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.

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.

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.

Inhibition of 11ß-Hydroxysteroid dehydrogenase-1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled, phase II study.

AIM: To evaluate whether short-term treatment with a selective 11ß-Hydroxysteroid dehydrogenase-1 (11ß-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). MATERIALS AND METHODS: 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 of 13 C cortisone to 13 C cortisol in the liver. RESULTS: A 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 of 13 C cortisone to 13 C cortisol was blocked in all patients in the AZD4017 group. There were no significant between-group differences (AZD4017 vs. placebo) in changes in fibrosis, weight, levels of liver enzymes or lipids, or insulin sensitivity. CONCLUSION: Although the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of 13 C cortisone to 13 C cortisol in the liver in all patients who received the drug. In patients with NASH and T2D, AZD4017 improved liver steatosis versus placebo.

Closed-form expressions and nonparametric estimation of COVID-19 infection rate.

Quantitative assessment of the infection rate of a virus is key to monitor the evolution of an epidemic. However, such variable is not accessible to direct measurement and its estimation requires the solution of a difficult inverse problem. In particular, being the result not only of biological but also of social factors, the transmission dynamics can vary significantly in time. This makes questionable the use of parametric models which could be unable to capture their full complexity. In this paper we exploit compartmental models which include important COVID-19 peculiarities (like the presence of asymptomatic individuals) and allow the infection rate to assume any continuous-time profile. We show that these models are universal, i.e. capable to reproduce exactly any epidemic evolution, and extract from them closed-form expressions of the infection rate time-course. Building upon such expressions, we then design a regularized estimator able to reconstruct COVID-19 transmission dynamics in continuous-time. Using real data collected in Italy, our technique proves to be an useful tool to monitor COVID-19 transmission dynamics and to predict and assess the effect of lockdown restrictions.

Exercise effect on insulin-dependent and insulin-independent glucose utilization in healthy individuals and individuals with type 1 diabetes: a modeling study.

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% V̇o2max 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.

Insulin secretion and action and the response of endogenous glucose production to a lack of glucagon suppression in nondiabetic subjects.

Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and endogenous glucose production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic insulin action to this variability was also examined. To do so, we studied 54 nondiabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (nonsuppressed day) or 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 50-g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose, and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose but not in integrated glucose concentrations attributable to nonsuppressed glucagon. The % change in integrated EGP was unaffected by insulin dose. Multivariate regression analysis, adjusted for age, sex, weight, and insulin dose, did not show a relationship between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action also did not show a relationship with the EGP response. These data indicate that the effect of impaired glucagon suppression on EGP is independent of anthropometric characteristics and insulin action.NEW & NOTEWORTHY In prediabetes, anthropometric characteristics as well as insulin action do not alter the hepatic response to glucagon. The postprandial suppression or lack of suppression of glucagon secretion is an important factor governing postprandial glucose tolerance independent of insulin secretion.

Limitations of the fasting proinsulin to insulin ratio as a measure of ß-cell health in people with and without impaired glucose tolerance.

BACKGROUND: The fasting proinsulin to insulin ratio is elevated in people with type 2 diabetes and has been suggested as a marker of ß-cell health. However, its utility in discriminating between individuals with varying degrees of ß-cell dysfunction is unclear. Proinsulin has a very different half-life to insulin and unlike insulin does not undergo hepatic extraction prior to reaching the systemic circulation. Given these limitations, we sought to examine the relationship between fasting and postprandial concentrations of ß-cell polypeptides (proinsulin, insulin and C-peptide) in people with normal and impaired glucose tolerance in differing metabolic environments. DESIGN: Subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, free fatty acids were elevated (to induce insulin resistance) by infusion of Intralipid with heparin. Proinsulin to insulin and proinsulin to C-peptide ratios were calculated for the 0-, 30-, 60- and 240-minute time points. Insulin action (Si) and ß-cell responsivity (Φ) indices were calculated using the oral minimal model. RESULTS: The fasting proinsulin to c-peptide or fasting proinsulin to insulin ratios did not differ between groups and did not predict subsequent ß-cell responsivity to glucose during the glycerol or Intralipid study days in either group. CONCLUSIONS: Among nondiabetic individuals, the fasting proinsulin to insulin ratio is not a useful marker of ß-cell function.

