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We consider the problem of correctly classifying a given quantum two-level system (qubit) which is known to be in one of two equally probable quantum states. We assume that this task should be performed by a quantum machine which does not have at its disposal a complete classical description of the two template states, but can only have partial prior information about their level of purity and mutual overlap. Moreover, similarly to the classical supervised learning paradigm, we assume that the machine can be trained by $n$ qubits prepared in the first template state and by $n$ more qubits prepared in the second template state. In this situation, we are interested in the optimal process which correctly classifies the input qubit with the largest probability allowed by quantum mechanics. The problem is studied in its full generality for a number of different prior information scenarios and for an arbitrary size $n$ of the training data. Finite size corrections around the asymptotic limit $n\rightarrow \infty $ are derived. When the states are assumed to be pure, with known overlap, the problem is also solved in the case of d-level systems. [ABSTRACT FROM AUTHOR]

In non-muscle invasive bladder cancer, Bacillus Calmette–Guérin (BCG) responders benefit from strong Th1-type inflammatory and T cell responses mediating tumor rejection. However, the corresponding lack of anti-inflammatory Th2-type immunity impairs tissue repair in the bladder wall and facilitates the development of cystitis, causing urinary pain, urgency, incontinence, and frequency. Mechanistically, the leakage of the glycosaminoglycan (GAG) layer enables an influx of potassium ions, bacteria, and urine solutes towards the underlying bladder tissue, promoting chronic inflammation. Treatments directed towards re-establishing this mucopolysaccharide-based protective barrier are urgently needed. We discuss the pathomechanisms, as well as the therapeutic rationale of how chondroitin and hyaluronic acid instillations can reduce or prevent BCG-induced irritative bladder symptoms. Moreover, we present a case series of five patients with refractory BCG-induced cystitis successfully treated with combined chondroitin and hyaluronic acid instillations. [ABSTRACT FROM AUTHOR]

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired β-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled β-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. β-Cell function parameters were derived from established mathematical models yielding β-cell glucose sensitivity (βCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-βCGS to the 2-h hyperglycemic clamp-βCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, βCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia. [ABSTRACT FROM AUTHOR]

Although GLP-1 has been suggested as a major factor for the marked improvement of glucose tolerance commonly seen after sleeve gastrectomy (SG), several observations challenge this hypothesis. To better understand the role of GLP-1 in the remission of type 2 diabetes mellitus (T2DM) long term after SG in humans, we conducted two separate cross-sectional studies: 1) the GLP-1 response to a standardized mixed liquid meal (SMLM) was compared in subjects with T2DM antedating SG but with different long-term (>2 years) T2DM outcomes (remission, relapse, or lack of remission) (study 1) and 2) the effect of GLP-1 receptor blockade with exendin (9-39) on glucose tolerance was examined in subjects with T2DM antedating surgery, who had undergone SG and presented with long-term T2DM remission (study 2). In study 1, we observed a comparable GLP-1 response to the SMLM regardless of the post-SG outcome of T2DM. In study 2, the blockade of GLP-1 action resulted in impaired insulin secretion but limited deterioration of glucose tolerance. Thus, our data suggest the enhanced GLP-1 secretion observed long term after SG is neither sufficient nor critical to maintain normal glucose tolerance in subjects with T2DM antedating the surgery. [ABSTRACT FROM AUTHOR]

The incretin effect on insulin secretion was investigated in 8 subjects with type 2 diabetes (T2D) and 8 with normal glucose tolerance (NGT), using 25, 75, and 125 g oral glucose tolerance tests (OGTT) and isoglycemic intravenous glucose infusions (IIGI). The ß-cell response was evaluated using a model embedding a dose-response (slope = glucose sensitivity), an early response (rate sensitivity), and potentiation (time-related secretion increase). The incretin effect, as OGTT/IIGI ratio, was calculated for each parameter. In NGT, the incretin effect on total secretion increased with dose (1.3±0.1, 1.7±0.2, 2.2±0.2 fold of IIGI, P<0.0001), mediated by a dose-dependent increase of the incretin effect on glucose sensitivity (1.9±0.4, 2.4±0.4, 3.1±0.4, P = 0.005), and a dose-independent enhancement of the incretin effect on rate sensitivity (894 [1145], 454 [516], 783 [1259] pmol m−2 L mmol−1 above IIGI; median [interquartile range], P<0.0001). The incretin effect on potentiation also increased (0.97±0.06, 1.45±0.20, 1.24±0.16, P<0.0001). In T2D, the incretin effect on total secretion (1.0±0.1, 1.1±0.1, 1.3±0.1, P = 0.004) and glucose sensitivity (1.2±0.2, 1.3±0.2, 2.0±0.2, P = 0.005) were impaired vs NGT; however, the incretin effect on rate sensitivity increased already at 25 g (269 [169], 284 [301], 193 [465] pmol m−2 L mmol−1 above IIGI; negligible IIGI rate sensitivity in T2D prevented the calculation of the fold increment). OGTT did not stimulate potentiation above IIGI (0.94±0.04, 0.89±0.06, 1.06±0.09; P<0.01 vs NGT). In the whole group, the incretin effect was inversely associated with total secretion during IIGI, although systematically lower in T2D. In conclusion, 1) In NGT, glucose sensitivity and potentiation mediate the dose-dependent incretin effect increase; 2) In T2D, the incretin effect is blunted vs NGT, but rate sensitivity is enhanced at all loads; 3) Relatively lower incretin effect in NGT is associated with higher secretion during IIGI, suggesting that the reduced incretin effect does not result from ß-cell dysfunction. [ABSTRACT FROM AUTHOR]

The increase in malnutrition due to excess supports the need to reassess the role of food environments in the well-being and food security of the population. The objective of this bibliographic review is to carry out a descriptive search of food environments and how these condition states of malnutrition due to excess and the food security of the population. Through a narrative investigation in search engines and databases (Medline, Scielo, Scopus, Virtual Health Library, Medes and Google Scholar), original articles or reviews in Spanish and English published between 2017 and 2021 were identified, served the purposes of the study. 56 articles were included, which allowed to study in more detail the five theoretical categories: institutional and organizational food environment, restoration, public thoroughfare, supply and home; as well as in the way in which these environments enhance malnutrition due to excess and put pressure on the food security of the population. The different environments or food environments direct the lifestyles and well-being of people and communities, in addition to influencing the etiology and maintenance of malnutrition due to excess and the food security of the population. [ABSTRACT FROM AUTHOR]

