Model-based simulation of glycaemic effect and body weight loss when switching from semaglutide or dulaglutide to once weekly tirzepatide.

OBJECTIVE: To evaluate the efficacy endpoints of HbA1c and body weight loss after switching from the GLP-1 receptor agonists, semaglutide or dulaglutide, to treatment with the GIP/GLP-1 receptor agonist (RA) tirzepatide. METHODS: Models were developed and validated to describe the HbA1c and weight loss time course for semaglutide (SUSTAIN 1-10), dulaglutide (AWARD-11) and tirzepatide (SURPASS 1-5, phase 3 global T2D program). The impact of switching from once weekly GLP-1 RAs to tirzepatide was described by simulating the efficacy time course. Semaglutide and dulaglutide doses were escalated in accordance with their respective labels. RESULTS: Model-predicted mean decreases from baseline in HbA1c and body weight for semaglutide 0.5 mg, 1 mg, and 2 mg were 1.22 to 1.79% and 3.62 to 6.87 kg respectively, at Week 26. Model-predicted mean decreases from baseline in HbA1c and body weight for dulaglutide 1.5 mg, 3 mg and 4.5 mg were 1.53 to 1.84% and 2.55 to 3.71 kg respectively, at Week 26. After switching to tirzepatide 5, 10 and 15 mg HbA1c reductions were predicted to range between 1.95 to 2.46% and body weight reductions between 6.50 to 12.1 kg by Week 66. CONCLUSION: In this model-based simulation, switching from approved maintenance doses of semaglutide or dulaglutide to tirzepatide, even at the lowest approved maintenance dose of 5 mg, showed the potential to further improve HbA1c and body weight reductions.

Type 2 diabetes is a disease of elevated blood sugar levels. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a type of medication used to treat type 2 diabetes that work on GLP-1 receptors in the body. Semaglutide and dulaglutide are examples of GLP-1 RAs, which lower blood sugar and body weight. Tirzepatide is a newer medication, which works on both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. It reduces blood sugar and body weight in people living with type 2 diabetes. Healthcare professionals and patients are interested in how switching medication from semaglutide or dulaglutide to tirzepatide might change blood glucose levels and body weight. However, because tirzepatide is a newer medication, there is not much information available on this aspect. Data from clinical trials of these medications were used to predict the effects of switching from semaglutide or dulaglutide to tirzepatide. These model-based simulations showed that switching to tirzepatide may further reduce HbA1c (a measure of blood sugar) and body weight. This may provide useful information to healthcare professionals and patients when making decisions about treatment with these medications.

Predictors of ≥15% Weight Reduction and Associated Changes in Cardiometabolic Risk Factors With Tirzepatide in Adults With Type 2 Diabetes in SURPASS 1-4.

OBJECTIVE: To identify predictors of body weight (BW) reduction of ≥15% with tirzepatide treatment and to describe associated clinical parameters of participants with type 2 diabetes (T2D) who achieved different categorical measures of BW reduction (<5%, ≥5 to <10%, ≥10 to <15%, and ≥15%) across four studies from the phase 3 SURPASS clinical trial program for T2D. RESEARCH DESIGN AND METHODS: The multivariate model for predictor of a BW reduction of ≥15% included age, sex, race, BW, HbA1c, tirzepatide dose and baseline metformin use, fasting serum glucose, and non-HDL cholesterol. Baseline characteristics and change from baseline to week 40/42 for efficacy parameters were described and analyzed in treatment-adherent participants (≥75% doses administered and on treatment at week 40/42) receiving once weekly tirzepatide (5 mg, 10 mg, or 15 mg) (N = 3,188). RESULTS: Factors significantly associated with achieving a BW reduction of ≥15% with tirzepatide were higher tirzepatide doses, female sex, White or Asian race, younger age, metformin background therapy, and lower HbA1c, fasting serum glucose, and non-HDL cholesterol at baseline. With higher categorical BW reduction, there were greater reductions in HbA1c, triglycerides, ALT, waist circumference, and blood pressure. CONCLUSIONS: Baseline factors associated with a higher likelihood of achieving a BW reduction of ≥15% with tirzepatide were higher tirzepatide doses, female sex, White or Asian race, younger age, metformin background therapy, better glycemic status, and lower non-HDL cholesterol. With greater BW reduction, participants with T2D achieved larger improvements in glycemia and cardiometabolic risk parameters. These findings help inform which people with T2D are most likely to achieve greater BW reduction with improved cardiometabolic risk factors with tirzepatide.