Improved postprandial glucose metabolism in type 2 diabetes by the dual glucagon-like peptide-1/glucagon receptor agonist SAR425899 in comparison with liraglutide.

AIM: To gain further insights into the efficacy of SAR425899, a dual glucagon-like peptide-1/glucagon receptor agonist, by providing direct comparison with the glucagon-like peptide-1 receptor agonist, liraglutide, in terms of key outcomes of glucose metabolism. RESEARCH DESIGN AND METHODS: Seventy overweight to obese subjects with type 2 diabetes (T2D) were randomized to receive once-daily subcutaneous administrations of SAR425899 (0.12, 0.16 or 0.20 mg), liraglutide (1.80 mg) or placebo for 26 weeks. Mixed meal tolerance tests were conducted at baseline (BSL) and at the end of treatment (EOT). Metabolic indices of insulin action and secretion were assessed via Homeostasis Model Assessment (HOMA2) and oral minimal model (OMM) methods. RESULTS: From BSL to EOT (median [25th, 75th] percentile), HOMA2 quantified a significant improvement in basal insulin action in liraglutide (35% [21%, 74%]), while secretion enhanced both in SAR425899 (125% [63%, 228%]) and liraglutide (73% [43%, 147%]). OMM quantified, both in SAR425899 and liraglutide, a significant improvement in insulin sensitivity (203% [58%, 440%] and 36% [21%, 197%]), basal beta-cell responsiveness (67% [34%, 112%] and 40% [16%, 59%]), and above-basal beta-cell responsiveness (139% [64%, 261%] and 69% [-15%, 120%]). A significant delay in glucose absorption was highlighted in SAR425899 (37% [52%,18%]). CONCLUSIONS: SAR425899 and liraglutide improved postprandial glucose control in overweight to obese subjects with T2D. A significantly higher enhancement in beta-cell function was shown by SAR425899 than liraglutide.

Impaired insulin signaling in unaffected siblings and patients with first-episode psychosis.

Patients with psychotic disorders are at high risk for type 2 diabetes mellitus, and there is increasing evidence that patients display glucose metabolism abnormalities before significant antipsychotic medication exposure. In the present study, we examined insulin action by quantifying insulin sensitivity in first-episode psychosis (FEP) patients and unaffected siblings, compared to healthy individuals, using a physiological-based model and comprehensive assessment battery. Twenty-two unaffected siblings, 18 FEP patients, and 15 healthy unrelated controls were evaluated using a 2-h oral glucose tolerance test (OGTT), with 7 samples of plasma glucose and serum insulin concentration measurements. Insulin sensitivity was quantified using the oral minimal model method. Lipid, leptin, free fatty acids, and inflammatory marker levels were also measured. Anthropometric, nutrient, and activity assessments were conducted; total body composition and fat distribution were determined using whole-body dual-energy X-ray absorptiometry. Insulin sensitivity significantly differed among groups (F = 6.01 and 0.004), with patients and siblings showing lower insulin sensitivity, compared to controls (P = 0.006 and 0.002, respectively). Body mass index, visceral adipose tissue area (cm2), lipids, leptin, free fatty acids, inflammatory markers, and activity ratings were not significantly different among groups. There was a significant difference in nutrient intake with lower total kilocalories/kilogram body weight in patients, compared to siblings and controls. Overall, the findings suggest that familial abnormal glucose metabolism or a primary insulin signaling pathway abnormality is related to risk for psychosis, independent of disease expression and treatment effects. Future studies should examine underlying biological mechanisms of insulin signaling abnormalities in psychotic disorders.

Dual glucagon-like peptide-1 receptor/glucagon receptor agonist SAR425899 improves beta-cell function in type 2 diabetes.