To characterize the defects in β-cell function in subjects with impaired fasting glucose (IFG) and compare the results to impaired glucose tolerance (IGT) and normal glucose tolerance (NGT) subjects, β-cell glucose sensitivity and rate sensitivity during the oral glucose tolerance test were measured with the model by Mari in 172 Mexican Americans. A subgroup (n = 70) received a 2-h hyperglycemic clamp (+125 mg/dL), and first- and second-phase insulin secretion were quantitated. Compared with NGT, subjects with IFG and IGT manifested a decrease in b-cell glucose sensitivity; IFG subjects, but not IGT subjects, had decreased β-cell rate sensitivity. In IFG subjects, the defect in β-cell glucose sensitivity was time dependent, began to improve after 60 min, and was comparable to NGT after 90 min. The incremental area under the plasma C-peptide concentration curve during the first 12 min of the hyperglycemic clamp (ΔC-pep [AUC]0-12) was inversely related with the increase in FPG concentration (r = 236, r = 0.001), whereas ΔC-pep[AUC]15-120 positively correlated with FPG concentration (r = 0.29, r , 0.05). When adjusted for the prevailing level of insulin resistance, first-phase insulin secretion was markedly decreased in both IFG and IGT, whereas second-phase insulin secretion was decreased only in IGT. These results demonstrate distinct defects in β-cell function in IFG and IGT. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Recent work has shown that insulin stimulates its own secretion in insulin-sensitive humans, suggesting that insulin resistance in the β-cell could cause β-cell dysfunction. We have tested whether insulin exposure and insulin sensitivity modulate β-cell function in subjects with normal glucose tolerance (NGT) and whether they contribute to dysglycemia in impaired glucose regulation (IGR). RESEARCH DESIGN AND METHODS--Insulin sensitivity (by euglycemic clamp), insulin-induced secretory response at isoglycemia (IISR) (as C-peptide percent change from basal during the clamp), glucose-induced secretory response (GISR) to an intravenous glucose bolus, and β-cell glucose sensitivity (β-GS) (by oral glucose tolerance test [OGTT] modeling) were measured in 1,151 NGT and 163 IGR subjects from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study. RESULTS--In NGT, IISR was related to both insulin sensitivity and antecedent insulin exposure; GISR was related to insulin exposure. IISR was positively, if weakly, related to β-GS (r = 0.16, P < 0.0001). Both IISR (-23 [39] vs. 29 [2]%, median [interquartile range], P < 0.03) and β-GS (69 [47] vs. 118 [83] pmol x min--1 x m--2 x mmol--1 x L, P < 0.0001) were decreased in IGR compared with NGT. Insulin sensitivity and β-GS were the major determinants of mean OGTT glucose in both NGT and IGR, with a minor role for IISR. In a multivariate logistic model, IGR was predicted by β-GS (odds ratio 4.84 [95% CI 2.89--8.09]) and insulin sensitivity (3.06 [2.19--4.27]) but not by IISR (1.11 [0.77--1.61]). CONCLUSIONS--Pre-exposure to physiological hyperinsulinemia stimulates insulin secretion to a degree that depends on insulin sensitivity. However, this phenomenon has limited impact on β-cell dysfunction and dysglycemia. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i.e., the gain in β-cell function after oral glucose versus intravenous glucose). RESEARCH DESIGN AND METHODS--Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20-61 kg/m[sup 2]). C-peptide deconvolution was used to reconstruct insulin secretion rates, and β-cell glucose sensitivity (slope of the insulin secretion/glucose concentration doseresponse curve) was determined by mathematical modeling. The incretin effect was defined as the oral-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique. RESULTS--The incretin effect on total insulin secretion and β-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P ≤ 0.05). The results were similar when subjects were stratified by BMI tertile (P ≤ 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r = 0.27-0.59, P ≤ 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r = 0.53, P < 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients. CONCLUSIONS--Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another. Diabetes 57:1340-1348, 2008 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- We studied the effects of the oral insulin secretagogue nateglinide on insulin secretion using a modeling approach to obtain β-cell function parameters from a meal test and examined the impact of the β-cell improvement on glucose tolerance. RESEARCH DESIGN AND METHODS -- Mild type 2 diabetic men and women (n = 108; fasting glucose 7.0-8.3 mmol/l) on diet treatment alone randomly received 30, 60, or 120 mg nateglinide or placebo for 24 weeks. β-Cell function parameters were derived by modeling (based on C-peptide deconvolution) from a standardized meal test at baseline and after 24 weeks of treatment. RESULTS -- The baseline demographic and metabolic characteristics of the four groups were similar. Nateglinide treatment resulted in dose-dependent reductions in the mean postprandial glucose response and at the 120-mg dose in fasting glucose. Fasting or total insulin secretion during the meal were not different. In contrast, we found differences in the model parameters. Rate sensitivity (expressing early insulin secretion when glucose is rising) was significantly enhanced at 24 weeks with the lowest nateglinide dose, with no further stimulation at higher doses. Early potentiation (expressing an initial insulin secretion enhancement), glucose sensitivity (the slope of the glucose-insulin secretion relationship), and insulin secretion at a fixed-reference 7-mmol/l glucose concentration all showed a trend toward increasing, with increasing nateglinide dose, and were significantly greater than placebo at the 120-mg dose. In multiple regression analyses, changes in rate sensitivity, glucose sensitivity, and potentiation all contributed to the observed glucose changes. CONCLUSIONS -- The model-derived parameters are sensitive measures of β-cell function, showing improvements after nateglinide treatment and predicting changes in glucose tolerance. [ABSTRACT FROM AUTHOR]

We investigated β-cell function and its relationship to insulin sensitivity in 17 normal volunteers. For insulin secretion (derived by C-peptide deconvolution), a mathematical model was applied to 24-h triple-meal tests (MT) as well as oral glucose tolerance tests (OGTT); insulin sensitivity was assessed by the euglycemic insulin clamp technique. The β-cell model featured a glucose concentration-insulin secretion dose response (characterized by secretion at 5 mM glucose and slope), a secretion component proportional to the glucose concentration derivative, and a time-dependent potentiation factor (modulating the dose response and accounting for effects of sustained hyperglycemia and incretins). The β-cell dose-response functions estimated from the whole 24-h MT, the first 2 h of the MT, and the OGTT differed systematically, because a different potentiation factor was involved. In fact, potentiation was higher than average during meals (1.6 ± 0.1-fold during the first meal) and had a different time course in the MT and OGTT. However, if potentiation was accounted for, the 24and 2-h MT and the OGTT yielded similar dose responses, and most β-cell function parameters were intercorrelated (r = 0.50-0.86, P ≤ 0.05). The potentiation factor was found to be related to plasma glucose-dependent insulin-releasing polypeptide concentrations (r = 0.49, P < 0.0001). Among β-cell function parameters, only insulin secretion at 5 mM glucose from MT correlated inversely with insulin sensitivity (24-h MT: r = -0.74, P < 0.001; 2-h MT: r = -0.52, P < 0.05), whereas the dose-response slope and the OGTT parameters did not. In nine other subjects, reproducibility of model parameters was evaluated from repeated MTs. Coefficients of variation were generally ∼20%, but the derivative component was less reproducible. We conclude that our model for the multiple MT yields useful information on β-cell function, particularly with regard to the role... [ABSTRACT FROM AUTHOR]

We developed a mathematical model of the glucose control of insulin secretion capable of quantifying beta-cell function from a physiological meal test. The model includes a static control, i.e., a secretion component that is a function of plasma glucose concentration (the dose-response function), and a dynamic control, i.e., a secretion component that is proportional to the positive values of the glucose concentration derivative. Furthermore, the dose-response function is assumed to be modulated by a time-varying potentiation factor. To test the model, nine nondiabetic control subjects and nine type 2 diabetic patients received three standardized mixed meals over a period of 14-15 h. Blood samples were drawn for the measurement of glucose, insulin, and C-peptide concentration. The dose-response function, the parameter of the dynamic control, and the potentiation factor were determined by fitting the model to glucose and C-peptide concentrations. In diabetic patients, the dose-response function was shifted to the right (glucose concentration at a reference insulin secretion of 300 pmol.min(-1).m(-2) was 11.7 +/- 1.1 vs. 7.2 +/- 0.7 mmol/l; P < 0.05), and decreased in slope (53 +/- 15 vs. 148 +/- 38 pmol.min(-1).m(-2).mmol(-1).l; P < 0.05) and the parameter of the dynamic control was decreased (220 +/- 67 vs. 908 +/- 276 pmol.m(-2).mmol(-1).l; P < 0.05) compared with the nondiabetic control subjects. Furthermore, potentiation was markedly blunted and delayed: maximum potentiation was observed at the first meal in normal subjects and at the second meal (about 4 h later) in diabetic subjects; the mean time for the potentiation factor was higher (7.1 +/- 0.2 vs. 5.9 +/- 0.2 h; P < 0.01), and the size of potentiation was reduced (2.6 +/- 0.5 vs. 7.2 +/- 1.5 fold increase; P < 0.005). In conclusion, our model of insulin secretion extracts multiple indexes of beta-cell function from a physiological meal test. Use of the model in patients with type 2 diabetes retrieves known defects in insulin secretion but also uncovers new facets of beta-cell dysfunction. [ABSTRACT FROM AUTHOR]

Objective: Available insulin sensitivity (IS) methods based on the oral glucose tolerance test (OGTT) are empirical. We used a glucose-insulin model to derive an OGTT-based IS (oral glucose insulin sensitivity [OGIS]) index, which predicts glucose clearance in a glucose clamp. We validated OGIS against clamp data.Research Design and Methods: OGIS requires glucose and insulin concentrations from a 75-g OGTT at 0, 2, and 3 h (3-h OGTT) or at 0, 1.5, and 2 h (2-h OGTT). The formula includes six constants optimized to match the clamp results. For this purpose, 15 lean nondiabetic subjects (BMI < 25 kg/m2), 38 obese nondiabetic subjects (BMI > 25 kg/m2), and 38 subjects with type 2 diabetes randomly underwent an OGTT and a 120 mU x min(-1) x m(-2) insulin infusion euglycemic clamp. Glucose clearance (Cl CLAMP), calculated as the ratio of glucose infusion to concentration during the last hour of the clamp, was compared with OGIS. OGIS was also tested on an independent group of 13 subjects with impaired glucose tolerance (IGT).Results: OGIS and Cl CLAMP were correlated in the whole group (R = 0.77, P < 0.0001), in the subgroups (lean: R = 0.59; obese: R = 0.73; type 2 diabetes: R = 0.49; P < 0.02), and in the independent IGT group (R = 0.65, P < 0.02). Reproducibility of OGIS and Cl CLAMP were similar (coefficients of variation: OGIS 7.1%, Cl CLAMP 6.4%). OGIS was as effective as Cl CLAMP in discriminating between groups (for OGIS, lean vs. obese: 440 +/- 16 vs. 362 +/- 11 ml x min(-1) x m(-2), p < 0.001; lean vs. type 2 diabetes: 440 +/- 16 vs. 239 +/- 7, P < 0.0001; obese vs. type 2 diabetes: 362 +/- 11 vs. 239 +/- 7, P < 0.0001; results were similar for Cl CLAMP). The relationships between IS and BMI, fasting plasma insulin, and insulin secretion (calculated from the OGTT insulin concentration) were examined. OGIS yielded results similar to Cl CLAMP and fully consistent with established physiological principles. The performance of the index for the 3-h and 2-h OGTT was similar.Conclusions: OGIS is an index of IS in good agreement with the clamp. Because of its simplicity (only three blood samples required), this method has potential use for clinical investigation including large-scale epidemiological studies. [ABSTRACT FROM AUTHOR]

