Finding no head-to-head research evaluating the cardiovascular and renal benefits of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) in patients with type 2 diabetes (T2D) at different baseline renal function, we performed a network meta-analysis to compare the two drugs indirectly. Systematic literature searches were conducted of the PubMed, Cochrane Library, Web of Science, and Embase databases, covering their inception until 7 January 2025. Randomized controlled trials (RCTs) comparing the effects of SGLT-2i and GLP-1RA in T2D with different glomerular filtration rates (eGFRs) were selected. Results were reported as risk ratios (RRs) with corresponding 95% CIs. Finally, 10 RCTs involving 87,334 patients with T2D were included. In patients with an eGFR >90 mL/min/1.73 m2, GLP-1RA exhibited a superior ability to reduce the risk of all-cause death compared with SGLT-2i (RR 0.75; 95% CI 0.58, 0.97), but it was less effective in reducing the risk of renal outcome (RR 1.80; 95% CI 1.15, 2.84) in patients with an eGFR 60-90 mL/min/1.73 m2. Conversely, in patients with eGFR 30-60 and 60-90 mL/min/1.73 m2, GLP-1RA did not show an advantage in reducing the risk of hospitalization for heart failure (RR 1.87 [95% CI 1.15, 3.04] and 1.37 [95% CI 1.05, 1.78], respectively).

Homeobox C4 (HOXC4) links metabolic pathways and correlates inversely with mouse body weight and positively with Ucp1 expression in mouse adipose tissue. Gain- and loss-of-function experiments in mice demonstrated HOXC4's essential role in promoting adipose thermogenesis and providing metabolic benefits. HOXC4 interacts with the nuclear receptor coactivator 1 cofactor via its hexapeptide motif to activate Ucp1 transcription, revealing a novel mechanism of thermogenic gene regulation.

Maternally inherited diabetes and deafness (MIDD) is a mitochondrial disorder characterized primarily by hearing impairment and diabetes. m.3243A>G, the most common phenotypic variant, causes a complex rewiring of the cell with discontinuous remodeling of both mitochondrial and nuclear genome expressions. We propose that MIDD depends on a combination of insulin resistance and impaired β-cell function that occurs in the presence of high skeletal muscle heteroplasmy (approximately ≥60%) and more moderate cell heteroplasmy (∼25%-72%) for m.3243A>G. Understanding the complex mechanisms of MIDD is necessary to develop disease-specific management guidelines that are presently lacking.

Embedded in the developmental origins of health and disease (DOHaD) hypothesis, maternal hyperglycemia in utero, from preexisting diabetes or gestational diabetes mellitus, predisposes the offspring to excess adiposity and heightened risk of prediabetes and type 2 diabetes development. This transmission creates a vicious cycle increasing the presence of diabetes from one generation to another, leading to the question: How can we interrupt this vicious cycle? In this article, we present the current state of knowledge on the intergenerational transmission of diabetes from epidemiological life course studies. Then, we discuss the potential mechanisms implicated in the intergenerational transmission of diabetes with a focus on epigenetics. We present novel findings stemming from epigenome-wide association studies of offspring DNA methylation in blood and placental tissues, which shed light on potential molecular mechanisms implicated in the mother-offspring transmission of diabetes. Lastly, with a perspective on how to break the cycle, we consider interventions to prevent offspring obesity and diabetes development before puberty, as a critical period of the intergenerational cycle. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program.