Major ß cell-specific functions of NKX2.2 are mediated via the NK2-specific domain.

The consolidation of unambiguous cell fate commitment relies on the ability of transcription factors (TFs) to exert tissue-specific regulation of complex genetic networks. However, the mechanisms by which TFs establish such precise control over gene expression have remained elusive-especially in instances in which a single TF operates in two or more discrete cellular systems. In this study, we demonstrate that ß cell-specific functions of NKX2.2 are driven by the highly conserved NK2-specific domain (SD). Mutation of the endogenous NKX2.2 SD prevents the developmental progression of ß cell precursors into mature, insulin-expressing ß cells, resulting in overt neonatal diabetes. Within the adult ß cell, the SD stimulates ß cell performance through the activation and repression of a subset of NKX2.2-regulated transcripts critical for ß cell function. These irregularities in ß cell gene expression may be mediated via SD-contingent interactions with components of chromatin remodelers and the nuclear pore complex. However, in stark contrast to these pancreatic phenotypes, the SD is entirely dispensable for the development of NKX2.2-dependent cell types within the CNS. Together, these results reveal a previously undetermined mechanism through which NKX2.2 directs disparate transcriptional programs in the pancreas versus neuroepithelium.

Efficacy and Safety of Tirzepatide in Adults With Type 2 Diabetes: A Perspective for Primary Care Providers.

This article reviews the efficacy and safety data of tirzepatide, a once-weekly, novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States, the European Union, and other regions for the treatment of type 2 diabetes. All doses of tirzepatide demonstrated superiority in reducing A1C and body weight from baseline versus placebo or active comparators. The safety profile of tirzepatide was consistent with that of the GLP-1 receptor agonist class, with mild to moderate and transient gastrointestinal side effects being the most common adverse events. With clinically and statistically significant reductions in A1C and body weight without increased risk of hypoglycemia in various populations, tirzepatide has demonstrated potential as a first-in-class treatment option for many people with type 2 diabetes.

Achievement of glycaemic targets with weight loss and without hypoglycaemia in type 2 diabetes with the once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide: A post hoc analysis of the SURPASS-1 to -5 studies.

AIM: To assess composite endpoints combining glycaemic control (HbA1c < 7.0%, ≤ 6.5% or < 5.7%) with weight loss (≥ 5%, ≥ 10% or ≥ 15%) and without hypoglycaemia with tirzepatide in type 2 diabetes (T2D). MATERIALS AND METHODS: Data from the phase 3 SURPASS programme were evaluated post hoc by trial. Participants with T2D were randomized to tirzepatide (5, 10 and 15 mg), placebo (SURPASS-1,5), semaglutide 1 mg (SURPASS-2) or titrated basal insulin (SURPASS-3,4). The proportions of participants achieving the composite endpoints were compared between tirzepatide and the respective comparator groups at week 40/52. RESULTS: The proportions of participants achieving an HbA1c value of less than 7.0% with 5% or more weight loss and without hypoglycaemia ranged from 43% to 82% with tirzepatide across the SURPASS-1 to -5 trials versus 4%-5% with placebo, 51% with semaglutide 1 mg and 5% with basal insulin (P < .001 vs. all comparators). The proportions of participants achieving an HbA1c value of less than 7.0% with 10% or more, or 15% or more weight loss and without hypoglycaemia were significantly higher with all tirzepatide doses versus comparators across trials (P < .001 or P < .05). Similar results were observed for all other combinations of endpoints with an HbA1c value of 6.5% or less, or less than 5.7%, with more tirzepatide-treated participants achieving these endpoints versus those in the comparator groups, including semaglutide. CONCLUSIONS: Across the SURPASS-1 to -5 clinical trials, more tirzepatide-treated participants with T2D achieved clinically meaningful composite endpoints, which included reaching glycaemic targets with various degrees of weight loss and without hypoglycaemia, than those in the comparator groups.

Computing a Stable Distance on Merge Trees.