Pancreatic β cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here, we report that succinate receptor 1 (SUCNR1) is expressed in β cells and is upregulated in hyperglycemic states in mice and humans. We found that succinate acted as a hormone-like metabolite and stimulated insulin secretion via a SUCNR1-GqPKC–dependent mechanism in human β cells. Mice with β cell–specific Sucnr1 deficiency exhibited impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance showed an enhanced nutrition-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states. [ABSTRACT FROM AUTHOR]

Background: Follow-up after radical cystectomy (RC) for bladder cancer can be divided into oncological and functional surveillance. It remains unclear how follow-up after RC should ideally be scheduled. The aim of this report was to gain insight into the organization of follow-up after RC in Europe, for which we conducted a roundtable inventory within the EAU Young Academic Urologists Urothelial Cancer working group. Methods: An inventory semi-structured survey was performed among urologists of the EAU Young Academic Urologists Urothelial Cancer working group to describe the organization of follow-up. The surveys were analyzed using a deductive approach. Similarities and differences in follow-up after RC for bladder cancer were described. Results: The survey included 11 urologists from six different European countries. An institutional follow-up scheme was used by six (55%); three (27%) used a national or international guideline, and two (18%) indicated that there was no defined follow-up scheme. Major divergent aspects included the time points of follow-up, the frequency, and the end of follow-up. Six centers (55%) adopted a risk-adapted follow-up approach tailored to (varying) patient and tumor characteristics. Laboratory tests and CT scans were used in all cases; however, the intensity and frequency varied. Functional follow-up overlapped with oncological follow-up in terms of frequency and duration. Patient-reported outcome measures were only used by two (18%) urologists. Conclusions: Substantial variability exists across European centers regarding the follow-up after RC for bladder cancer. This highlights the need for an international analysis focusing on its organization and content as well as on opportunities to improve patients' needs during follow-up after RC. [ABSTRACT FROM AUTHOR]

Examines the role of model assumptions on assessment of insulin sensitivity using minimal model (MM). Basic definitions; MM expression of glucose logarithmic slope; Adequacy of MM expression of glucose logarithmic slope; Physiological determinants of glucose logarithmic slope; Role of glucose production and hepatic insulin sensitivity.

Type 2 diabetes (T2D) risk is lower in females than males. It has been reported that females have greater pancreatic 훽‐cell function than males, which may at least in part contribute to the T2D risk in females. 훽‐cell function is influenced by exercise training; however, previous trials comparing 훽‐cell function between the sexes have not included participants matched for training status. Furthermore, the acute effects of different modes of exercise on 훽‐cell function, and whether sex inherently influences these effects, are largely unexamined. Males and females (12/sex) completed a 120‐min oral glucose tolerance test (OGTT) at rest (CON) and following acute bouts of high‐intensity interval exercise (HIIE), moderate intensity continuous (MIC) exercise, and low‐load high‐repetition (LLHR) resistance exercise to assess whether sex inherently influences baseline and/or post‐exercise pancreatic function in the absence of pathology. We found no sex differences in basal pancreatic 훽‐cell function. Females had greater basal insulin clearance following MIC exercise compared to males (p = 0.01) and males tended to have a higher potentiation ratio following HIIE (p = 0.07). Females also had lower glucose sensitivity following MIC exercise compared to HIIE (p = 0.007) and LLHR (p = 0.003). Insulin clearance during the OGTT was greater following HIIE as compared with CON and MIC exercise (p = 0.02). 2‐H oral glucose insulin sensitivity was greater following LLHR compared to CON (p = 0.01). Acute bouts of different modes of exercise do not differentially influence 훽‐cell function but do influence insulin clearance and insulin sensitivity. Therefore, sex and exercise mode interact to differentially influence insulin clearance and glucose sensitivity. [ABSTRACT FROM AUTHOR]

The article offers information on the incretin effect (IE) and its role in regulating β cell functional response and insulin secretion dynamics. Topics include the impact of IE reduction in type 2 diabetes, a study using surgical removal of β cell mass as a model for diabetes development, and findings suggesting that preexisting defects in β cell response to incretins predict the risk of developing impairments in glucose tolerance after β cell mass reduction.

Simple Summary: This study provides a thorough review of robot-assisted partial nephrectomy (RAPN) in managing renal hilar masses. It focuses on the evaluation of RAPN's effectiveness and the exploration of varied surgical methods for these complex tumors. The research underscores the reliability of RAPN and emerging surgical techniques in addressing these challenges with a manageable risk of complications. The findings are poised to significantly contribute to the medical community's understanding and management of renal hilar masses, especially in terms of effectively balancing treatment efficacy and complication risks. Background: Robot-assisted partial nephrectomy (RAPN) is increasingly being employed in the management of renal cell carcinoma (RCC) and it is expanding in the field of complex renal tumors. The aim of this systematic review was to consolidate and assess the results of RAPN when dealing with entirely central hilar masses and to examine the various methods used to address the surgical difficulties associated with them. Methods: A thorough literature search in September 2023 across various databases focused on RAPN for renal hilar masses, adhering to PRISMA guidelines. The primary goal was to evaluate RAPN's surgical and functional outcomes, with a secondary aim of examining different surgical techniques. Out of 1250 records, 13 full-text manuscripts were reviewed. Results: Evidence is growing in favor of RAPN for renal hilar masses. Despite a predominance of retrospective studies and a lack of long-term data, RAPN shows positive surgical outcomes and preserves renal function without compromising cancer treatment effectiveness. Innovative suturing and clamping methods are emerging in surgical management. Conclusions: RAPN is a promising technique for managing renal hilar masses in RCC, offering effective surgical outcomes and renal function preservation. The study highlights the need for more long-term data and prospective studies to further validate these findings. [ABSTRACT FROM AUTHOR]

The Restoring Insulin Secretion (RISE) Study found that compared to adults (A), youth (Y) with early DM (33 Y, 104 A) or IGT (53 Y, 250 A) have higher insulin and C-peptide responses, even after adjusting for differences in insulin sensitivity. To better understand these differences, we compared mathematical modeling data from OGTTs to those from a hyperglycemic clamp within the RISE Study. Modeled measures were the dose-response relationship between glucose and insulin secretion (glucose sensitivity [GS], rate sensitivity [RS]) and the oral glucose insulin sensitivity index (OGIS). Clamp measures were insulin sensitivity (steady state glucose infusion rate/insulin [M/I]), acute (0-10 minutes) C-peptide (ACPRg) and insulin (AIRg) responses to glucose, steady-state C-peptide (SSCP) at plasma glucose of 11.1 mmol/L, and arginine-stimulated maximum C-peptide (ACPRmax) response at glucose >25 mmol/L. Linear regression models were fit to assess relationships between OGTT model and clamp measures by age group. GS (r2 = 0.29, p<0.01) and RS (r2 = 0.22, p<0.01) were inversely correlated with M/I. GS was directly correlated with ACPRg (r2 = 0.55, p<0.01), AIRg (r2 = 0.52, p<0.01), SSCP (r2 = 0.46, p<0.01) and ACPRmax (r2 = 0.33, p<0.01), with a steeper slope in Y vs. A for AIRg and ACPRg vs. GS (p's < 0.01), and in IGT vs. DM for ACPRg vs. GS (p=0.03). RS was directly correlated with ACPRg (slope r2 = 0.55, p<0.01), with a steeper slope in Y vs. A (P < 0.01) and in IGT vs. DM (p=0.04). M/I was directly correlated with OGIS (r2 = 0.34, p<0.01). The inverse correlation of GS with M/I in both Y and A suggests that differences in insulin sensitivity should be accounted for when comparing GS across groups. The fact that relationships between acute insulin and C-peptide responses from the clamp and GS and RS from OGTTs differed between Y and A, while these relationships were similar for SSCP and ACPRmax, suggest fundamental differences exist in the early-phase response between Y and A with IGT or early DM. Disclosure: K. Utzschneider: Consultant; Self; Novo Nordisk Inc. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. M. Tripputi: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. K.J. Nadeau: None. S. Edelstein: None. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. S.A. Arslanian: None. M. Cree-Green: None. T.A. Buchanan: Research Support; Self; Allergan, Apollo EndoSurgery. S. Caprio: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. R. Consortium: None. Funding: American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases [ABSTRACT FROM AUTHOR]