AIM: To evaluate the change in insulin sensitivity, ß-cell function and glucose absorption after 28 days of treatment with high and low doses of SAR425899, a novel dual glucagon-like peptide-1 receptor/glucagon receptor agonist, versus placebo. MATERIALS AND METHODS: Thirty-six overweight to obese subjects with type 2 diabetes were randomized to receive daily subcutaneous administrations of low-dose SAR425899 (0.03, 0.06 and 0.09 mg) and high-dose SAR425899 (0.06, 0.12 and 0.18 mg) or placebo for 28 days; dose escalation occurred after days 7 and 14. Mixed meal tolerance tests were conducted before treatment (day -1) and on days 1 and 28. Oral glucose and C-peptide minimal models were used to quantify metabolic indices of insulin sensitivity, ß-cell responsiveness and glucose absorption. RESULTS: With low-dose SAR425899, high-dose SAR425899 and placebo, ß-cell function from day -1 to day 28 increased by 163%, 95% and 23%, respectively. The change in area under the curve for the rate of meal glucose appearance between 0 and 120 minutes was -32%, -20% and 8%, respectively. CONCLUSIONS: After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing ß-cell function and slowing glucose absorption rate.

A novel natural tracer method to measure complex carbohydrate metabolism.

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 ß-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 ß-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 ß-cell responsivity with complex than with simple carbohydrates in mixed meals of identical calorie and macronutrient compositions in healthy adults.

Assessment of pulsatile insulin secretion derived from peripheral plasma C-peptide concentrations by nonparametric stochastic deconvolution.

The characteristics of pulsatile insulin secretion are important determinants of type 2 diabetes pathophysiology, but they are understudied due to the difficulties in measuring pulsatile insulin secretion noninvasively. Deconvolution of either peripheral C-peptide or insulin concentrations offers an appealing alternative to hepatic vein catheterization. However, to do so, there are a series of methodological challenges to overcome. C-peptide has a relatively long half-life and accumulates in the circulation. On the other hand, peripheral insulin concentrations reflect relatively fast clearance and hepatic extraction as it leaves the portal circulation to enter the systemic circulation. We propose a method based on nonparametric stochastic deconvolution of C-peptide concentrations, using individually determined C-peptide kinetics, to overcome these limitations. The use of C-peptide (instead of insulin) concentrations allows estimation of portal (and not post-hepatic) insulin pulses, whereas nonparametric stochastic deconvolution allows evaluation of pulsatile signals without any a priori assumptions of pulse shape and occurrence. The only assumption required is the degree of smoothness of the (unknown) secretion rate. We tested this method first on simulated data and then on 29 nondiabetic subjects studied during euglycemia and hyperglycemia and compared our estimates with the profiles obtained from hepatic vein insulin concentrations. This method produced satisfactory results both in the ability to fit the data and in providing reliable estimates of pulsatile secretion, in agreement with hepatic vein measurements. In conclusion, the proposed method enables reliable and noninvasive measurement of pulsatile insulin secretion. Future studies will be needed to validate this method in people with type 2 diabetes.

Intranasal oxytocin fails to acutely improve glucose metabolism in obese men.

The hypothalamic neuropeptide oxytocin not only modulates psychosocial function, but also contributes to metabolic regulation. We have recently shown that intranasal oxytocin acutely improves beta-cell responsivity and glucose tolerance in normal-weight men. In the present experiment, we investigated the acute glucoregulatory impact of oxytocin in obese men with impaired insulin sensitivity. Fifteen obese healthy men with an average body mass index of 35 kg/m2 and an average body fat content of 33% received a single intranasal dose (24 IU) of oxytocin before undergoing an oral glucose tolerance test. Results were analysed according to the oral minimal model and compared with our findings in normal-weight participants. In contrast to the results in normal-weight subjects, oxytocin did not blunt postprandial glucose and insulin excursions in obese men, and moreover failed to enhance beta-cell responsivity and glucose tolerance. These results indicate that pronounced obesity may be associated with a certain degree of resistance to the glucoregulatory impact of exogenous oxytocin, and underlines the need for further investigations into the potential of oxytocin to improve glucose homeostasis in the clinical context.

What do healthcare professionals need to turn risk models for type 2 diabetes into usable computerized clinical decision support systems? Lessons learned from the MOSAIC project.