Distances on merge trees facilitate visual comparison of collections of scalar fields. Two desirable properties for these distances to exhibit are 1) the ability to discern between scalar fields which other, less complex topological summaries cannot and 2) to still be robust to perturbations in the dataset. The combination of these two properties, known respectively as stability and discriminativity, has led to theoretical distances which are either thought to be or shown to be computationally complex and thus their implementations have been scarce. In order to design similarity measures on merge trees which are computationally feasible for more complex merge trees, many researchers have elected to loosen the restrictions on at least one of these two properties. The question still remains, however, if there are practical situations where trading these desirable properties is necessary. Here we construct a distance between merge trees which is designed to retain both discriminativity and stability. While our approach can be expensive for large merge trees, we illustrate its use in a setting where the number of nodes is small. This setting can be made more practical since we also provide a proof that persistence simplification increases the outputted distance by at most half of the simplified value. We demonstrate our distance measure on applications in shape comparison and on detection of periodicity in the von Kármán vortex street.

Demonstration of a two-bit controlled-NOT quantum-like gate using classical acoustic qubit-analogues.

The Controlled-NOT (CNOT) gate is the key to unlock the power of quantum computing as it is a fundamental component of a universal set of gates. We demonstrate the operation of a two-bit C-NOT quantum-like gate using classical qubit acoustic analogues, called herein logical phi-bits. The logical phi-bits are supported by an externally driven nonlinear acoustic metamaterial composed of a parallel array of three elastically coupled waveguides. A logical phi-bit has a two-state degree of freedom associated with the two independent relative phases of the acoustic wave in the three waveguides. A simple physical manipulation involving the detuning of the frequency of one of the external drivers is shown to operate on the complex vectors in the Hilbert space of pairs of logical phi-bits. This operation achieves a systematic and predictable C-NOT gate with unambiguously measurable input and output. The possibility of scaling the approach to more phi-bits is promising.

Are we there yet? Increasing use of cardioprotective antihyperglycemic agents in patients with T2D and CVD or CV risk in the United States.

OBJECTIVE: To report on the use of antihyperglycemic agents (AHAs) by age (i.e. <65, ≥65 years) in patients with type 2 diabetes (T2D) and cardiovascular disease (CVD) or cardiovascular risk (CV risk) factors in the United States. METHODS: Patients with T2D and CVD (CVD cohort) or T2D and an additional CV risk factor without pre-existing CVD (CV risk cohort) were identified from 2015 to 2019 in a claims database. Patients were followed from their first observed CVD diagnosis or CV risk factor for each year they were continuously enrolled or until occurrence of a CVD diagnosis (CV risk cohort only). Classes of AHAs received were reported by year, cohort, and age group. RESULTS: From 2015 to 2019, the percentage of patients <65 years on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) increased (CVD: 9-17%, CV risk: 9-17%) and was approximately twice that of those ≥65 years (CVD: 4-8%, CV risk: 4-8%); the percentage of patients <65 years on sodium-glucose cotransporter-2 (SGLT2) inhibitors increased (CVD: 11-16%, CV risk: 11-17%) and was approximately triple that of those ≥65 years (CVD: 3-6%, CV risk: 4-7%). CONCLUSIONS: The use of GLP-1 RAs and SGLT2 inhibitors increased during the study period; however, most patients did not receive these medications. Patients aged ≥65 years were particularly disadvantaged.

Examining the evidence for weight management in individuals with type 2 diabetes.

The obesity epidemic has been linked to the worsening diabetes epidemic. Despite this, weight reduction for individuals with obesity is seen as a secondary, or even tertiary, consideration in the treatment of type 2 diabetes (T2D). The aim of this review is to examine the benefits of weight management in individuals with T2D. A literature review of current available published data on the benefits of weight reduction in individuals with T2D was conducted. In individuals with T2D who have obesity or overweight, modest and sustained weight reduction results in improvement in glycaemic control and decreased utilization of glucose-lowering medication. A total body weight loss of 5% or higher reduces HbA1c levels and contributes to mitigating risk factors of cardiovascular disease, such as hyperlipidaemia and hypertension, as well as other disease-related complications of obesity. Progressive improvements in glycaemic control and cardiometabolic risk factors can occur when the total body weight loss increases to 10% or more. In the approach to treating patients with T2D and obesity, prioritizing weight management and the use of therapeutics that offer glycaemic control as well as the additional weight loss should be emphasized given their potential to attenuate the progression and severity of T2D.

Efficacy of tirzepatide 5, 10 and 15 mg versus semaglutide 2 mg in patients with type 2 diabetes: An adjusted indirect treatment comparison.