Results from hyperglycemic clamps in the Restoring Insulin Secretion (RISE) Study found that youth (10-19 y) with impaired glucose tolerance (IGT) or early type 2 diabetes (T2D) are more insulin resistant and secrete more insulin than adults (20-65 y), despite similar BMI. Here we use Mari modeling of RISE 3-h OGTT data to explore differences in β-cell function between youth and adults. The Mari model describes the relationship between insulin secretion rate (ISR) and glucose concentration. The slope of the relationship is β-cell glucose sensitivity (GS); ISR at a fixed glucose is also calculated. Derived terms include the 3-h to baseline potentiation factor ratio (PFR; a relative insulin secretion increase during the OGTT) and rate sensitivity (RS; the dependence of ISR on the glucose rate of change). Analysis of covariance was used to compare youth vs. adults, with secretion measures adjusted for insulin sensitivity (M/I) from hyperglycemic clamps. Adjusted GS was significantly higher in youth vs. adults with IGT but not in those with T2D. Adjusted RS and ISR at plasma glucose of 5 and 7 mmol/L were higher in youth vs. adults for both IGT and T2D. The PFR was lower in youth than adults, suggesting possible differences in either incretin effects or glucose potentiation. Our OGTT findings provide additional evidence that β-cells in youth are more responsive to glucose than adults, with reduced secretion parameters in those with T2D. Disclosure: K. Utzschneider: Consultant; Self; Novo Nordisk Inc. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. M. Tripputi: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. K.J. Nadeau: None. S. Edelstein: None. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. S.A. Arslanian: None. M. Cree-Green: None. T.A. Buchanan: Research Support; Self; Allergan, Apollo EndoSurgery. S. Caprio: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. R. Consortium: None. Funding: American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases [ABSTRACT FROM AUTHOR]

Aims: Ataxia telangiectasia (A-T) is a rare genetic condition associated with diabetes. OGTT data show that nondiabetic adults with A-T are insulin resistant. ATM-ko mice are glucose intolerant, insulin resistant with abnormal fat distribution, which improve with TZD treatment. The RAMP study assessed the effects of pioglitazone in A-T. Methods: This open label, non-randomised, crossover study compared 8 nondiabetic people with A-T and 15 healthy controls. Dual tracer mixed meal tests, indirect calorimetry, and adipocyte function were used to assess response to treatment. Results: Groups were matched for age, BMI and HbA1c. Pioglitazone reduced fasting (61 [IQR 26 - 135] to 28.0 [IQR 20.9 - 110.1] pmol/l, p=0.008) and meal (393 [IQR 275 - 2103] to 252 [IQR 195 - 823], p=0.02) insulin in the A-T group, with unchanged fasting but reduced mean glucose (6.3 [IQR 6.1 - 6.7] to 5.9 [IQR 5.7 - 6.2] mmol/l, p=0.02). Pioglitazone did not affect glucose or insulin in controls. Pioglitazone improved insulin sensitivity in the A-T group, with reduced HOMA-IR (2.19 [IQR 0.96 - 4.14] to 0.97 [IQR 0.76 - 3.54], p=0.023) and increased Matsuda index (2.7 [IQR 1.2 - 5.9] to 5.3 [IQR 1.6 - 7.1], p=0.008). Pioglitazone increased adiponectin in both groups (A-T: 2528 [IQR 2008 - 4887] to 12461 [IQR 4451 - 15843] ng/ml, p=0.008; control 6262 [IQR 4051 - 89940] to 15123 [IQR 9594 - 19384] ng/ml, p=0.001). NEFAs were reduced in A-T (0.25 [IQR 0.22 - 0.28] to 0.18 [IQR 0.14 - 0.20] mmol/l, p=0.016). Pioglitazone increased the fasting respiratory quotient (RQ) in A-T (0.9 [IQR 0.8 - 1.0] to 1.1 [IQR 1.0 - 1.2], p=0.04). A mixed effects model of insulin sensitivity identified a significant gene * drug interaction (p=0.001) between A-T and pioglitazone. Conclusion: Pioglitazone treatment improved insulin sensitivity and adipocyte function in A-T. Pioglitazone reduced NEFAs and increased RQ, indicating a reduction in fatty acid oxidation. These data suggest that pioglitazone may be an appropriate first line treatment for diabetes in A-T. Disclosure: L.J. McCreight: None. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. E. Pearson: None. Funding: UK Wellcome Trust (to E.P.) [ABSTRACT FROM AUTHOR]

Bioactive glasses (BG) possess significant bone-bonding and osteogenic properties that support their use for bone defects repair in orthopaedic and dental procedures. Recent advancement enables the manufacturing of BG-based scaffolds providing structural support during bone regeneration. Despite the wide number of studies on BG and BG-based materials, little information on their aging mechanisms and shelf life is available in the literature. In this study, the evolution of chemical species on BG-based foams was investigated via accelerated tests in the presence of CO2 and humidity. The aging process led to the formation of carbonates (Na2CO3 and CaCO3) and hydrocarbonates (NaHCO3). The amount and composition of nucleated species evolved with time, affecting the structure, properties, and bioactivity of the scaffolds. This study provides a first structured report of aging effects on the structure and chemico-physical properties of bioactive glass-based scaffolds, offering an insight about the importance of their storage and packaging. [ABSTRACT FROM AUTHOR]

Background: Chronic Prostatitis/Chronic Pelvic Pain syndrome NIH-class III is a widespread condition affecting men universally, with existing treatments showing limited success. This study evaluated the efficacy and safety of a natural supplement, composed of Serenoa repens, Solanum lycopersicum, lycopene, and bromelain, in managing symptoms of this condition among a substantial patient group. Methods: In this prospective study, 245 patients diagnosed with Chronic Prostatitis/Chronic Pelvic Pain syndrome NIH-class III were treated with the aforementioned supplement, alongside lifestyle alterations, such as refraining from spicy foods, alcohol, caffeine, and cycling, for a duration of three months. Patients' progress was assessed at one and three months using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), the International Prostate Symptom Index (IPSS), quality of life (QoL) scores, and changes in total prostate-specific antigen (PSA) levels. Results: The supplement was well received with no serious adverse events reported. Significant improvements were observed in NIH-CPSI scores, IPSS, QoL scores, and a substantial decrease in total PSA levels at three months compared to baseline, with a positive trend noted from one-month to three-month evaluations. This was consistent in either patients with predominantly voiding or storage urinary symptoms. Conclusions: Our results suggest that this natural supplement in conjunction with lifestyle changes could offer a safe and effective alternative treatment for patients suffering from Chronic Prostatitis/Chronic Pelvic Pain syndrome NIH-class III. However, these findings require validation through further large-scale randomized controlled trials. [ABSTRACT FROM AUTHOR]

The article focuses on the study that aims to assess the effects of liraglutide on β-cell function in normal living. The study examined thirteen type 2 diabetic patients. The β-cell function of the patients was assessed using a model that describes the relationship between insulin secretion (ISR) and glucose concentration. It concludes that liraglutide treatment significantly enhances β-cell function evaluated under conditions of normal living.

Purpose: The present study sought to provide reproducible and patient-oriented metrics to assess the rate of “successful” outcomes (Trifecta) following holmium laser enucleation of the prostate (HoLEP). Clinical and surgical predictors of failure to achieve Trifecta were investigated. Materials and Methods: We queried our prospectively collected database of all patients treated with HoLEP between March 2017 and January 2021. Trifecta was defined as the contemporary presence of: (1) no postoperative complication within 3 months; (2) no urinary incontinence at 3-months follow-up; and (3) 3-month postoperative max flow-rate >15 mL/s. Cases were grouped according to Trifecta achievement. All surgical procedures were carried out by a single surgeon. Surgical experience was divided into two different eras according to the number of procedures conducted (surgical era). Multivariate logistic regression analysis was performed to assess predictors of Trifecta failure. Results: Overall 305 patients were included. Of these, 192 patients (63.0%) achieved Trifecta. Preoperative patient-related features were comparable between the two groups, except for a higher post-void residual (PVR) in non-Trifecta patients (median 180 vs. 130 mL, p=0.003). A significant proportion of Trifecta patients (88.5%) were treated in the second surgical era and in 126 (65.6%) cases an en-bloc enucleation was performed. Multivariate analysis confirmed PVR ≥250 mL, first surgical era and standard three-lobes enucleation technique as independent predictors of Trifecta failure. Conclusions: In our experience the rate of “successful” HoLEP, defined according to our newly introduced Trifecta metric, was 63.0%. We demonstrated that surgical strategy together with rising experience and baseline PVR are key elements to forecast the outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Lymph node involvement is a prognostic determinant in the diagnostic work-up and management of muscle-invasive bladder cancer. Thus, it is crucial to provide an accurate staging of the bladder tumor to better identify the best therapeutic strategies to improve the chances of survival and the quality of life of patients affected by bladder cancer. Positron Emission Tomography/Computed Tomography (PET/CT) has been increasingly used in bladder cancer staging to improve the accuracy of lymph node detection and to overcome the lack of sensitivity and the understaging showed by conventional imaging. The aim of this narrative literature review is to provide an overview of the current evidence on the use of 18F-FDG PET/CT in the diagnosis, staging, and restaging of bladder cancer, with a particular focus on its sensitivity and specificity for the detection of LN metastasis. We aim to provide clinicians with a better understanding of 18F-FDG PET/CT's potential benefits and limitations in clinical practice. Despite the heterogeneity of the studies in the literature and the lack of a consensus, 18F-FDG PET/CT provides important incremental staging and restaging information that can potentially influence the clinical management of patients affected by muscle-invasive bladder cancer. Introduction: Lymph node (LN) involvement is a crucial determinant of prognosis for patients with bladder cancer, and an accurate staging is of utmost importance to better identify timely and appropriate therapeutic strategies. To improve the accuracy of LN detection, as an alternative to traditional methods such as CT or MRI, 18F-FDG PET/CT has been increasingly used. 18F-FDG PET/CT is also used in post-treatment restaging after neoadjuvant chemotherapy. The aim of this narrative literature review is to provide an overview of the current evidence on the use of 18F-FDG PET/CT in the diagnosis, staging, and restaging of bladder cancer, with a particular focus on its sensitivity and specificity for the detection of LN metastasis. We aim to provide clinicians with a better understanding of 18F-FDG PET/CT's potential benefits and limitations in clinical practice. Materials and Methods: We designed a narrative review starting from a wide search in the PubMed/MEDLINE and Embase databases, selecting full-text English articles that have examined the sensibility and specificity of PET/CT for nodal staging or restaging after neoadjuvant therapy in patients with bladder cancer. The extracted data were analyzed and synthesized using a narrative synthesis approach. The results are presented in a tabular format, with a summary of the main findings of each study. Results: Twenty-three studies met the inclusion criteria: fourteen studies evaluated 18F-FDG PET/CT for nodal staging, six studies examined its accuracy for restaging after neoadjuvant therapy, and three studies evaluated both applications. To date, the use of F-18 FDG PET/TC for detection of LN metastasis in bladder cancer is controversial and uncertain: some studies showed low accuracy rates, but over the years other studies have reported evidence of high sensitivity and specificity. Conclusions: 18F-FDG PET/CT provides important incremental staging and restaging information that can potentially influence clinical management in MIBC patients. Standardization and development of a scoring system are necessary for its wider adoption. Well-designed randomized controlled trials in larger populations are necessary to provide consistent recommendations and consolidate the role of 18F-FDG PET/CT in the management of bladder cancer patients. [ABSTRACT FROM AUTHOR]

