimal Model applied to estimate SIH and SID. The model well predicted the data. SIH was significantly higher, while SID was numerically but not statistically higher in CC than SC meals (Figure 1). This implies that the higher SI with CC meals is likely due to higher hepatic insulin sensitivity. Taken together, the data suggest that a single, naturally occurring [13C]-PS tracer can measure postprandial SI and its components without the need for the triple tracer method. Disclosure C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R. Visentin: None. M. Schiavon: None. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. C. Cobelli: None. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. Funding National Institutes of Health (DK085516, DK94331, DK29953); Italian Minister for Education

Hepatic extraction of insulin is associated with insulin sensitivity in humans. It is unknown if a diurnal pattern of HE exists and if this differs between nondiabetic (ND) and type 2 diabetes (T2D) subjects. Here are data presented for 10 ND (BMI 29.4±1.3 kg/m2, age 57±3 yrs) and 9 T2D subjects (BMI 33±2 kg/m2, age 58±4 yrs, HbA1c 57±4 mM/mol) studied thus far. They ingested identical mixed meals (75 g carbs; 8 kcal/kg) at either breakfast (B), lunch (L) or dinner (D) in randomized Latin square order on three consecutive days with frequent sampling of plasma glucose (G), insulin (I) and C-peptide (C) concentrations. Fasting and post-meal glucose concentrations were higher while fasting and post-meal insulin, C-peptide concentrations were lower during meals in T2D as compared to ND subjects. Total and basal hepatic insulin extraction (HE and HEb, respectively) were estimated using the Oral Insulin and C-peptide Minimal Models. Differences with B, L and D and between ND and T2D were assessed by N-way ANOVA (a p-value Disclosure D. Romeres: None. Y.R. Yadav: None. F. Ruchi: None. C. Cobelli: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

The existence of a diurnal pattern of post prandial glucose tolerance is relevant for management of patients with type 2 diabetes (T2D). We studied 10 healthy (4M) and 9 T2D (6M) subjects matched for age (56±3 vs. 58±3 yrs) and BMI (29±2 vs. 32±2 kg/m2). OGTT was done in healthy subjects to rule out diabetes. Identical mixed meals (8 kcal/kg/meal; 75 gm carb) were ingested during breakfast (B), lunch (L), and dinner (D) at 0700, 1300, and 1900 h in randomized latin square order with one labeled test meal/day on 3 consecutive days. Physical activity was kept same. Postprandial glucose turnover was measured utilizing the triple tracer technique modified with all stable isotopes ([1-13C] Glucose, [2-13C] Glucose and [6, 6-2H2] Glucose). Results shown in Fig 1. Fasting and post-meal glucose were higher while fasting and post-meal insulin and C-peptide concentrations lower in T2D for all three meals compared to healthy. Although meal glucose appearance did not differ between meals in either group, fasting endogenous glucose production (EGP) was higher, percent suppression of EGP lower in T2D and glucose disappearance (corrected for urine glucose loss) lower in T2D than healthy for all meals consumed. This data correlates with lower insulin sensitivity, B-cell responsivity to glucose and disposition index in T2D than healthy throughout the day. Our results suggest an emerging diurnal pattern to glucose tolerance and fluxes in humans, and that the pattern is different in T2D. Disclosure Y.R. Yadav: None. D. Romeres: None. F. Ruchi: None. S. Sawleh: None. R. Carter: None. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