BACKGROUND: To understand user needs, system requirements and organizational conditions towards successful design and adoption of Clinical Decision Support Systems for Type 2 Diabetes (T2D) care built on top of computerized risk models. METHODS: The holistic and evidence-based CEHRES Roadmap, used to create eHealth solutions through participatory development approach, persuasive design techniques and business modelling, was adopted in the MOSAIC project to define the sequence of multidisciplinary methods organized in three phases, user needs, implementation and evaluation. The research was qualitative, the total number of participants was ninety, about five-seventeen involved in each round of experiment. RESULTS: Prediction models for the onset of T2D are built on clinical studies, while for T2D care are derived from healthcare registries. Accordingly, two set of DSSs were defined: the first, T2D Screening, introduces a novel routine; in the second case, T2D Care, DSSs can support managers at population level, and daily practitioners at individual level. In the user needs phase, T2D Screening and solution T2D Care at population level share similar priorities, as both deal with risk-stratification. End-users of T2D Screening and solution T2D Care at individual level prioritize easiness of use and satisfaction, while managers prefer the tools to be available every time and everywhere. In the implementation phase, three Use Cases were defined for T2D Screening, adapting the tool to different settings and granularity of information. Two Use Cases were defined around solutions T2D Care at population and T2D Care at individual, to be used in primary or secondary care. Suitable filtering options were equipped with "attractive" visual analytics to focus the attention of end-users on specific parameters and events. In the evaluation phase, good levels of user experience versus bad level of usability suggest that end-users of T2D Screening perceived the potential, but they are worried about complexity. Usability and user experience were above acceptable thresholds for T2D Care at population and T2D Care at individual. CONCLUSIONS: By using a holistic approach, we have been able to understand user needs, behaviours and interactions and give new insights in the definition of effective Decision Support Systems to deal with the complexity of T2D care.

Prospective evaluation of insulin and incretin dynamics in obese adults with and without diabetes for 2 years after Roux-en-Y gastric bypass.

AIMS/HYPOTHESIS: In this prospective case-control study we tested the hypothesis that, while long-term improvements in insulin sensitivity (SI) accompanying weight loss after Roux-en-Y gastric bypass (RYGB) would be similar in obese individuals with and without type 2 diabetes mellitus, stimulated-islet-cell insulin responses would differ, increasing (recovering) in those with diabetes but decreasing in those without. We investigated whether these changes would occur in conjunction with favourable alterations in meal-related gut hormone secretion and insulin processing. METHODS: Forty participants with type 2 diabetes and 22 participants without diabetes from the Longitudinal Assessment of Bariatric Surgery (LABS-2) study were enrolled in a separate, longitudinal cohort (LABS-3 Diabetes) to examine the mechanisms of postsurgical diabetes improvement. Study procedures included measures of SI, islet secretory response and gastrointestinal hormone secretion after both intravenous glucose (frequently-sampled IVGTT [FSIVGTT]) and a mixed meal (MM) prior to and up to 24 months after RYGB. RESULTS: Postoperatively, weight loss and SI-FSIVGTT improvement was similar in both groups, whereas the acute insulin response to glucose (AIRglu) decreased in the non-diabetic participants and increased in the participants with type 2 diabetes. The resulting disposition indices (DIFSIVGTT) increased by three- to ninefold in both groups. In contrast, during the MM, total insulin responsiveness did not significantly change in either group despite durable increases of up to eightfold in postprandial glucagon-like peptide 1 levels, and SI-MM and DIMM increased only in the diabetes group. Peak postprandial glucagon levels increased in both groups. CONCLUSIONS/INTERPRETATION: For up to 2 years following RYGB, obese participants without diabetes showed improvements in DI that approach population norms. Those with type 2 diabetes recovered islet-cell insulin secretion response yet continued to manifest abnormal insulin processing, with DI values that remained well below population norms. These data suggest that, rather than waiting for lifestyle or medical failure, RYGB is ideally considered before, or as soon as possible after, onset of type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00433810.

A novel triple-tracer approach to assess postprandial protein turnover.