Objective: We investigated, using population-based data, whether worse autonomic function, estimated from lower 24-hour heart rate variability (HRV), was associated with beta cell function, assessed from beta cell response during an oral glucose tolerance test (OGTT). Research design and methods: We used cross-sectional data from The Maastricht Study, a population-based cohort study (N = 2,007; age, mean ± SD:60 ± 8 years; 52% men; and 24% with type 2 diabetes). We used linear regression analyses with adjustment for potential confounders (demographic, cardiovascular, and lifestyle factors) to study the associations of time- and frequency-domain HRV (composite scores) with overall beta cell response (estimated from a composite score calculated from: C-peptidogenic index, overall insulin secretion, beta cell glucose sensitivity, beta cell potentiation factor, and beta cell rate sensitivity). In addition, we tested for interaction by sex and glucose metabolism status. Results: After full adjustment, lower time- and frequency-domain HRV was significantly associated with lower overall beta cell response composite score (standardized beta, -0.055 [-0.098; -0.011] and − 0.051 [-0.095; -0.007], respectively). These associations were not modified by sex and there was no consistent pattern of interaction by glucose metabolism status. Conclusion: The present etiological study found that worse autonomic function, estimated from lower HRV, was associated with worse beta cell function, estimated from a composite score in a population-based sample which covered the entire spectrum of glucose metabolism. Hence, autonomic dysfunction may contribute to beta cell dysfunction and, ultimately, to the alteration of glucose metabolism status from normal glucose metabolism to prediabetes and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Simple Summary: Bacillus of Calmette-Guérin (BCG) is the gold standard as per adjuvant intravesical treatment for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC). Nevertheless, drug-related toxicity, compliance, and a shortage of BCG availability make the completion of the planned treatment schedule challenging in many patients, thus possibly impacting survival outcomes. No one specific BCG strain out of the several available ones worldwide has so far demonstrated its superiority profile in prolonging time to recurrence and progression. In our systematic review and network meta-analysis, we compared to most widely adopted BCG strains and demonstrated that BCG strain Tice, RIVM, and Tokyo 172 could display potential enhanced benefits, thus possibly supporting the use of such strains for future BCG trials in NMIBCs. Background: In an era of Bacillus of Calmette-Guérin (BCG) shortages, the comparative efficacy from different adjuvant intravesical BCG strains in non-muscle invasive bladder cancer (NMIBC) has not been clearly elucidated. We aim to compare, through a systematic review and meta-analysis, the cumulative BC recurrence rates and the best efficacy profile of worldwide available BCG strains over the last forty years. Methods: PubMed, Scopus, Web of Science, Embase, and Cochrane databases were searched from 1982 up to 2022. A meta-analysis of pooled BC recurrence rates was stratified for studies with ≤3-y vs. >3-y recurrence-free survival (RFS) endpoints and the strain of BCG. Sensitivity analysis, sub-group analysis, and meta-regression were implemented to investigate the contribution of moderators to heterogeneity. A random-effect network meta-analysis was performed to compare BCG strains on a multi-treatment level. Results: In total, n = 62 series with n = 15,412 patients in n = 100 study arms and n = 10 different BCG strains were reviewed. BCG Tokyo 172 exhibited the lowest pooled BC recurrence rate among studies with ≤3-y RFS (0.22 (95%CI 0.16–0.28). No clinically relevant difference was noted among strains at >3-y RFS outcomes. Sub-group and meta-regression analyses highlighted the influence of NMIBC risk-group classification and previous intravesical treated categories. Out of the n = 11 studies with n = 7 BCG strains included in the network, BCG RIVM, Tice, and Tokyo 172 presented with the best-predicted probability for efficacy, yet no single strain was significantly superior to another in preventing BC recurrence risk. Conclusion: We did not identify a BCG stain providing a clinically significant lower BC recurrence rate. While these findings might discourage investment in future head-to-head randomized comparison, we were, however, able to highlight some potential enhanced benefits from the genetically different BCG RIVM, Tice, and Tokyo 172. This evidence would support the use of such strains for future BCG trials in NMIBCs. [ABSTRACT FROM AUTHOR]

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities. Clinical multi-omics data are integrated and analyzed using a generative deep-learning model. [ABSTRACT FROM AUTHOR]

Simple Summary: The growth of minimally invasive techniques for radical nephroureterectomy (RNU) has significantly changed the surgical treatment landscape of non-metastatic upper urinary tract urothelial carcinoma in recent decades. The aim of this study was to compare perioperative and oncologic outcomes between open, laparoscopic, and robotic RNU using a retrospective, multicenter, multinational database. Using 756 propensity-score-matched patients out of a total of 2434, we found a worse bladder recurrence-free survival in patients undergoing laparoscopic and robotic RNU compared with open RNU. Recurrence-free, cancer-specific, and overall survival were similar between the three surgical approaches. Laparoscopic and robotic RNU revealed a shorter hospital length of stay and fewer major postoperative complications compared to open RNU. Although minimally invasive RNU techniques are associated with improved perioperative outcomes, further studies are warranted to investigate the underlying factors responsible for the worse bladder recurrence-free survival of patients treated with these techniques. Objectives: To identify correlates of survival and perioperative outcomes of upper tract urothelial carcinoma (UTUC) patients undergoing open (ORNU), laparoscopic (LRNU), and robotic (RRNU) radical nephroureterectomy (RNU). Methods: We conducted a retrospective, multicenter study that included non-metastatic UTUC patients who underwent RNU between 1990–2020. Multiple imputation by chained equations was used to impute missing data. Patients were divided into three groups based on their surgical treatment and were adjusted by 1:1:1 propensity score matching (PSM). Survival outcomes per group were estimated for recurrence-free survival (RFS), bladder recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS). Perioperative outcomes: Intraoperative blood loss, hospital length of stay (LOS), and overall (OPC) and major postoperative complications (MPCs; defined as Clavien–Dindo > 3) were assessed between groups. Results: Of the 2434 patients included, 756 remained after PSM with 252 in each group. The three groups had similar baseline clinicopathological characteristics. The median follow-up was 32 months. Kaplan–Meier and log-rank tests demonstrated similar RFS, CSS, and OS between groups. BRFS was found to be superior with ORNU. Using multivariable regression analyses, LRNU and RRNU were independently associated with worse BRFS (HR 1.66, 95% CI 1.22–2.28, p = 0.001 and HR 1.73, 95%CI 1.22–2.47, p = 0.002, respectively). LRNU and RRNU were associated with a significantly shorter LOS (beta −1.1, 95% CI −2.2–0.02, p = 0.047 and beta −6.1, 95% CI −7.2–5.0, p < 0.001, respectively) and fewer MPCs (OR 0.5, 95% CI 0.31–0.79, p = 0.003 and OR 0.27, 95% CI 0.16–0.46, p < 0.001, respectively). Conclusions: In this large international cohort, we demonstrated similar RFS, CSS, and OS among ORNU, LRNU, and RRNU. However, LRNU and RRNU were associated with significantly worse BRFS, but a shorter LOS and fewer MPCs. [ABSTRACT FROM AUTHOR]