Glucagon metabolism in humans is poorly understood and is currently under active investigation. We have recently developed a novel isotope dilution method using nonradioactive, stable human glucagon (Phe 6 13C9, 15N; Phe 22 13C9, 15N) tracer to measure glucagon turnover. In this study we combined this method with organ catheterization technique to estimate splanchnic and leg glucagon extraction and uptake. We present data from the first 6 healthy subjects (age 25±3.6 yrs; BMI 26.7±4.5 kg/m2; fasting glucose 4.6±0.5 mM; HbA1c 5.1±0.3%) completed thus far. After IRB approval and informed consent, subjects were admitted in the morning after an overnight fast to Interventional Radiology, where catheters were placed in the right femoral artery and vein under local anesthesia with aseptic precautions. Under fluoroscopic guidance, a hepatic venous catheter was positioned through the femoral vein. Glucagon tracer was infused intravenously and Indocyanine Green infused via the femoral artery sheath to measure splanchnic and femoral plasma flows. Plasma samples were collected periodically from femoral artery, femoral vein and hepatic vein for concentrations of glucagon tracer (Tandem Mass Spectrometry), glucagon, glucose and Indocyanine Green (Spectrophotometry) concentrations. Fractional splanchnic glucagon extraction was 24.0±12.5 % while total splanchnic glucagon uptake was 214.3±56.1 ng/kg total body weight/min. Net splanchnic glucagon balance was -34.4±10.0 ng/kg total body weight/min implying net splanchnic glucagon production. Fractional leg glucagon extraction was 13.5±3.8% while total leg glucagon uptake was 53.0±21.2 pg/kg total body weight/min. To the best of our knowledge, these initial data provide the first direct assessment of regional glucagon metabolism in healthy humans in the post absorptive fasting state. Disclosure F. Ruchi: None. Y.R. Yadav: None. D. Romeres: None. S. Sawleh: None. L.M. Benson: None. K.L. Johnson: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. C. Cobelli: None. D.J. McCormick: None. L.R. Wilkins: None. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

To shed light on how acute exercise affects blood glucose (BG) concentrations in nondiabetic subjects, we develop a physiological pharmacokinetic/pharmacodynamic model of postprandial glucose dynamics during exercise. We unify several concepts of exercise physiology to derive a multiscale model that includes three important effects of exercise on glucose dynamics: increased endogenous glucose production (EGP), increased glucose uptake in skeletal muscle (SM), and increased glucose delivery to SM by capillary recruitment (i.e. an increase in surface area and blood flow in capillary beds). We compare simulations to experimental observations taken in two cohorts of healthy nondiabetic subjects (resting subjects (n = 12) and exercising subjects (n = 12)) who were each given a mixed-meal tolerance test. Metabolic tracers were used to quantify the glucose flux. Simulations reasonably agree with postprandial measurements of BG concentration and EGP during exercise. Exercise-induced capillary recruitment is predicted to increase glucose transport to SM by 100%, causing hypoglycemia. When recruitment is blunted, as in those with capillary dysfunction, the opposite occurs and higher than expected BG levels are predicted. Model simulations show how three important exercise-induced phenomena interact, impacting BG concentrations. This model describes nondiabetic subjects, but it is a first step to a model that describes glucose dynamics during exercise in those with type 1 diabetes (T1D). Clinicians and engineers can use the insights gained from the model simulations to better understand the connection between exercise and glucose dynamics and ultimately help patients with T1D make more informed insulin dosing decisions around exercise.

ContextPlasma betaine correlates with insulin sensitivity in humans. Betaine supplementation improves metabolic effects in mice fed a high-fat diet.ObjectiveTo assess metabolic effects of oral betaine in obese participants with prediabetes.DesignA 12-week, parallel arm, randomized, double-masked, placebo-controlled trial.SettingUniversity-affiliated hospital.Participants and InterventionsPersons with obesity and prediabetes (N = 27) were randomly assigned to receive betaine 3300 mg orally twice daily for 10 days, then 4950 mg twice daily for 12 weeks, or placebo.Main Outcome MeasuresChanges from baseline in insulin sensitivity, glycemia, hepatic fat, and endothelial function.ResultsThere was a 16.5-fold increase in plasma dimethylglycine [dimethylglycine (DMG); P < 0.0001] levels, but modest 1.3- and 1.5-fold increases in downstream serine and methionine levels, respectively, in the betaine vs placebo arm. Betaine tended to reduce fasting glucose levels (P = 0.08 vs placebo) but had no other effect on glycemia. Insulin area under curve after oral glucose was reduced for betaine treatment compared with placebo (P = 0.038). Insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp, was not improved. Serum total cholesterol levels increased after betaine treatment compared with placebo (P = 0.032). There were no differences in change in intrahepatic triglyceride or endothelial function between groups.ConclusionDMG accumulation supports DMG dehydrogenase as rate limiting for betaine metabolism in persons with prediabetes. Betaine had little metabolic effect. Additional studies may elucidate mechanisms contributing to differences between preclinical and human responses to betaine, and whether supplementation of metabolites downstream of DMG improves metabolism.