MG53 is predominantly expressed in striated muscles. The role of MG53 in diabetes has gradually been elucidated but is still full of controversy. Some reports have indicated that MG53 is upregulated in animal models with metabolic disorders and that muscle-specific MG53 upregulation is sufficient to induce whole-body insulin resistance and metabolic syndrome through targeting both the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) for ubiquitin-dependent degradation. Additionally, MG53 has been identified as a myokine/cardiokine that is secreted from striated muscles into the bloodstream, and circulating MG53 has further been shown to trigger insulin resistance by binding to the extracellular domain of the IR, thereby allosterically inhibiting insulin signaling. Conversely, findings have been reported from other studies that contradict these results. Specifically, no significant change in MG53 expression in striated muscles or serum has been observed in diabetic models, and the MG53-mediated degradation of IRS-1 may be insufficient to induce insulin resistance due to the compensatory roles of other IRS subtypes. Furthermore, sustained elevation of MG53 levels in serum or systemic administration of recombinant human MG53 (rhMG53) has shown no impact on metabolic function. In this article, we will fully characterize these two disparate views, strive to provide critical insights into their contrasts, and propose several specific experimental approaches that may yield additional evidence. Our goal is to encourage the scientific community to elucidate the effects of MG53 on metabolic diseases and the molecular mechanisms involved, thereby providing the theoretical basis for the treatment of metabolic diseases and the applications of rhMG53.

Shared medical appointments (SMAs) for diabetes and group prenatal care (GPC) for pregnant patients have emerged as innovative care delivery models. They have the potential to transform diabetes care by overcoming many of the time limitations of traditional one-on-one clinical visits. There is compelling evidence that SMAs improve glycemic control for nonpregnant patients with diabetes, GPC reduces Black and White health disparities in preterm birth, and diabetes GPC increases postpartum glucose tolerance test uptake among patients with gestational diabetes mellitus. GPC models stand out as one of few interventions that reduce racial health disparities, which we hypothesize occurs because their effect is inadvertently exerted on both the patient and clinician through an over 20-h meaningful shared experience. In this article I explore the evidence for SMAs and GPC in diabetes and pregnancy, theoretical underpinnings of the models, their potential to promote more equitable care, and future directions from my perspective as a physician in high-risk obstetrics and 2019 American Diabetes Association Pathway Accelerator Award recipient. This article is part of a series of perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program.

Incidences of childhood obesity and type 2 diabetes (T2D) are climbing at alarming rates. Evidence points to prenatal exposures to maternal obesity and gestational diabetes mellitus (GDM) as key contributors to these upward trends. Children born to mothers with these conditions face higher risks of obesity and T2D, beyond genetic or shared environmental factors. The underpinnings of this maternal-fetal programming are complex. However, animal studies have shown that such prenatal exposures can lead to changes in brain pathways, particularly in the hypothalamus, leading to obesity and T2D later in life. This article highlights significant findings stemming from research funded by my American Diabetes Association Pathway Accelerator Award and is part of a series of Perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program. This critical support, received more than a decade ago, paved the way for groundbreaking discoveries, translating the neural programming findings from animal models into human studies and exploring new avenues in maternal-fetal programming. Our BrainChild cohort includes >225 children, one-half of whom were exposed in utero to maternal GDM and one-half born to mothers without GDM. Detailed studies in this cohort, including neuroimaging and metabolic profiling, reveal that early fetal exposure to maternal GDM is linked to alterations in brain regions, including the hypothalamus. These neural changes correlate with increased energy intake and predict greater increases in BMI, indicating that early neural changes may underlie and predict later obesity and T2D, as observed in animal models. Ongoing longitudinal studies in this cohort will provide critical insights toward breaking the vicious cycle of maternal-child obesity and T2D.

There are key differences between the central nervous system (CNS) (brain and spinal cord) and peripheral nervous system (PNS), such as glial cell types, whether there is protection by the blood-brain barrier, modes of synaptic connections, etc. However, there are many more similarities between these two arms of the nervous system, including neuronal structure and function, neuroimmune and neurovascular interactions, and, perhaps most essentially, the balance between neural plasticity (including processes like neuron survival, neurite outgrowth, synapse formation, gliogenesis) and neurodegeneration (neuronal death, peripheral neuropathies like axonopathy and demyelination). This article brings together current research evidence on shared mechanisms of nervous system health and disease between the CNS and PNS, particularly with metabolic diseases like obesity and diabetes. This evidence supports the claim that the two arms of the nervous system are critically linked and that previously understudied conditions of central neurodegeneration or peripheral neurodegeneration may actually be manifesting across the entire nervous system at the same time, through shared genetic and cellular mechanisms. This topic has been critically underexplored due to the research silos between studies of the brain and studies of peripheral nerves and an overemphasis on the brain in neuroscience as a field of study. There are likely shared and linked mechanisms for how neurons stay healthy versus undergo damage and disease among this one nervous system in the body-providing new opportunities for understanding neurological disease etiology and future development of neuroprotective therapeutics.

