Diabetes-associated Genetic Variation in MTNR1B and Its Effect on Islet Function.

Context: Multiple common genetic variants have been associated with type 2 diabetes, but the mechanism by which they predispose to diabetes is incompletely understood. One such example is variation in MTNR1B, which implicates melatonin and its receptor in the pathogenesis of type 2 diabetes. Objective: To characterize the effect of diabetes-associated genetic variation at rs10830963 in the MTNR1B locus on islet function in people without type 2 diabetes. Design: The association of genetic variation at rs10830963 with glucose, insulin, C-peptide, glucagon, and indices of insulin secretion and action were tested in a cohort of 294 individuals who had previously undergone an oral glucose tolerance test (OGTT). Insulin sensitivity, ß-cell responsivity to glucose, and Disposition Indices were measured using the oral minimal model. Setting: The Clinical Research and Translation Unit at Mayo Clinic, Rochester, MN. Participants: Two cohorts were utilized for this analysis: 1 cohort was recruited on the basis of prior participation in a population-based study in Olmsted County. The other cohort was recruited on the basis of TCF7L2 genotype at rs7903146 from the Mayo Biobank. Intervention: Two-hour, 7-sample OGTT. Main Outcome Measures: Fasting, nadir, and integrated glucagon concentrations. Results: One or 2 copies of the G-allele at rs10830963 were associated with increased postchallenge glucose and glucagon concentrations compared to subjects with the CC genotype. Conclusion: The effects of rs10830963 on glucose homeostasis and predisposition to type 2 diabetes are likely to be partially mediated through changes in α-cell function.

The longitudinal effect of Diabetes-associated variation in TCF7L2 on islet function in humans.

The T allele at rs7903146 in TCF7L2 increases the rate of conversion from prediabetes to type 2 diabetes. This has been associated with impaired ß-cell function and also with defective suppression of α-cell secretion by glucose. However, the temporal relationship of these abnormalities is uncertain. To study the longitudinal changes in islet function, we recruited 128 subjects with 67 homozygous for the diabetes-associated allele (TT) at rs7903146 and 61 homozygous for the protective allele (CC). Subjects were studied on 2 occasions, 3 years apart using an oral 75g glucose challenge. The oral minimal model was used to quantitate ß-cell function; the glucagon secretion rate was estimated from deconvolution of glucagon concentrations. Glucose tolerance worsened in people with the TT genotype. This was accompanied by impaired post-challenge glucagon suppression but appropriate ß-cell responsivity to rising glucose concentrations. These data suggest that α-cell abnormalities associated with the TT genotype (rs7903146) occur early and may precede ß-cell dysfunction in people as they develop glucose intolerance and type 2 diabetes.

Hyperglycemia suppresses Lactate Clearance during Exercise in Type 1 Diabetes.

CONTEXT: Circulating lactate concentration is an important determinant of exercise tolerance. OBJECTIVE: To determine the role of hyperglycemia on lactate metabolism during exercise in type 1 diabetes (T1D). DESIGN: Protocol involved compared T1D participants and participants without diabetes (ND) at euglycemia [5.5mM] or hyperglycemia [9.2mM] in random order in T1D and at euglycemia in ND. SETTING: Clinical Research Unit, University of Virginia, Charlottesville, VA. PARTICIPANTS: 7 T1D and 7 ND. INTERVENTION: [1-13C] lactate infusion, exercise at 65% VO2max, euglycemia and hyperglycemia visits. MAIN OUTCOME MEASURE: Lactate turnover before, during and after 60 min of exercise at 65% VO2max. RESULTS: A two-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 (p=0.76) and concordant to plasma volume (∼40ml/kg). Circulating lactate concentrations were higher (p<0.001) in T1D participants during exercise at hyperglycemia than euglycemia. Exercise induced lactate appearance did not differ (p=0.13) between hyperglycemia and euglycemia. However, lactate clearance was lower (p=0.03) during hyperglycemia than euglycemia in T1D. There were no differences in any of the above parameters between T1D and ND during euglycemia. CONCLUSIONS: Hyperglycemia modulates lactate metabolism during exercise by lowering lactate clearance leading to higher circulating lactate concentrations in T1D. 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 for both providers and recreationally active people with Type 1 diabetes.