AIM: To conduct an adjusted indirect treatment comparison (aITC) of the efficacy of tirzepatide 5/10/15 mg versus semaglutide 2 mg in patients with type 2 diabetes. MATERIALS AND METHODS: The primary analysis was a Bucher aITC of the change from baseline at week 40 in HbA1c (%) and body weight (kg). Aggregate data from the SURPASS-2 study that met the HbA1c inclusion criterion of the SUSTAIN FORTE study and from SUSTAIN FORTE metformin-only treated patients were used for primary analysis. RESULTS: The SURPASS-2 refined population comprised 238/245/240 and 240 participants for tirzepatide 5/10/15 mg and semaglutide 1 mg, respectively. The SUSTAIN FORTE metformin-only population comprised 222 and 227 participants for semaglutide 1 and 2 mg, respectively. In this aITC, tirzepatide 10 and 15 mg significantly reduced HbA1c versus semaglutide 2 mg with an estimated treatment difference (ETD) of -0.36% (95% confidence interval [CI] -0.63, -0.09) and -0.4% (95% CI -0.67, -0.13), respectively. Tirzepatide 10 and 15 mg significantly reduced body weight versus semaglutide 2 mg with an ETD of -3.15 kg (95% CI -4.84, -1.46) and -5.15 kg (95% CI -6.85, -3.45), respectively. There were no significant differences between tirzepatide 5 mg and semaglutide 2 mg on change from baseline in HbA1c and body weight. CONCLUSIONS: In this aITC, HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus semaglutide 2 mg and were similar for tirzepatide 5 mg versus semaglutide 2 mg. These findings provide comparative effectiveness insights in the absence of a head-to-head clinical trial.

Particle Merging-and-Splitting.

Robustly handling collisions between individual particles in a large particle-based simulation has been a challenging problem. We introduce particle merging-and-splitting, a simple scheme for robustly handling collisions between particles that prevents inter-penetrations of separate objects without introducing numerical instabilities. This scheme merges colliding particles at the beginning of the time-step and then splits them at the end of the time-step. Thus, collisions last for the duration of a time-step, allowing neighboring particles of the colliding particles to influence each other. We show that our merging-and-splitting method is effective in robustly handling collisions and avoiding penetrations in particle-based simulations. We also show how our merging-and-splitting approach can be used for coupling different simulation systems using different and otherwise incompatible integrators. We present simulation tests involving complex solid-fluid interactions, including solid fractures generated by fluid interactions.

Inhibition of PAI-1 Promotes Lipolysis and Enhances Weight Loss in Obese Mice.

OBJECTIVE: This study investigates the therapeutic potential of a small molecule inhibitor of plasminogen activator inhibitor-1 (PAI-1), TM5441, in reversing diet-induced obesity in mice. METHODS: Wild-type C57BL/6J mice were fed a high-fat high-sugar (HFHS) diet for 8 weeks to induce obesity. After the first 8 weeks, TM5441 was added to the diet for an additional 8 weeks. In order to determine the efficacy of PAI-1 inhibition in conjunction with dietary modification, mice were fed an HFHS diet for 8 weeks to induce obesity and were then switched to a low-fat diet with or without TM5441 for an additional 2 to 8 weeks. RESULTS: Obese mice showed weight reduction and significant improvement in hepatic steatosis when TM5441 was added to the HFHS diet. Obese mice that were treated with TM5441 in conjunction with dietary modification showed enhanced weight loss and a more rapid reversal of hepatic steatosis compared with obese mice treated with dietary modification alone. The enhanced weight loss among mice treated with TM5441 was associated with increased adipose tissue expression of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and phosphorylated perilipin-1 as well as induction of adipose tissue lipolysis. CONCLUSIONS: Pharmacologic PAI-1 inhibition stimulates adipose tissue lipolysis and enhances weight loss in obese mice.

Role of PAI-1 in hepatic steatosis and dyslipidemia.

Plasminogen activator inhibitor 1 (PAI-1) is a functional biomarker of the metabolic syndrome. Previous studies have demonstrated that PAI-1 is a mechanistic contributor to several elements of the syndrome, including obesity, hypertension and insulin resistance. Here we show that PAI-1 is also a critical regulator of hepatic lipid metabolism. RNA sequencing revealed that PAI-1 directly regulates the transcriptional expression of numerous genes involved in mammalian lipid homeostasis, including PCSK9 and FGF21. Pharmacologic or genetic reductions in plasma PAI-1 activity ameliorates hyperlipidemia in vivo. These experimental findings are complemented with the observation that genetic deficiency of PAI-1 is associated with reduced plasma PCSK9 levels in humans. Taken together, our findings identify PAI-1 as a novel contributor to mammalian lipid metabolism and provides a fundamental mechanistic insight into the pathogenesis of one of the most pervasive medical problems worldwide.