AIM To investigate the mechanisms behind the lower postprandial glucose (PPG) concentrations achieved with fast-acting insulin aspart (faster aspart) than with insulin aspart (IAsp). MATERIALS AND METHODS In a randomized, double-blind, crossover trial, 41 people with type 1 diabetes received identical subcutaneous single faster aspart and IAsp doses (individualized for each participant), together with a standardized mixed meal (including 75 g carbohydrate labelled with [1-13 C] glucose). PPG turnover was determined by the triple-tracer meal method using continuous, variable [6-3 H] glucose and [6,6-2 H2 ] glucose infusion. RESULTS Insulin exposure within the first hour was 32% greater with faster aspart than with IAsp (treatment ratio faster aspart/IAsp 1.32 [95% confidence interval {CI} 1.18;1.48]; P < .001), leading to a 0.59-mmol/L non-significantly smaller PPG increment at 1 hour (ΔPG1h ; treatment difference faster aspart-IAsp -0.59 mmol/L [95% CI -1.19; 0.01]; P = .055). The trend towards reduced ΔPG1h with faster aspart was attributable to 12% greater suppression of endogenous glucose production (EGP; treatment ratio 1.12 [95% CI 1.01; 1.25]; P = .040) and 23% higher glucose disappearance (1.23 [95% CI 1.05; 1.45]; P = .012) with faster aspart than with IAsp during the first hour. Suppression of free fatty acid levels during the first hour was 36% greater for faster aspart than for IAsp (1.36 [95% CI 1.01;1.88]; P = .042). CONCLUSIONS The trend towards improved PPG control with faster aspart vs IAsp in this study was attributable to both greater early suppression of EGP and stimulation of glucose disappearance.

We have previously shown that low insulin coupled with euglycemia or mild hyperglycemia appear to be the most favorable milieu for type 1 diabetes (T1D) during exercise. However, the contributions of insulin-dependent (IDGU) and insulin independent (IIGU) effects of exercise on glucose utilization are unknown. To do so, we studied 6 T1D (age 29±3 years, BMI 28.3±2.0 kg/m2, VO2 max 28.7±2.9 ml/kg/min, mean±SE) and 6 ND (age=28.2±4.2 year, BMI=23.6 ±1.0 kg/m2, VO2 max 36.6±2.9 ml/kg/min) subjects with a glucose clamp, during, before and after a 60 min exercise session at 65% VO2max, on three visits: euglycemia-low insulin (V1); euglycemia-high insulin (V2) and hyperglycemia-low insulin (V3) in random order. Glucose turnover was measured with the isotope dilution technique using [6,6-2H2]glucose. We modified the minimal model to measure the IDGU and IIGU components of glucose utilization (Figure 1, upper panel). Results demonstrate that while IDGU was similar in both groups (data not shown), IIGU (expressed as percent change from baseline) during exercise was significantly lower in T1D than ND subjects, though the trend across the visits were similar (Figure 1, lower panel). Further studies are necessary to determine the cause for this abnormality in T1D to optimize glucose control. Disclosure D. Romeres: None. M. Schiavon: None. A. Basu: Research Support; Spouse/Partner; AstraZeneca. C. Cobelli: None. R. Basu: Other Relationship; Self; AstraZeneca. C. Dalla Man: None. Funding National Institutes of Health (R01090541)