Background: Insulin secretion and glucose tolerance is annually assessed in patients with cystic fibrosis (PwCF) through oral glucose tolerance tests (OGTTs) as a screening measure for cystic fibrosis-related diabetes. We aimed to describe the distribution and provide reference quartiles of OGTT-related variables in the Italian cystic fibrosis population. Methods: Cross-sectional study of PwCF receiving care in three Italian cystic fibrosis centers of excellence, from 2016 to 2020. We performed a modified 2-h OGTT protocol (1.75 g/kg, maximum 75 g), sampling at baseline and at 30-min intervals, analyzing plasma glucose, serum insulin, and C-peptide. The modified OGTT allowed for the modeling of β cell function. For all variables, multivariable quantile regression was performed to estimate the median, the 25th, and 75th percentiles, with age, sex, and pancreatic insufficiency as predictors. Results: We have quantified the deterioration of glucose tolerance and insulin secretion with age according to sex and pancreatic insufficiency, highlighting a deviation from linearity both for patients <10 years and >35 years of age. Conclusions: References of OGTT variables for PwCF provide a necessary tool to not only identify patients at risk for CFRD or other cystic fibrosis-related complications, but also to evaluate the effects of promising pharmacological therapies. [ABSTRACT FROM AUTHOR]

Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is caused by heterozygous inactivating mutations in glucokinase (GK, gene symbolGCK) and impaired glucose sensing. We investigated effects of dorzagliatin, a novel allosteric GK activator, on insulin secretion rates (ISR) and beta-cell glucose-sensitivity (βCGS) in GCK-MODY and recent-onset type 2 diabetes. In a double-blind, randomized cross-over study, eight participants with GCK-MODY and 10 with type 2 diabetes underwent 2-hour 12-mmol/L hyperglycemic clamps following a single oral dose of dorzagliatin 75mg or matched placebo. Effects of dorzagliatin on wild-type and mutant GK enzyme activity were investigated using a nicotinamide adenine dinucleotide phosphate (NADP+) coupled assay with glucose-6-phosphate dehydrogenase (G6PD) in vitro. In GCK-MODY, dorzagliatin significantly increased absolute and incremental second-phase ISR versus placebo but not the acute insulin response. Dorzagliatin improved βCGS in GCK-MODY with a upward and leftward shift in ISR-glucose response. Dorzagliatin increased basal ISR in type 2 diabetes with smaller changes in second-phase ISR compared with GCK-MODY. In vitro, dorzagliatin directly reduced the glucose half saturation concentration (S0.5) of wild-type GK and selected GK mutants to varying degrees. Dorzagliatin directly restored enzyme activity of select GK mutants and enhanced wild-type GK activity, thereby correcting the primary defect of glucose sensing in GCK-MODY. [ABSTRACT FROM AUTHOR]

Relatives of type 1 diabetic patients are at enhanced risk of developing diabetes (DM). We investigated the mechanisms by which risk progresses to disease. In 144 islet-cell autoantibody-positive, non-diabetic relatives from the close observation (control) group of the DPT-1 Parenteral Insulin Trial (73 female, age=12 [10] years (median [interquartile range]), BMI=18.3 [6.1] kg⋅m[sup -2], 42 IGT and 102 NGT). A frequently-sampled OGTT was performed at baseline and again 2.5 [2.8] years later, when 61 subjects (33 female/28 male, 28 from IGT, 33 from NGT) had developed DM. β-cell glucose sensitivity (β-GS, slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity (IS) were obtained by mathematical modelling of glucose/C-peptide responses to OGTT. Relatives progressing to DM had worse β-GS at follow up (18 [21] vs 62 [50] pmol⋅min[sub -1]⋅m[sub -2], p<0.0001 [Mann Whitney]) as well as at baseline (41 [30] vs 75 [68] pmol⋅min[sup -1]⋅m[sup -2]⋅mM[sup -1], p<0.0001). In contrast, IS was only marginally lower in progressors than non-progressors both at baseline (418 [79] vs 427 [61 ] ml⋅min[sup -1]⋅m[sup -2], p=0.77) and follow up (386 [66] vs 405 [64] ml⋅min[sup -1]⋅m[sup -2], p=0.12). By Kaplan-Meier modelling, DM-free survival was significantly (log-rank p<0.0001) worse in the bottom β-GS tertile (30 [21] pmol⋅min[sup -1]⋅m[sup -2]⋅mM[sup -1]) as compared to the middle (56 [13]) or top tertile (117 [53]). By proportional hazards analysis, incident DM was predicted (as relative risk, RR and [95% confidence interval] per 1 SD of the predictor) by baseline β-GS (RR=0.42 [0.32-0.56]), age (RR=0.27 [0.14-0.52]), female gender (RR=3.08 [1.73-5.45]), baseline IS (RR=0.66 [0.49-0.90]) and baseline BMI (RR=1.64 [0.98-2.73]), in that order of strength (χ²=36.9, 15.3, 14.8, 6.8 and 3.6, respectively). In this multivariate model, baseline glucose tolerance, fasting and 2-hour plasma glucose levels were not significant predictors. We conclude that, in high-risk relatives of type 1 patients progression to DM is mainly predicted by impaired β-cell glucose sensitivity, with younger age, female sex, reduced insulin sensitivity and higher BMI making additional contributions to DM risk. ADA-Funded Research [ABSTRACT FROM AUTHOR]

We studied whether parameters of beta cell function were similar during an oral glucose tolerance test (OGTT) and a -physiologically more relevant-mixed meal tolerance test (MTT) in different glucose tolerance groups. Individuals with normal glucose tolerance (NGT, n=150), intermediate hyperglycaemia (IH, n=19) and diabetes (DM, n=19) underwent an OGTT and an MTT, both containing 75g carbohydrates. The meal also contained 50g fat and 24g proteins. Plasma glucose, insulin and C-peptide were sampled before and 15, 30, 60, 90 and 120 minutes after OGTT and MTT. Insulin secretion rate (ISR) and beta cell function parameters were calculated from C-peptide using a mathematical model. These parameters included beta cell glucose sansitivity, i.e., the slope of the glucose concentration - ISR relationship and potentiation, which expresses a relative increase of ISR from the beginning to the end of the test. ANOVA and dependent t-tests with Bonferroni corrections were used to test for differences. Beta cell glucose sensitivity was higher during MTT than during OGTT in all groups (Table 1). Diabetic subjects had significantly lower beta cell glucose sensitivity than IH- and NGT-subjects. Potentiation was similar (NGT-or DM-subjects) or slightly higher (IH-subjects) during MTT. Beta cells were more sensitive to glucose (i.e. insulin secretion per glucose unit was higher) during a mixed meal load than during a glucose load while the ability to modulate this relationship (potentiation) was similar or slightly higher. Individuals with IH, unlike diabetic subjects, did not have lower beta cell sensitivity than NGT-individuals. We conclude that beta cell response is stronger after a mixed meal than after an OGTT with equal-carbohydrate quantity. [ABSTRACT FROM AUTHOR]

OBJECTIVE A gene mutation of the Wnt/β-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/β-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and β-cell function. RESEARCH DESIGN AND METHODS We performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer. RESULTS Sclerostin levels were higher in IGR compared with NGT (50.8 ± 2.4 vs. 38.7 ± 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = 20.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r =20.52 and r =20.44, respectively; both P < 0.001). Sclerostin levels were not correlated with β-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r² associated with HOMA-IR (r² change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r² change: 0.059; F change: 4.938; P = 0.033). CONCLUSIONS Sclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship. [ABSTRACT FROM AUTHOR]

Introduction: It is uncertain whether lixisenatide has postprandial insulinotropic effects when its effect on slowing gastric emptying is considered, in healthy subjects and type 2 diabetes mellitus (T2DM). We evaluated the effects of single administration of 10 μg sc lixisenatide on glycaemia, insulin secretion and gastric emptying (GE), measured using the 'gold standard' technique of scintigraphy following an oral glucose load (75 g glucose). Methods: Fifteen healthy subjects (nine men, six women; age 67.2 ± 2.3 years) and 15 patients with T2DM (nine men, six women; age 61.9 ± 2.3 years) had measurements of GE, plasma glucose, insulin and C-peptide for 180 min after a radiolabeled 75 g glucose drink on two separate days. All subjects received lixisenatide (10 μg sc) or placebo in a randomised, double-blind, crossover fashion 30 min before the drink. Insulin secretory response (ISR) was determined using the C-peptide deconvolution method. Results: GE was markedly slowed by lixisenatide compared with placebo in both healthy subjects (1.45 ± 0.10 kcal/min for placebo vs. 0.60 ± 0.14 kcal/min for lixisenatide) and diabetes (1.57 ± 0.06 kcal/min for placebo vs. 0.75 ± 0.13 kcal/min for lixisenatide) (both P < 0.001) with no difference between the two groups (P = 0.42). There was a moderate to strong inverse correlation between the early insulin secretory response calculated at 60 min and gastric retention at 60 min with lixisenatide treatment in healthy subjects (r = − 0.8, P = 0.0003) and a trend in type 2 diabetes (r = − 0.4, P = NS), compared with no relationships in the placebo arms (r = − 0.02, P = NS, healthy subjects) and (r = − 0.16, P = NS, type 2 diabetes). Conclusion: The marked slowing of GE of glucose induced by lixisenatide is associated with attenuation in the rise of postprandial glucose in both healthy subjects and diabetes and early insulin secretory response in healthy subjects. Clinical Trials Registration Number: NCT02308254. [ABSTRACT FROM AUTHOR]