The brain coordinates the homeostatic defense of multiple metabolic variables, including blood glucose levels, in the context of ever-changing external and internal environments. The biologically defended level of glycemia (BDLG) is the net result of brain modulation of insulin-dependent mechanisms in cooperation with the islet, and insulin-independent mechanisms through direct innervation and neuroendocrine control of glucose effector tissues. In this article, we highlight evidence from animal and human studies to develop a framework for the brain's core homeostatic functions-sensory/afferent, integration/processing, and motor/efferent-that contribute to the normal BDLG in health and its elevation in diabetes.

The approval of teplizumab to delay the onset of type 1 diabetes is an important inflection point in the decades-long pursuit to treat the cause of the disease rather than its symptoms. The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop of the Diabetes Mellitus Interagency Coordinating Committee titled "Evolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes" to review this accomplishment and identify future goals. Speakers representing Type 1 Diabetes TrialNet (TrialNet) and the Immune Tolerance Network emphasized that the ability to robustly identify individuals destined to develop type 1 diabetes was essential for clinical trials. The presenter from the U.S. Food and Drug Administration described how regulatory approval relied on data from the single clinical trial of TrialNet with testing of teplizumab for delay of clinical diagnosis, along with confirmatory evidence from studies in patients after diagnosis. The workshop reviewed the etiology of type 1 diabetes as a disease involving multiple immune pathways, highlighting the current understanding of prognostic markers and proposing potential strategies to improve the therapeutic response of disease-modifying therapies based on the mechanism of action. While celebrating these achievements funded by the congressionally appropriated Special Diabetes Program, panelists from professional organizations, nonprofit advocacy/funding groups, and industry also identified significant hurdles in translating this research into clinical care.

Type 1 diabetes (T1D) results from β-cell destruction due to autoimmunity. It has been proposed that β-cell loss is relatively quiescent in the early years after seroconversion to islet antibody positivity (stage 1), with accelerated β-cell loss only developing around 6-18 months prior to clinical diagnosis. This construct implies that immunointervention in this early stage will be of little benefit, since there is little disease activity to modulate. Here, we argue that the apparent lack of progression in early-stage disease may be an artifact of the modality of assessment used. When substantial β-cell function remains, the standard assessment, the oral glucose tolerance test, represents a submaximal stimulus and underestimates the residual function. In contrast, around the time of diagnosis, glucotoxicity exerts a deleterious effect on insulin secretion, giving the impression of disease acceleration. Once glucotoxicity is relieved by insulin therapy, β-cell function partially recovers (the honeymoon effect). However, evidence from recent trials suggests that glucose control has little effect on the underlying disease process. We therefore hypothesize that the autoimmune destruction of β-cells actually progresses at a more or less constant rate through all phases of T1D and that early-stage immunointervention will be both beneficial and desirable.

The islets of Langerhans reside within the endocrine pancreas as highly vascularized microorgans that are responsible for the secretion of key hormones, such as insulin and glucagon. Islet function relies on a range of dynamic molecular processes that include Ca2+ waves, hormone pulses, and complex interactions between islet cell types. Dysfunction of these processes results in poor maintenance of blood glucose homeostasis and is a hallmark of diabetes. Recently, the development of optogenetic methods that rely on light-sensitive molecular actuators has allowed perturbation of islet function with near physiological spatiotemporal acuity. These actuators harness natural photoreceptor proteins and their engineered variants to manipulate mouse and human cells that are not normally light-responsive. Until recently, optogenetics in islet biology has primarily focused on controlling hormone production and secretion; however, studies on further aspects of islet function, including paracrine regulation between islet cell types and dynamics within intracellular signaling pathways, are emerging. Here, we discuss the applicability of optogenetics to islets cells and comprehensively review seminal as well as recent work on optogenetic actuators and their effects in islet function and diabetes mellitus.