Insulin and nutrients have profound effects on proteome homeostasis. Currently no reliable methods are available to measure postprandial protein turnover. A triple-tracer method was developed using phenylalanine stable isotope tracers to estimate appearance rates of ingested (Ra meal) and endogenous phenylalanine and the rate of phenylalanine disposal (Rd). This was compared with the "traditional" dual-tracer method, using one (1-CM)- and two (2-CM)-compartment models. For both methods, [13C6]phenylalanine was given orally, and [15N]phenylalanine was constantly infused; the triple-tracer method added [2H5]phenylalanine, infused at rates to mimic meal [13C6]phenylalanine appearance. Additionally, incorporation of meal-derived phenylalanine into specific proteins was measured after purification by two-dimensional electrophoresis. The triple-tracer approach reduced modeling errors, allowing improved reconstruction of Ra meal with a tracer-to-tracee ratio that was more constant and better estimated Rd. The 2-CM better described phenylalanine kinetics and Rd than 1-CM. Thus, the triple-tracer approach using 2-CM is superior for measuring non-steady-state postprandial protein turnover. This novel approach also allows measurement of postprandial synthesis rates of specific plasma proteins. We offer a valid non-steady-state model to measure postprandial protein turnover and synthesis of plasma proteins that can safely be applied in adults, children, and pregnant women.

Procedural Pain during Insertion of a Continuous Glucose Monitoring Device in Preterm Infants.

Procedural pain was compared between the insertion of a continuous glucose monitoring sensor and heel stick using the Premature Infant Pain Profile in a single-blinded controlled trial in preterm infants (≤32 weeks of gestation or birth weight ≤1500 g) (ClinicalTrials.govNCT02583776). Continuous glucose monitoring insertion was associated with lower pain scores compared with the heel stick.

Differential effects of the circadian system and circadian misalignment on insulin sensitivity and insulin secretion in humans.

Glucose tolerance is lower at night and higher in the morning. Shift workers, who often eat at night and experience circadian misalignment (i.e. misalignment between the central circadian pacemaker and the environmental/behavioural cycles), have an increased risk of type 2 diabetes. To determine the separate and relative impacts of the circadian system, behavioural/environmental cycles, and their interaction (i.e. circadian misalignment) on insulin sensitivity and ß-cell function, the oral minimal model was used to quantitatively assess the major determinants of glucose control in 14 healthy adults using a randomized, cross-over design with two 8-day laboratory protocols. Both protocols involved 3 baseline inpatient days with habitual sleep/wake cycles, followed by 4 inpatient days with the same nocturnal bedtime (circadian alignment) or with 12-hour inverted behavioural/environmental cycles (circadian misalignment). The data showed that circadian phase and circadian misalignment affect glucose tolerance through different mechanisms. While the circadian system reduces glucose tolerance in the biological evening compared to the biological morning mainly by decreasing both dynamic and static ß-cell responsivity, circadian misalignment reduced glucose tolerance mainly by lowering insulin sensitivity, not by affecting ß-cell function.

Performance of individually measured vs population-based C-peptide kinetics to assess ß-cell function in the presence and absence of acute insulin resistance.

AIMS: To compare the performance of population-based kinetics with that of directly measured C-peptide kinetics when used to calculate ß-cell responsivity indices, and to study people with and without acute insulin resistance to ensure that population-based kinetics apply to all conditions where ß-cell function is measured. METHODS: Somatostatin was used to inhibit endogenous insulin secretion in 56 people without diabetes. Subsequently, a C-peptide bolus was administered and the changing concentrations were used to calculate individual kinetic measures of C-peptide clearance. In addition, the participants were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid elevation, to cause insulin resistance, was achieved by infusion of Intralipid + heparin. The Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics. RESULTS: There were marked differences in the exchange variables (k 12 and k 21 ) of the model describing C-peptide kinetics, but smaller differences in the fractional clearance; that is, the irreversible loss from the accessible compartment (k 01 ), obtained from population-based estimates compared with experimental measurement. Because it is predominantly influenced by k 01 , DI estimated using individual kinetics correlated well with DI estimated using population-based kinetics. CONCLUSIONS: These data support the use of population-based measures of C-peptide kinetics to estimate ß-cell function during an OGTT.