Simple Summary: Measuring the quality of care is important in health care to improve the treatment of patients. In this investigation, we sought to identify five indicators ("pentafecta") that reflect the quality of care of patients who have cancer of the upper urinary tract (kidney and/or ureter) and are treated with surgical removal of the affected kidney and ureter. Furthermore, we searched for conditions that can predict a failure to achieve these criteria during treatment. The five indicators that define the pentafecta are the complete removal of the tumor without residuals, the complete removal of the ureter and its bladder part, the absence of complications related to the blood, the absence of severe complications related to the surgery, and the absence of tumor recurrence 12 months after the surgery. Of the 1718 patients included, 844 (49%) achieved all pentafecta criteria. These patients had higher chances at 5 years after the surgery to be alive and not to die from any cause (A) or from cancer (B) compared to those who did not achieve the pentafecta criteria (A: 68.7 vs. 50.1% and B: 79.8 vs. 62.7%, respectively). There were no conditions related to the patient that were found to predict a failure to achieve the pentafecta. Using quality indicators such as the proposed pentafecta for the assessment of the treatment of cancer patients may help define prognosis and improve patient care. Background: Measuring quality of care indicators is important for clinicians and decision making in health care to improve patient outcomes. Objective: The primary objective was to identify quality of care indicators for patients with upper tract urothelial carcinoma (UTUC) and to validate these in an international cohort treated with radical nephroureterectomy (RNU). The secondary objective was to assess the factors associated with failure to validate the pentafecta. Design: We performed a retrospective multicenter study of patients treated with RNU for EAU high-risk (HR) UTUC. Outcome measurements and statistical analysis: Five quality indicators were consensually approved, including a negative surgical margin, a complete bladder-cuff resection, the absence of hematological complications, the absence of major complications, and the absence of a 12-month postoperative recurrence. After multiple imputations and propensity-score matching, log-rank tests and a Cox regression were used to assess the survival outcomes. Logistic regression analyses assessed predictors for pentafecta failure. Results: Among the 1718 included patients, 844 (49%) achieved the pentafecta. The median follow-up was 31 months. Patients who achieved the pentafecta had superior 5-year overall- (OS) and cancer-specific survival (CSS) compared to those who did not (68.7 vs. 50.1% and 79.8 vs. 62.7%, respectively, all p < 0.001). On multivariable analyses, achieving the pentafecta was associated with improved recurrence-free survival (RFS), CSS, and OS. No preoperative clinical factors predicted a failure to validate the pentafecta. Conclusions: Establishing quality indicators for UTUC may help define prognosis and improve patient care. We propose a pentafecta quality criteria in RNU patients. Approximately half of the patients evaluated herein reached this endpoint, which in turn was independently associated with survival outcomes. Extended validation is needed. [ABSTRACT FROM AUTHOR]

OBJECTIVE Leptin administration is known to directly modulate pancreatic β-cell function in leptin-deficient rodent models. However, human studies examining the effects of leptin administration on β-cell function are lacking. In this study, we examined the effects (16-20 weeks) of leptin replacement on β-cell function in patients with lipodystrophy. RESEARCH DESIGN AND METHODS In a prospective, open-label, currently ongoing study, we studied the effects of leptin replacement on β-cell function in 13 patients with congenital or acquired lipodystrophy. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution from plasma glucose and C-peptide levels measured during oral glucose tolerance tests (OGTTs) performed at baseline and after 16-20 weeks of leptin replacement. β-Cell glucose sensitivity and rate sensitivity were assessed by mathematical modeling of OGTT. RESULTS There was a significant decrease in triglycerides, free fatty acids, and glycosylated hemoglobin levels (A1C) after leptin therapy. Patients with lipodystrophy have high fasting and glucose-stimulated ISR. However, leptin therapy had no significant effect on fasting ISR, total insulin secretion during OGTT, β-cell glucose sensitivity, rate sensitivity, or insulin clearance. CONCLUSIONS In contrast to the suppressive effects of leptin on β-cell function in rodents, 16-20-week treatment with leptin in lipodystrophy patients did not significantly affect insulin secretion or b-cell function in leptin-deficient individuals with lipodystrophy. [ABSTRACT FROM AUTHOR]

Insulin hypersecretion and insulin resistance are physiologically linked features of obesity. We tested whether extreme hypersecretion impairs β-cell function under free-living conditions and whether major weight loss modifies insulin hypersecretion, insulin sensitivity, and β-cell function. Plasma glucose, C-peptide, and free fatty acid concentrations were measured at hourly intervals during 24 h of normal life (including calorie-standardized meals) in 20 morbidly obese nondiabetic patients (BMI 48.4 ± 1.7 kg/2) and 7 nonobese age-and sex-matched control subjects; 8 of the obese patients were restudied 6 months and 2 years following biliopancreatic diversion. Insulin secretion was reconstructed from C-peptide levels by deconvolution and related to concurrent glucose levels through a mathematical model incorporating key features of β-cell function: rate sensitivity, β-cell glucose sensitivity, and potentiation. Insulin sensitivity (by the euglycemic insulin clamp technique) was reduced by 50% in obese subjects (23.1 ± 2.5 of obese subjects vs. 52.9 ± 4.9 µmol ⋅ min-1 ⋅ kgFFM-1 of control subjects, means ± SE, P = 0.0004) as was mean 24-h insulin clearance (median 809 [interquartile range 451] vs. 1,553 [520] ml ⋅ min-1 ⋅ m-2, P < 0.001) due to a 50% reduction in hepatic insulin extraction (P < 0.01). Over 24 h, insulin secretion was doubled in obese subjects (468 nmol [202] in obese subjects vs. 235 [85] of control subjects, P = 0.0002). Despite the hypersecretion, β-cell glucose sensitivity, rate sensitivity, and potentiation were similar in obese and control subjects. Six months postoperatively (weight loss = 33 ± 3 kg), both insulin hypersecretion (282 nmol [213]) and insulin sensitivity (51.6 ± 3.7 µmol ⋅ min-1 ⋅ kgFFM-1) were normalized. At 2 years (weight loss = 50 ± 8 kg), insulin sensitivity was supernormal (68.7 ± 3.3 µmol ⋅ min-1 ⋅ kgFFM-1) and insulin secretion was lower than normal (167 nmol [37]) (both P < 0.05 vs. control subjects). In conclusion, severe uncomplicated obesity is characterized by gross insulin hypersecretion and insulin resistance, but the dynamic aspects of β-cell function are intact. Malabsorptive bariatric surgery corrects both the insulin hypersecretion and the insulin resistance at a time when BMI is still high. With continued weight loss over a 2-year period, moderately obese subjects become supersensitive to insulin and, correspondingly, insulin hyposecretors. Diabetes 54:2382-2389, 2005 [ABSTRACT FROM AUTHOR]

The classical model of coronary physiology implies lhe presence of maximal microcirculatory vasodilation during myocardial ischemia. However, Doppler monitoring of coronary blood flow (CBF) documented severe microcirculatory vasoconstriction during pacing-induced ischemia in patients with coronary artery disease. This study investigates the mechanisms that underlie this paradoxical behavior in nine patients with stable angina and single-vessel coronary disease who were candidates for stenting. While transstenotic pressures were continuously monitored, input CBF (in ml/min) to the poststenotic myocardium was measured by Doppler catheter and angiographic cross- sectional area. Simultaneously, specific myocardial blood flow (MBF, in ml·min-1·g-1) was measured by 133Xe washout. Perfused tissue mass was calculated as CBFIMBF. Measurements were obtained at baseline, during pacing-induced ischemia, and after stenting. CBF and distal coronary pressure values were also measured during pacing with intracoronary adenosine administration. During pacing, CBF decreased to 64 ± 24% of baseline and increased to 265 ± 100% of ischemic flow after adenosine administration. In contrast, pacing increased MBF to 184 ± 66% of baseline, measured as a function of the increased rate-pressure product (r = 0.69; P < 0.05). Thus, during pacing, perfused myocardial mass drastically decreased from 30 ± 23 to 12 ± 11 g (P < 0.01). Distal coronary pressure remained stable during pacing but decreased after adenosine administration. Stenting increased perfused myocardial mass to 39 ± 23 g (P < 0.05 vs. baseline) as a function of the increase in distal coronary pressure (r = 0.71; P < 0.02). In conclusion, the vasoconstrictor response to pacing-induced ischemia is heterogeneously distributed and excludes a tissue fraction from perfusion. Within perfused tissue, the metabolic demand still controls the vasomotor tone. [ABSTRACT FROM AUTHOR]