While the triple tracer isotope dilution method has enabled accurate estimation of carbohydrate turnover after a mixed meal, use of the simple carbohydrate glucose as the carbohydrate source limits its translational applicability to everyday meals that typically contain complex carbohydrates. Hence, utilizing the natural enrichment of [13C]polysaccharide in commercially available grains, we devised a novel tracer method to measure postprandial complex carbohydrate turnover and indices of insulin action and β-cell function and compared the parameters to those obtained after a simple carbohydrate containing mixed meal. We studied healthy volunteers after either rice ( n = 8) or sorghum ( n = 8) and glucose ( n = 16) containing mixed meals and modified the triple tracer technique to calculate carbohydrate turnover. All meals were matched for calories and macronutrient composition. Rates of meal glucose appearance (2,658 ± 736 vs. 4,487 ± 909 μM·kg−1·2 h−1), endogenous glucose production (−835 ± 283 vs. −1,123 ± 323 μM·kg−1·2 h−1) and glucose disappearance (1,829 ± 807 vs. 3,606 ± 839 μM·kg−1·2 h−1) differed ( P < 0.01) between complex and simple carbohydrate containing meals, respectively. Interestingly, there were significant increase in indices of insulin sensitivity (32.5 ± 3.5 vs. 25.6 ± 3.2 10−5(dl·kg−1·min−2)/pM, P = 0.006) and β-cell responsivity (disposition index: 1,817 ± 234 vs. 1,236 ± 159 10−14(dl·kg−1·min−2)/pM, P < 0.005) with complex than simple carbohydrate meals. We present a novel triple tracer approach to estimate postprandial turnover of complex carbohydrate containing mixed meals. We also report higher insulin sensitivity and β-cell responsivity with complex than with simple carbohydrates in mixed meals of identical calorie and macronutrient compositions in healthy adults.

In the last two decades, diabetes technology has considerably matured, with the introduction of subcutaneous glucose sensors and insulin pumps and, in the last 10 years, with the subcutaneous wearable artificial pancreas. As a result, there has been a resurgence of mechanistic studies in T1D, also using tracers, and modeling has become an integral component of contemporary diabetes technology. In this chapter, we review various classes of models that have helped the artificial pancreas field. We start with the paradigm-change of the UVA/Padova T1D simulator, which has been accepted by the US FDA in 2008 as a substitute for preclinical (animal) studies for certain insulin treatments including the AP, an unprecedented event in the modeling community. Then we turn to the oral minimal model method, which has allowed the description of the circadian pattern of insulin sensitivity and glucose absorption in T1D, features which have been subsequently incorporated into the simulator. Models of various insulin molecules, from inhaled to ultrafast subcutaneous insulins, and of pramlintide are then discussed. We then move into the modeling of the subcutaneous glucose sensor delay and on the successful use of the UVA/Padova T1D simulator to prove safety and efficacy of nonadjunctive use of subcutaneous glucose sensors. Finally, we discuss in silico design of robust adaptive algorithms capable to follow intra- and interday T1D subject variability in month-long trials and their role in informing AP clinical trials.

We have previously reported differences in insulin sensitivity (SI) between T1D and nondiabetic (ND) subjects throughout the day. To explore differences in the diurnal pattern of SI, beta-cell responsivity to glucose (Φ) and disposition index (DI) between type 2 diabetes (T2D) and ND subjects, we present novel preliminary data from 5 ND (BMI 26.6±1.8 kg/m2, age 62.6±4.8 years, Mean±SE) and 5 T2D subjects (BMI 33.6±2.4 kg/m2, age 60.0±6.0 years, HbA1c 55±11 mmol/mol). Studies were conducted in the Clinical Research Unit. Subjects ingested identical mixed meals (75 g carbs, 55% carbohydrate, 15% protein, 30% fat) at either breakfast (B), lunch (L) or dinner (D) in randomized Latin Square order on three consecutive days. Plasma glucose (G), insulin (I) and C-peptide (C) concentrations were frequently sampled. Oral glucose and C-peptide minimal models were applied to estimate SI, Φ and DI. Differences among B, L and D and between ND and T2D were assessed by two-way ANOVA (a p-value Disclosure D. Romeres: None. M. Schiavon: None. C. Cobelli: None. C. Dalla Man: None. A. Basu: Research Support; Spouse/Partner; AstraZeneca. R. Basu: Other Relationship; Self; AstraZeneca. Funding National Institutes of Health (R01029953)