Short- and Long-Term Effects on Glucose Control of Nonadherence to Insulin Therapy in People With Type 2 Diabetes An In Silico Study.

BACKGROUND: Strict adherence to multiple daily insulin (MDI) therapy is a cornerstone for the achievement of good glucose control in people with advanced type 2 diabetes (T2D). Here, we aim to in silico assess glucose control in T2D subjects with poor adherence to MDI therapy. METHODS: We tuned the Padova T2D Simulator, originally describing early-stage T2D physiology, around advanced T2D people. One hundred in silico advanced T2D subjects were generated and equipped with optimal MDI therapy: specifically, basal and bolus insulin amounts and injection times were individualized for each subject by applying titration algorithms that iteratively update insulin dose based on glucose deviation from its target. Then, the effect of nonadhering to MDI therapy was assessed using standard glucose control metrics calculated in two 6-month 3-meal/day in silico scenarios: in Scenario 1, subjects received the optimal basal and prandial insulin bolus at each meal; in Scenario 2, subjects received optimal basal insulin and randomly delayed or skipped the prandial insulin bolus in 3 lunches during working days and 1 dinner during weekends. RESULTS: A statistically significant degradation was found in all glucose control outcome metrics in Scenario 2 versus Scenario 1: e.g., percent time above 180 mg/dL increased by 22.2% and glucose management index by 0.2%. CONCLUSIONS: Impaired adherence to MDI therapy in T2D leads to glucose control deteriorations in both short and long terms. Interestingly, short-term hyperglycemia seems being contrasted by residual endogenous insulin secretion, which statistically increased by 3-fold after delayed/skipped insulin boluses compared with optimal ones.

Controlling and powering a fully implantable artificial pancreas refillable by ingestible pills.

Over the past decade, there has been a growing interest in the development of an artificial pancreas for intraperitoneal insulin delivery. Intraperitoneal implantable pumps guarantee more physiological glycemic control than subcutaneous wearable ones, for the treatment of type 1 diabetes. In this work, a fully implantable artificial pancreas refillable by ingestible pills is presented. In particular, solutions enabling the communication between the implanted pump and external user interfaces and novel control algorithms to intraperitoneally release an adequate amount of insulin based on glycemic data are shown. In addition, the powering and the wireless battery recharging are addressed. Specifically, the design and optimization of a customized transcutaneous energy transfer with two independent wireless channels are presented. The system was tested in terms of recharging efficacy, possible temperature rise within the body, during the recharging process and reliability of the wireless connection in the air and in the presence of ex vivo tissues.Clinical Relevance- This work aims to improve the control, battery recharging, and wireless communication of a fully implantable artificial pancreas for type 1 diabetes treatment.

Developing the UVA/Padova Type 1 Diabetes Simulator: Modeling, Validation, Refinements, and Utility.

Arguably, diabetes mellitus is one of the best quantified human conditions. In the past 50 years, the metabolic monitoring technologies progressed from occasional assessment of average glycemia via HbA1c, through episodic blood glucose readings, to continuous glucose monitoring (CGM) producing data points every few minutes. The high-temporal resolution of CGM data enabled increasingly intensive treatments, from decision support assisting insulin injection or oral medication, to automated closed-loop control, known as the "artificial pancreas." Throughout this progress, mathematical models and computer simulation of the human metabolic system became indispensable for the technological progress of diabetes treatment, enabling every step, from assessment of insulin sensitivity via the now classic Minimal Model of Glucose Kinetics, to in silico trials replacing animal experiments, to automated insulin delivery algorithms. In this review, we follow these developments, beginning with the Minimal Model, which evolved through the years to become large and comprehensive and trigger a paradigm change in the design of diabetes optimization strategies: in 2007, we introduced a sophisticated model of glucose-insulin dynamics and a computer simulator equipped with a "population" of N = 300 in silico "subjects" with type 1 diabetes. In January 2008, in an unprecedented decision, the Food and Drug Administration (FDA) accepted this simulator as a substitute to animal trials for the pre-clinical testing of insulin treatment strategies. This opened the field for rapid and cost-effective development and pre-clinical testing of new treatment approaches, which continues today. Meanwhile, animal experiments for the purpose of designing new insulin treatment algorithms have been abandoned.