Objective: Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors.Research Design and Methods: We estimated standardized EIC (EICISR) by mathematical modeling in nine different studies with insulin and glucose infusions (N = 2,067). EICISR association with various traits was analyzed by stepwise multivariable regression in studies with both euglycemic clamp and oral glucose tolerance test (OGTT) (N = 1,410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N = 1,555).Results: Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EICISR, approximately four times more influential than insulin resistance-related hypersecretion. EICISR independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ∼10% EIC reduction is necessary to explain the observed insulin concentration profiles.Conclusions: Based on EICISR, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EICISR with insulin resistance (not with higher BMI per se) and is more relevant than the concomitant hypersecretion; the second reduces EICISR with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance. [ABSTRACT FROM AUTHOR]

Objective: Glucagon-like peptide 1 (GLP-1) is an incretin that augments insulin secretion after meal intake and is developed for treatment of type 2 diabetes. As a novel therapeutic agent, characteristics of its beta-cell effects are important to establish. Previously, beta-cell effects of GLP-1 have been characterized in humans during graded intravenous infusions of glucose, whereas its effects after more physiological stimuli, like meal intake, are not known.Research Design and Methods: Eight women (aged 69 years, fasting glucose 3.7-10.3 mmol/l, BMI 22.4-43.9 kg/m(2)) who had fasted overnight were served a breakfast (450 kcal) with intravenous infusion of saline or synthetic GLP-1 (0.75 pmol x kg(-1) x min(-1)), and beta-cell function was evaluated by estimating the relationship between glucose concentration and insulin secretion (calculated by deconvolution of C-peptide data).Results: -GLP-1 markedly augmented insulin secretion, despite lower glucose. Total insulin secretion was 29.7 +/- 4.2 nmol/m(2) with GLP-1 versus 21.0 +/- 1.6 nmol/m(2) with saline (P = 0.048). GLP-1 increased the dose-response relationship between glucose concentration and insulin secretion (70 +/- 26 with GLP-1 versus 38 +/- 16 pmol insulin. min(-1 x m(2). mmol(-1) glucose. l without, P = 0.037) and augmented the potentiation factor that modulates the dose response (2.71 +/- 0.42 with GLP-1 versus 0.97 +/- 0.17 without, P = 0.005). The potentiation factor correlated to GLP-1 concentration (r = 0.53, P < 0.001); a 10-fold increase in GLP-1 levels produced a twofold increase in the potentiation factor. These effects of GLP-1 did not correlate with fasting glucose levels or BMI.Conclusions: Administration of GLP-1 along with ingestion of a meal augments insulin secretion in humans by a dose-dependent potentiation of the dose-response relationship between plasma glucose and insulin secretion. [ABSTRACT FROM AUTHOR]

OBJECTIVE — Glucagon-like peptide 1 (GLP-1) is an incretin that augments insulin secretion after meal intake and is developed for treatment of type 2 diabetes. As a novel therapeutic agent, characteristics of its β-cell effects are important to establish. Previously, β-cell effects of GLP-1 have been characterized in humans during graded intravenous infusions of glucose, whereas its effects after more physiological stimuli, like meal intake, are not known. RESEARCH DESIGN AND METHODS — Eight women (aged 69 years, fasting glucose 3.7-10.3 mmol/l, BMI 22.4-43.9 kg/m²) who had lasted overnight were served a breakfast (450 kcal) with intravenous infusion of saline or synthetic GLP-1 (0.75 pmol · kg[sup -1] · min[sup -1]), and β-cell function was evaluated by estimating the relationship between glucose concentration and insulin secretion (calculated by deconvolution of C-peptide data). RESULTS — GLP-1 markedly augmented insulin secretion, despite lower glucose. Total insulin secretion was 29.7 ± 4.2 nmol/m² with GLP-1 versus 21.0 ± 1.6 nmol/m² with saline (P = 0.048). GLP-1 increased the dose-response relationship between glucose concentration and insulin secretion (70 ± 26 with GLP-1 versus 38 ± 16 pmol insulin · min[sup -1] · m² · mmol[sup -1] glucose · 1 without, P = 0.037) and augmented the potentiation factor that modulates the dose response (2.71 ± 0.42 with GLP-1 versus 0.97 ± 0.17 without, P = 0.005). The potentiation factor correlated to GLP-1 concentration (r = 0.53, P < 0.001); a 10-fold increase in GLP-1 levels produced a twofold increase in the potentiation factor. These effects of GLP-1 did not correlate with fasting glucose levels or BMI. CONCLUSIONS — Administration of GLP-1 along with ingestion of a meal augments insulin secretion in humans by a dose-dependent potentiation of the dose-response relationship between plasma glucose and insulin secretion. [ABSTRACT FROM AUTHOR]

Peyronie’s disease (PD), a fibrotic disorder of the tunica albuginea fully described in 1793 by French physician Francois de la Peyronie, is characterized by pain, plaque formation, penile deformity, and ultimately sexual function decline. The epidemiological data on PD vary considerably across previous studies, with recent evidence reporting a prevalence of up to 9%. PD is generally divided into two different phases: active or acute and stable or chronic. Plaque formation generally occurs during the acute phase, while during chronic phase pain usually tends to complete resolution and penile deformity stabilizes. PD’s pathophysiology is still subject of great discussion. Tunical mechanical stress and microvascular trauma are major contributory factors. However, better understanding of the molecular pathophysiology of this condition remains paramount towards an in-depth comprehension of the disorder and the development of newer and more effective disease-targeted interventions. In this review we provide a detailed overview of natural history of PD, specifically focusing on clinical manifestations and the underlying molecular regulation patterns. [ABSTRACT FROM AUTHOR]

BACKGROUND. The appearance of hyperglycemia is due to insulin resistance, functional deficits in the secretion of insulin, and a reduction of β cell mass. There is a long-standing debate as to the relative contribution of these factors to clinically manifesting β cell dysfunction. The aim of this study was to verify the acute effect of one of these factors, the reduction of β cell mass, on the subsequent development of hyperglycemia. METHODS. To pursue this aim, nondiabetic patients, scheduled for identical pancreaticoduodenectomy surgery, underwent oral glucose tolerance tests (OGTT) and hyperglycemic clamp (HC) procedures, followed by arginine stimulation before and after surgery. Based on postsurgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal glucose tolerance (post-NGT), impaired glucose tolerance (post-IGT), or having diabetes mellitus (post-DM). RESULTS. At baseline, the 3 groups showed similar fasting glucose and insulin levels; however, examining the various parameters, we found that reduced first-phase insulin secretion, reduced glucose sensitivity, and rate sensitivity were predictors of eventual postsurgery development of IGT and diabetes. CONCLUSION. Despite comparable functional mass and fasting glucose and insulin levels at baseline and the very same 50% mass reduction, only reduced first-phase insulin secretion and glucose sensitivity predicted the appearance of hyperglycemia. These functional alterations could be pivotal to the pathogenesis of type 2 diabetes (T2DM). [ABSTRACT FROM AUTHOR]

Purpose: To compare the efficacy and safety of intralesional hyaluronic acid (HA) as compared with verapamil injection in patients with Peyronie's disease (PD). Materials and Methods: Between January 2015 and December 2018, men in PD acute phase were prospectively recruited. This open-label, prospective study included 2 different protocols. Group A: 8-week cycle of weekly intraplaque injections with HA; Group B: 8-week cycle of weekly intraplaque injections with verapamil. Penile curvature, plaque size, International Index of Erectile Function (IIEF)-15 score and visual analogue scale (VAS) were assessed at baseline and after 3 months. Results: Two-hundred forty-four patients were enrolled. Of these, 125 received intralesional HA (Group A), 119 received intralesional verapamil (Group B). At enrollment, median age was 56.0 years (interquartile range [IQR]=47.0-63.0 years), median curvature 35.0° (IQR=25.0°-45.0°), median IIEF-15 score 19.0 (IQR=16.0-23.0), median VAS 4.0 (IQR=4.0-5.0). Median difference for IIEF-15 was 1.0 (95% confidence interval [CI]=1.12-1.94) in Group A and 0.0 (95% CI=-0.04-0.14) in Group B (p<0.05) and median difference for VAS score was -4.0 (95% CI=-4.11-3.65) in Group A and -1.0 (95% CI=-0.50-2.01) in Group B (p<0.05). Plaque size decreased by -1.50 mm (IQR=1.60-2.10 mm) in Group A and -1.20 in Group B (p=0.10), while penile curvature decreased by -9.50° (IQR=4.50°-13.00°) in group A and -4.50 (IQR=2.50-7.50) in Group B (p<0.01). Conclusions: Intralesional HA injections could represent a reliable treatment option for the conservative management of patients with acute phase of PD. [ABSTRACT FROM AUTHOR]