The Effect of Data Transformations on Scalar Field Topological Analysis of High-Order FEM Solutions.

High-order finite element methods (HO-FEM) are gaining popularity in the simulation community due to their success in solving complex flow dynamics. There is an increasing need to analyze the data produced as output by these simulations. Simultaneously, topological analysis tools are emerging as powerful methods for investigating simulation data. However, most of the current approaches to topological analysis have had limited application to HO-FEM simulation data for two reasons. First, the current topological tools are designed for linear data (polynomial degree one), but the polynomial degree of the data output by these simulations is typically higher (routinely up to polynomial degree six). Second, the simulation data and derived quantities of the simulation data have discontinuities at element boundaries, and these discontinuities do not match the input requirements for the topological tools. One solution to both issues is to transform the high-order data to achieve low-order, continuous inputs for topological analysis. Nevertheless, there has been little work evaluating the possible transformation choices and their downstream effect on the topological analysis. We perform an empirical study to evaluate two commonly used data transformation methodologies along with the recently introduced L-SIAC filter for processing high-order simulation data. Our results show diverse behaviors are possible. We offer some guidance about how best to consider a pipeline of topological analysis of HO-FEM simulations with the currently available implementations of topological analysis.

A Generative Model for Volume Rendering.

We present a technique to synthesize and analyze volume-rendered images using generative models. We use the Generative Adversarial Network (GAN) framework to compute a model from a large collection of volume renderings, conditioned on (1) viewpoint and (2) transfer functions for opacity and color. Our approach facilitates tasks for volume analysis that are challenging to achieve using existing rendering techniques such as ray casting or texture-based methods. We show how to guide the user in transfer function editing by quantifying expected change in the output image. Additionally, the generative model transforms transfer functions into a view-invariant latent space specifically designed to synthesize volume-rendered images. We use this space directly for rendering, enabling the user to explore the space of volume-rendered images. As our model is independent of the choice of volume rendering process, we show how to analyze volume-rendered images produced by direct and global illumination lighting, for a variety of volume datasets.

CENTRAL DIABETES INSIPIDUS AND CHEMOTHERAPY: USE OF A CONTINUOUS ARGININE VASOPRESSIN INFUSION FOR FLUID AND SODIUM BALANCE.

OBJECTIVE: Central diabetes insipidus can occur in the setting of primary or metastatic tumors that disrupt the hypothalamic-pituitary axis. Usual treatment consists of water intake to replace ongoing fluid losses and desmopressin administration aimed at decreasing the urine output to enable maintenance of eunatremia without polyuria. Marked derangement in plasma sodium concentration can occur when high-volume intravenous fluid administration is required during chemotherapy to prevent nephrotoxicity, particularly if obligate fluid intake exceeds the total daily fluid intake necessary to maintain eunatremia. METHODS: We developed a protocol for a rapidly titratable low-dose continuous intravenous arginine vasopressin infusion to maintain eunatremia in patients with central diabetes insipidus during periods of obligate fluid intake. RESULTS: We successfully maintained eunatremia in 2 patients with central nervous system lymphoma who underwent several cycles of obligate intravenous fluid administration with 5% dextrose in 0.45% sodium chloride for chemotherapy. CONCLUSION: Obligate fluid administration can result in dangerous and severe fluctuations in plasma sodium concentration in patients with central diabetes insipidus receiving conventional desmopressin therapy. The use of a rapidly titratable low-dose continuous vasopressin infusion successfully maintained eunatremia in this setting. This protocol can be replicated to prevent the wide and potentially dangerous fluctuations in plasma sodium concentration that can occur in patients with central diabetes insipidus who require high-volume intravenous fluid administration. This protocol has not been assessed among patients with impaired renal function and, thus, may not be generalizable to this population. (AACE Clinical Case Rep. 2018;4:e487-e492).

The Topology ToolKit.