Glucagon-like peptide-1 receptor blockade impairs islet secretion and glucose metabolism in humans.

BACKGROUNDProglucagon can be processed to glucagon-like peptide1 (GLP-1) within the islet, but its contribution to islet function in humans remains unknown. We sought to understand whether pancreatic GLP-1 alters islet function in humans and whether this is affected by type 2 diabetes.METHODSWe therefore studied individuals with and without type 2 diabetes on two occasions in random order. On one occasion, exendin 9-39, a competitive antagonist of the GLP-1 Receptor (GLP1R), was infused, while on the other, saline was infused. The tracer dilution technique ([3-3H] glucose) was used to measure glucose turnover during fasting and during a hyperglycemic clamp.RESULTSExendin 9-39 increased fasting glucose concentrations; fasting islet hormone concentrations were unchanged, but inappropriate for the higher fasting glucose observed. In people with type 2 diabetes, fasting glucagon concentrations were markedly elevated and persisted despite hyperglycemia. This impaired suppression of endogenous glucose production by hyperglycemia.CONCLUSIONThese data show that GLP1R blockade impairs islet function, implying that intra-islet GLP1R activation alters islet responses to glucose and does so to a greater degree in people with type 2 diabetes.TRIAL REGISTRATIONThis study was registered at ClinicalTrials.gov NCT04466618.FUNDINGThe study was primarily funded by NIH NIDDK DK126206. AV is supported by DK78646, DK116231 and DK126206. CDM was supported by MIUR (Italian Minister for Education) under the initiative "Departments of Excellence" (Law 232/2016).

Aetiology of Type 2 diabetes in people with a 'normal' body mass index: testing the personal fat threshold hypothesis.

Weight loss in overweight or obese individuals with Type 2 diabetes (T2D) can normalize hepatic fat metabolism, decrease fatty acid oversupply to ß cells and restore normoglycaemia. One in six people has BMI <27 kg/m2 at diagnosis, and their T2D is assumed to have different aetiology. The Personal Fat Threshold hypothesis postulated differing individual thresholds for lipid overspill and adverse effects on ß-cell function. To test this hypothesis, people with Type 2 diabetes and body mass index <27kg/m2 (n = 20) underwent repeated 5% weight loss cycles. Metabolic assessments were carried out at stable weight after each cycle and after 12 months. To determine how closely metabolic features returned to normal, 20 matched normoglycemic controls were studied once. Between baseline and 12 months: BMI fell (mean ± SD), 24.8 ± 0.4 to 22.5 ± 0.4 kg/m2 (P<0.0001) (controls: 21.5 ± 0.5); total body fat, 32.1 ± 1.5 to 27.6 ± 1.8% (P<0.0001) (24.6 ± 1.5). Liver fat content and fat export fell to normal as did fasting plasma insulin. Post-meal insulin secretion increased but remained subnormal. Sustained diabetes remission (HbA1c < 48 mmol/mol off all glucose-lowering agents) was achieved by 70% (14/20) by initial weight loss of 6.5 (5.5-10.2)%. Correction of concealed excess intra-hepatic fat reduced hepatic fat export, with recovery of ß-cell function, glycaemic improvement in all and return to a non-diabetic metabolic state in the majority of this group with BMI <27 kg/m2 as previously demonstrated for overweight or obese groups. The data confirm the Personal Fat Threshold hypothesis: aetiology of Type 2 diabetes does not depend on BMI. This pathophysiological insight has major implications for management.

Effects of acute changes in fasting glucose and free fatty acid concentrations on indices of ß-cell function and glucose metabolism in subjects without diabetes.