Background & Aims Obese patients with nonalcoholic steatohepatitis (NASH) are at risk for cirrhosis if significant weight loss is not achieved. The single fluid-filled intragastric balloon (IGB) induces meaningful weight loss and might be used in NASH treatment. We performed an open-label prospective study to evaluate the effects of IGB placement on metabolic and histologic features of NASH. Methods Twenty-one patients with early hepatic fibrosis (81% female; mean age, 54 years; average body mass index, 44 kg/m2) underwent magnetic resonance elastography (MRE) and endoscopic ultrasound with core liver biopsy collection at time IGB placement and removal at a single center from October 2016 through March 2018. The primary outcome measure was the changes in liver histology parameters after IGB, including change in nonalcoholic fatty liver disease activity score (NAS) and fibrosis score. We also evaluated changes in weight, body mass index, waist to hip ratio, aminotransaminases, fasting levels of lipids, fasting glucose, glycosylated hemoglobin, and MRE-detected liver stiffness. Results Six months after IGB, patients' mean total body weight loss was 11.7% ± 7.7%, with significant reductions in HbA1c (1.3% ± 0.5%) (P = .02). Waist circumference decreased by 14.4 ± 2.2 cm (P = .001). NAS improved in 18 of 20 patients (90%), with a median decrease of 3 points (range, 1–4 points); 16 of 20 patients (80%) had improvements of 2 points or more. Fibrosis improved by 1.17 stages in 15% of patients, and MRE-detected fibrosis improved by 1.5 stages in 10 of 20 patients (50%). Half of patients reached endpoints approved by the Food and Drug Administration of for NASH resolution and fibrosis improvement. Percent total body weight loss did not correlate with reductions in NAS or fibrosis. Other than post-procedural pain (in 5% of patients), no serious adverse events were reported. Conclusion In a prospective study, IGB facilitated significant metabolic and histologic improvements in NASH. IGB appears to be safe and effective for NASH management when combined with a prescribed diet and exercise program. ClinicalTrials.gov no: NCT02880189

The economic reforms since 1991 have brought changes to the environment of Indian companies previously operated and have put new pressures and realities in front of the bank employees, iced with a huge pile of inconsistencies. Bank Officers have perhaps felt the maximum heat. At this juncture the questions come in mind about the effectiveness of the employee performance linked with the new or revised thought about the influencing factors for the job satisfaction of employees. The study conducted was mainly descriptive & analytical. It is mainly to analyze the level and important factors of job satisfaction among public & private bank employees through a structured close ended tailor made questionnaire and analyzed with Garret Ranking technique. Contributory factors for job satisfaction of bank officers of India mainly depend on organizational image and practice of learning organization.

Background: Glucose sensors measure glucose concentration in the interstitial fluid (ISF), remote from blood. ISF glucose is well known to be “delayed” with respect to blood glucose (BG). However, ISF glucose is not simply a shifted-in-time version of BG but exhibits a more complex pattern. Methods: To gain insight into this problem, one can use linear systems theory. However, this may lose a more clinical readership, thus we use simulation and two case studies to convey our thinking in an easier way. In particular, we consider BG concentration measured after meal and exercise in 12 healthy volunteers, whereas ISF glucose is simulated using a well-accepted model of blood–ISF glucose kinetics, which permits calculation of the equilibration time, a parameter characterizing the system. Two metrics are defined: blood and ISF glucose difference at each time point and time to reach the same glucose value in blood and ISF. Results: The simulation performed and the two metrics show that the relationship between blood–ISF glucose profiles is more complex than a pure shift in time and that the pattern depends on both equilibration time and BG. Conclusions: In this in silico study, we have illustrated, with simple case studies, the meaning of the of ISF glucose with respect to BG. Understanding that ISF glucose is not just a shifted-in-time version but a distorted mirror of BG is important for a correct use of continuous glucose monitoring for diabetes management.