This system paper presents the Topology ToolKit (TTK), a software platform designed for the topological analysis of scalar data in scientific visualization. While topological data analysis has gained in popularity over the last two decades, it has not yet been widely adopted as a standard data analysis tool for end users or developers. TTK aims at addressing this problem by providing a unified, generic, efficient, and robust implementation of key algorithms for the topological analysis of scalar data, including: critical points, integral lines, persistence diagrams, persistence curves, merge trees, contour trees, Morse-Smale complexes, fiber surfaces, continuous scatterplots, Jacobi sets, Reeb spaces, and more. TTK is easily accessible to end users due to a tight integration with ParaView. It is also easily accessible to developers through a variety of bindings (Python, VTK/C++) for fast prototyping or through direct, dependency-free, C++, to ease integration into pre-existing complex systems. While developing TTK, we faced several algorithmic and software engineering challenges, which we document in this paper. In particular, we present an algorithm for the construction of a discrete gradient that complies to the critical points extracted in the piecewise-linear setting. This algorithm guarantees a combinatorial consistency across the topological abstractions supported by TTK, and importantly, a unified implementation of topological data simplification for multi-scale exploration and analysis. We also present a cached triangulation data structure, that supports time efficient and generic traversals, which self-adjusts its memory usage on demand for input simplicial meshes and which implicitly emulates a triangulation for regular grids with no memory overhead. Finally, we describe an original software architecture, which guarantees memory efficient and direct accesses to TTK features, while still allowing for researchers powerful and easy bindings and extensions. TTK is open source (BSD license) and its code, online documentation and video tutorials are available on TTK's website [108].

SGLT2-I in the Hospital Setting: Diabetic Ketoacidosis and Other Benefits and Concerns.

PURPOSE OF REVIEW: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents. They are increasingly being prescribed in the outpatient diabetic population. In this review, we examine the risks and benefits of continuation and initiation of SGLT2 inhibitors in the inpatient setting. RECENT FINDINGS: There are currently no published data regarding safety and efficacy of SGLT2 inhibitor use in the hospital. Outpatient data suggests that SGLT2 inhibitors have low hypoglycemic risk. They also decrease systolic blood pressure and can prevent cardiovascular death. The EMPA-REG study also showed a decrease in admissions for acute decompensated heart failure. There have been increasing cases of diabetic ketoacidosis, and specifically the euglycemic manifestation, associated with SGLT2 inhibitors use. We present two cases of inpatient SGLT2 inhibitor use, one of continuation of outpatient therapy and one of new initiation of therapy. We then discuss potential risks and methods to mitigate these as well as benefits of these medications in the inpatient setting. We cautiously suggest the use of SGLT2 inhibitors in the hospital. However, these must be used judiciously and the practitioner must be aware of euglycemic diabetic ketoacidosis and its risk factors in this population.

Dapagliflozin-Induced Acute-on-Chronic Liver Injury.

Sodium-glucose cotransporter 2 inhibitors are a new class of oral hypoglycemic agents, and thus safety data are limited. We present a 48-year-old woman with type 2 diabetes mellitus and Child's Class A cirrhosis secondary to nonalcoholic steatohepatitis presenting with jaundice and acute cholestatic liver injury. Other than starting dapagliflozin, she reported no medication changes or supplement use. Before treatment, her total bilirubin was 1.2 mg/dL. On admission, her liver values were elevated and liver biopsy was consistent with drug-induced liver injury. This report raises awareness about the potential hepatotoxic effects of dapagliflozin, particularly in patients with chronic liver disease.

Long-term activation of PKA in ß-cells provides sustained improvement to glucose control, insulin sensitivity and body weight.

Type 2 diabetes is associated with obesity, insulin resistance and ß-cell failure. Therapeutic aims are to reduce adiposity, improve insulin sensitivity and enhance ß-cell function. However, it has been proposed that chronically increasing insulin release leads to ß-cell exhaustion and failure. We previously developed mice to have increased activity of the cAMP-dependent protein kinase (PKA), specifically in ß-cells (ß-caPKA mice). ß-caPKA mice have enhanced acute phase insulin release, which is the primary determinant of the efficacy of glucose clearance. Here these mice were used to determine the sustainability of enhanced insulin secretion, and to characterize peripheral effects of enhanced ß-cell function. Increased PKA activity was induced by tamoxifen administration at 10 weeks of age. Male mice were aged to 12 months of age and female mice to 16 months. Glucose control in both male and female ß-caPKA mice was significantly improved relative to littermate controls with ad libitum feeding, upon refeeding after fasting, and in glucose tolerance tests. In female mice insulin release was both greater and more rapid than in controls. Female mice were more insulin sensitive than controls. Male and female ß-caPKA mice had lower body weights than controls. DEXA analysis of male mice revealed that this was due to reduced adiposity and not due to changes in lean body mass. This study indicates that targeting ß-cells to enhance insulin release is sustainable, maintains insulin sensitivity and reduces body weight. These data identify ß-cell PKA activity as a novel target for obesity therapies.