Elevated fasting free fatty acids (FFAs) and fasting glucose are additively associated with impaired glucose tolerance (IGT) and decreased ß-cell function [quantified as disposition index (DI)]. We sought to examine how changes in fasting FFA and glucose alter islet function. We studied 10 subjects with normal fasting glucose (NFG) and normal glucose tolerance (NGT) on two occasions. On one occasion, Intralipid and glucose were infused overnight to mimic conditions present in IFG/IGT. In addition, we studied seven subjects with IFG/IGT on two occasions. On one occasion, insulin was infused to lower overnight FFA and glucose concentrations to those observed in people with NFG/NGT. The following morning, a labeled mixed meal was used to measure postprandial glucose metabolism and ß-cell function. Elevation of overnight fasting FFA and glucose in NFG/NGT did not alter peak or integrated glucose concentrations (2.0 ± 0.1 vs. 2.0 ± 0.1 Mol per 5 h, Saline vs. Intralipid/glucose, P = 0.55). Although overall ß-cell function quantified by the Disposition Index was unchanged, the dynamic component of ß-cell responsivity (ϕd) was decreased by Intralipid and glucose infusion (9 ± 1 vs. 16 ± 3 10-9, P = 0.02). In people with IFG/IGT, insulin did not alter postprandial glucose concentrations or indices of ß-cell function. Endogenous glucose production and glucose disappearance were also unchanged in both groups. We conclude that acute, overnight changes in FFA, and glucose concentrations do not alter islet function or glucose metabolism in prediabetes.NEW & NOTEWORTHY This experiment studied the effect of changes in overnight concentrations of free fatty acids (FFAs) and glucose on ß-cell function and glucose metabolism. In response to elevation of these metabolites, the dynamic component of the ß-cell response to glucose was impaired. This suggests that in health overnight hyperglycemia and FFA elevation can deplete preformed insulin granules in the ß-cell.

In silico design and validation of a time-varying PID controller for an artificial pancreas with intraperitoneal insulin delivery and glucose sensing.

Type 1 diabetes (T1D) is a chronic autoimmune disease featured by the loss of beta cell function and the need for lifetime insulin replacement. Over the recent decade, the use of automated insulin delivery systems (AID) has shifted the paradigm of treatment: the availability of continuous subcutaneous (SC) glucose sensors to guide SC insulin delivery through a control algorithm has allowed, for the first time, to reduce the daily burden of the disease as well as to abate the risk for hypoglycemia. AID use is still limited by individual acceptance, local availability, coverage, and expertise. A major drawback of SC insulin delivery is the need for meal announcement and the peripheral hyperinsulinemia that, over time, contributes to macrovascular complications. Inpatient trials using intraperitoneal (IP) insulin pumps have demonstrated that glycemic control can be improved without meal announcement due to the faster insulin delivery through the peritoneal space. This calls for novel control algorithms able to account for the specificities of IP insulin kinetics. Recently, our group described a two-compartment model of IP insulin kinetics demonstrating that the peritoneal space acts as a virtual compartment and IP insulin delivery is virtually intraportal (intrahepatic), thus closely mimicking the physiology of insulin secretion. The FDA-accepted T1D simulator for SC insulin delivery and sensing has been updated for IP insulin delivery and sensing. Herein, we design and validate-in silico-a time-varying proportional integrative derivative controller to guide IP insulin delivery in a fully closed-loop mode without meal announcement.

Intraperitoneal Insulin Delivery: Evidence of a Physiological Route for Artificial Pancreas From Compartmental Modeling.

BACKGROUND: Intraperitoneal insulin delivery has proven to safely overcome a major limit of subcutaneous delivery-meal announcement-and has been able to optimize glycemic control in adults under controlled experimental conditions. In addition, intraperitoneal delivery avoids peripheral hyperinsulinemia resulting from the subcutaneous route and restores a physiological liver gradient. METHODS: Relying on a unique data set of intraperitoneal closed-loop insulin delivery obtained with a Model Predictive Controller (MPC), we develop a compartmental model of intraperitoneal insulin kinetics, which, once included in the UVa/Padova T1D simulator, will facilitate the investigation of various control strategies, for example, the simpler Proportional Integral Derivative controller versus MPC. RESULTS: Intraperitoneal insulin kinetics can be described with a 2-compartment model including liver and plasma. CONCLUSION: Intraperitoneal insulin transit is fast enough to render irrelevant the addition of a peritoneal compartment, proving the peritoneum being a virtual-not actual-transit space for insulin delivery.

ß-Cell Function and Insulin Sensitivity in Youth With Early Type 1 Diabetes From a 2-Hour 7-Sample OGTT.

CONTEXT: The oral minimal model is a widely accepted noninvasive tool to quantify both ß-cell responsiveness and insulin sensitivity (SI) from glucose, C-peptide, and insulin concentrations during a 3-hour 9-point oral glucose tolerance test (OGTT). OBJECTIVE: Here, we aimed to validate a 2-hour 7-point protocol against the 3-hour OGTT and to test how variation in early sampling frequency impacts estimates of ß-cell responsiveness and SI. METHODS: We conducted a secondary analysis on 15 lean youth with stage 1 type 1 diabetes (T1D; ≥ 2 islet autoantibodies with no dysglycemia) who underwent a 3-hour 9-point OGTT. The oral minimal model was used to quantitate ß-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of ß-cell function by the disposition index (DI = φtotal × SI). Seven- and 5-point 2-hour OGTT protocols were tested against the 3-hour 9-point gold standard to determine agreement between estimates of φtotal and its dynamic and static components, SI, and DI across different sampling strategies. RESULTS: The 2-hour estimates for the disposition index exhibited a strong correlation with 3-hour measures (r = 0.975; P < .001) with similar results for ß-cell responsiveness and SI (r = 0.997 and r = 0.982; P < .001, respectively). The agreement of the 3 estimates between the 7-point 2-hour and 9-point 3-hour protocols fell within the 95% CI on the Bland-Altman grid with a median difference of 16.9% (-35.3 to 32.5), 0.2% (-0.6 to 1.3), and 14.9% (-1.4 to 28.3) for DI, φtotal, and SI. Conversely, the 5-point protocol did not provide reliable estimates of φ dynamic and static components. CONCLUSION: The 2-hour 7-point OGTT is reliable in individuals with stage 1 T1D for assessment of ß-cell responsiveness, SI, and DI. Incorporation of these analyses into current 2-hour diabetes staging and monitoring OGTTs offers the potential to more accurately quantify risk of progression in the early stages of T1D.

The Effect of Glucagon-Like Peptide 1 Receptor Blockade on Glucagon-Induced Stimulation of Insulin Secretion.

Data from transgenic rodent models suggest that glucagon acts as an insulin secretagogue by signaling through the glucagon-like peptide 1 receptor (GLP-1R) present on ß-cells. However, its net contribution to physiologic insulin secretion in humans is unknown. To address this question, we studied individuals without diabetes in two separate experiments. Each subject was studied on two occasions in random order. In the first experiment, during a hyperglycemic clamp, glucagon was infused at 0.4 ng/kg/min, increasing by 0.2 ng/kg/min every hour for 5 h. On one day, exendin-9,39 (300 pmol/kg/min) was infused to block GLP-1R, while on the other, saline was infused. The insulin secretion rate (ISR) was calculated by nonparametric deconvolution from plasma concentrations of C-peptide. Endogenous glucose production and glucose disappearance were measured using the tracer-dilution technique. Glucagon concentrations, by design, did not differ between study days. Integrated ISR was lower during exendin-9,39 infusion (213 ± 26 vs. 191 ± 22 nmol/5 h, saline vs. exendin-9,39, respectively; P = 0.02). In the separate experiment, exendin-9,39 infusion, compared with saline infusion, also decreased the ß-cell secretory response to a 1-mg glucagon bolus. These data show that, in humans without diabetes, glucagon partially stimulates the ß-cell through GLP-1R.

Differential contribution of alpha and beta cell dysfunction to impaired fasting glucose and impaired glucose tolerance.

AIMS/HYPOTHESIS: People with isolated impaired fasting glucose (IFG) have normal beta cell function. We hypothesised that an increased glucose threshold for beta cell secretion explains IFG. METHODS: We used graded glucose infusion to examine the relationship of insulin secretion rate (ISR) and glucagon secretion rate (GSR) with rising glucose. We studied 39 non-diabetic individuals (53 ± 2 years, BMI 30 ± 1 kg/m2), categorised by fasting glucose and glucose tolerance status. After an overnight fast, a variable insulin infusion was used to maintain glucose at ~4.44 mmol/l (07:00 to 08:30 hours). At 09:00 hours, graded glucose infusion commenced at 1 mg kg-1 min-1 and doubled every 60 min until 13:00 hours. GSR and ISR were calculated by nonparametric deconvolution from concentrations of glucagon and C-peptide, respectively. RESULTS: The relationship of ISR with glucose was linear and the threshold for insulin secretion in isolated IFG did not differ from that in people with normal fasting glucose and normal glucose tolerance. GSR exhibited a single-exponential relationship with glucose that could be characterised by G50, the change in glucose necessary to suppress GSR by 50%. G50 was increased in IFG compared with normal fasting glucose regardless of the presence of impaired or normal glucose tolerance. CONCLUSIONS/INTERPRETATION: These data show that, in non-diabetic humans, alpha cell dysfunction contributes to the pathogenesis of IFG independently of defects in insulin secretion. We also describe a new index that quantifies the suppression of glucagon secretion by glucose.

Consensus Recommendations for the Use of Automated Insulin Delivery Technologies in Clinical Practice.

The significant and growing global prevalence of diabetes continues to challenge people with diabetes (PwD), healthcare providers, and payers. While maintaining near-normal glucose levels has been shown to prevent or delay the progression of the long-term complications of diabetes, a significant proportion of PwD are not attaining their glycemic goals. During the past 6 years, we have seen tremendous advances in automated insulin delivery (AID) technologies. Numerous randomized controlled trials and real-world studies have shown that the use of AID systems is safe and effective in helping PwD achieve their long-term glycemic goals while reducing hypoglycemia risk. Thus, AID systems have recently become an integral part of diabetes management. However, recommendations for using AID systems in clinical settings have been lacking. Such guided recommendations are critical for AID success and acceptance. All clinicians working with PwD need to become familiar with the available systems in order to eliminate disparities in diabetes quality of care. This report provides much-needed guidance for clinicians who are interested in utilizing AIDs and presents a comprehensive listing of the evidence payers should consider when determining eligibility criteria for AID insurance coverage.

Impaired Diurnal Pattern of Meal Tolerance and Insulin Sensitivity in Type 2 Diabetes: Implications for Therapy.

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 ß-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 ß-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.

A software interface for in silico testing of type 2 diabetes treatments.

BACKGROUND AND OBJECTIVE: The increasing incidence of diabetes continuously stimulates the research on new antidiabetic drugs. Computer simulation can save time and costs, alleviating the need of animal trials and providing useful information for optimal experiment design and drug dosing. We recently presented a type 2 diabetes (T2D) simulator as tool for in silico testing of new molecules and guiding treatment optimization. Here we present a user-friendly interface aimed to increase the usability of the simulator. METHOD: The simulator, based on a large-scale glucose, insulin, and C-peptide model and equipped with 100 virtual subjects well describing system dynamics in a real T2D population, is extended to incorporate pharmacokinetics/pharmacodynamics (PK/PD) of a drug of interest. A graphical interface is developed on top of the simulator, allowing an easy design of in silico experiments: specifically, it is possible to select the population size to test, design the experiment (crossover or parallel), its duration and the sampling grid, choose glucose and insulin doses, and define treatment PK/PD and dose administered. The simulator also provides the outcome metrics requested by the user, and performs statistical comparisons among treatments and/or placebo. RESULTS: To illustrate the potential of the simulator, we provided a case study using metformin and liraglutide. Literature-based PK/PD models of metformin and liraglutide have been incorporated in the simulator, by modulating key drug-sensitive model parameters. An in silico placebo-controlled trial has been done by simulating a three-arm meal tolerance test with subjects receiving placebo, metformin 850 mg, liraglutide 1.80 mg, respectively. The obtained results are in agreement with the clinical evidences, in terms of main glucose, insulin, and C-peptide outcome metrics. CONCLUSIONS: We developed a user-friendly software interface for the T2D simulator to support the design and test of new antidiabetic drugs and treatments. This increases the simulator usability, making it suitable also for users who have low experience with computer programming.

The relationship between insulin and glucagon concentrations in non-diabetic humans.

Abnormal postprandial suppression of glucagon in Type 2 diabetes (T2DM) has been attributed to impaired insulin secretion. Prior work suggests that insulin and glucagon show an inverse coordinated relationship. However, dysregulation of α-cell function in prediabetes occurs early and independently of changes in ß-cells, which suggests insulin having a less significant role on glucagon control. We therefore, sought to examine whether hepatic vein hormone concentrations provide evidence to further support the modulation of glucagon secretion by insulin. As part of a series of experiments to measure the effect of diabetes-associated genetic variation in TCF7L2 on islet cell function, hepatic vein insulin and glucagon concentrations were measured at 2-minute intervals during fasting and a hyperglycemic clamp. The experiment was performed on 29 nondiabetic subjects (age = 46 ± 2 years, BMI 28 ± 1 Kg/m2 ) and enabled post-hoc analysis, using Cross-Correlation and Cross-Approximate Entropy (Cross-ApEn) to evaluate the interaction of insulin and glucose. Mean insulin concentrations rose from fasting (33 ± 4 vs. 146 ± 12 pmol/L, p < 0.01) while glucagon was suppressed (96 ± 8 vs. 62 ± 5 ng/L, p < 0.01) during the clamp. Cross-ApEn was used to measure pattern reproducibility in the two hormones using glucagon as control mechanism (0.78 ± 0.03 vs. 0.76 ± 0.03, fasting vs. hyperglycemia) and using insulin as a control mechanism (0.78 ± 0.02 vs. 0.76 ± 0.03, fasting vs. hyperglycemia). Values did not differ between the two scenarios. Cross-correlation analysis demonstrated a small in-phase coordination between insulin and glucagon concentrations during fasting, which inverted during hyperglycemia. This data suggests that the interaction between the two hormones is not driven by either. On a minute-to-minute basis, direct control and secretion of glucagon is not mediated (or restrained) by insulin.

Diabetes Technology Meeting 2021.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting on November 4 to November 6, 2021. This meeting brought together speakers to discuss various developments within the field of diabetes technology. Meeting topics included blood glucose monitoring, continuous glucose monitoring, novel sensors, direct-to-consumer telehealth, metrics for glycemia, software for diabetes, regulation of diabetes technology, diabetes data science, artificial pancreas, novel insulins, insulin delivery, skin trauma, metabesity, precision diabetes, diversity in diabetes technology, use of diabetes technology in pregnancy, and green diabetes. A live demonstration on a mobile app to monitor diabetic foot wounds was presented.

The Effect of Diabetes-Associated Variation in TCF7L2 on Postprandial Glucose Metabolism When Glucagon and Insulin Concentrations Are Matched.

Background: The rs7903146 variant in the TCF7L2 gene is associated with defects in postprandial insulin and glucagon secretion and increased risk of type 2 diabetes. However, it is unclear if this variant has effects on glucose metabolism that are independent of islet function. Methods: We studied 54 nondiabetic subjects on two occasions where endogenous hormone secretion was inhibited by somatostatin. Twenty-nine subjects were homozygous for the diabetes-associated allele (TT) and 25 for the diabetes-protective allele (CC) at rs7903146, but otherwise matched for anthropometric characteristics. On 1 day, glucagon infused at a rate of 0.65 ng/kg/min, and at 0 min prevented a fall in glucagon (nonsuppressed day). On the contrary, infusion commenced at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-3H]-glucose) infused to mimic the systemic appearance of oral glucose. Insulin was infused to mimic a prandial insulin response. Endogenous glucose production (EGP) was measured using the tracer dilution technique. Results: Lack of glucagon suppression increased postchallenge glucose concentrations and impaired EGP suppression. However, in the presence of matched insulin and glucagon concentrations, genetic variation in TCF7L2 did not alter glucose metabolism. Conclusion: These data suggest that genetic variation in TCF7L2 alters glucose metabolism through changes in islet hormone secretion.