The stress response protein regulated in development and DNA damage response 1 (REDD1) has emerged as a key player in the pathogenesis of diabetes. Diabetes upregulates REDD1 in a variety of insulin-sensitive tissues, where the protein acts to inhibit signal transduction downstream of the insulin receptor. REDD1 functions as a cytosolic redox sensor that suppresses Akt/mTORC1 signaling to reduce energy expenditure in response to cellular stress. Whereas a transient increase in REDD1 contributes to an adaptive cellular response, chronically elevated REDD1 levels are implicated in disease progression. Recent studies highlight the remarkable benefits of both whole-body and tissue-specific REDD1 deletion in preclinical models of type 1 and type 2 diabetes. In particular, REDD1 is necessary for the development of glucose intolerance and the consequent rise in oxidative stress and inflammation. Here, we review studies that support a role for chronically elevated REDD1 levels in the development of diabetes complications, reflect on limitations of prior therapeutic approaches targeting REDD1 in patients, and discuss potential opportunities for future interventions to improve the lives of people living with diabetes. This article is part of a series of Perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program.

This article summarizes the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organized by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: 1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g., genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomization in humans; 2) the highly individualized nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; 3) because single-time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and 4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.

Insulin replacement therapy is indispensable in the treatment of type 1 and advanced type 2 diabetes. However, insulin's clinical application is challenging due to its narrow therapeutic index. To mitigate acute and chronic risks of glucose excursions, glucose-responsive insulin (GRI) has long been pursued for clinical application. By integrating GRI with glucose-sensitive elements, GRI is capable of releasing or activating insulin in response to plasma or interstitial glucose levels without external monitoring, thereby improving glycemic control and reducing hypoglycemic risk. In this Perspective, we first introduce the history of GRI development and then review major glucose-responsive components that can be leveraged to control insulin delivery. Subsequently, we highlight the recent advances in GRI delivery carriers and insulin analogs. Finally, we provide a look to the future and the challenges of clinical application of GRI.

An agreed-upon consensus model of glucose-stimulated insulin secretion from healthy β-cells is essential for understanding diabetes pathophysiology. Since the discovery of the KATP channel in 1984, an oxidative phosphorylation (OxPhos)-driven rise in ATP has been assumed to close KATP channels to initiate insulin secretion. This model lacks any evidence, genetic or otherwise, that mitochondria possess the bioenergetics to raise the ATP/ADP ratio to the triggering threshold, and conflicts with genetic evidence demonstrating that OxPhos is dispensable for insulin secretion. It also conflates the stoichiometric yield of OxPhos with thermodynamics, and overestimates OxPhos by failing to account for established features of β-cell metabolism, such as leak, anaplerosis, cataplerosis, and NADPH production that subtract from the efficiency of mitochondrial ATP production. We have proposed an alternative model, based on the spatial and bioenergetic specializations of β-cell metabolism, in which glycolysis initiates insulin secretion. The evidence for this model includes that 1) glycolysis has high control strength over insulin secretion; 2) glycolysis is active at the correct time to explain KATP channel closure; 3) plasma membrane-associated glycolytic enzymes control KATP channels; 4) pyruvate kinase has favorable bioenergetics, relative to OxPhos, for raising ATP/ADP; and 5) OxPhos stalls before membrane depolarization and increases after. Although several key experiments remain to evaluate this model, the 1984 model is based purely on circumstantial evidence and must be rescued by causal, mechanistic experiments if it is to endure.

The canonical model of glucose-induced increase in insulin secretion involves the metabolism of glucose via glycolysis and the citrate cycle, resulting in increased ATP synthesis by the respiratory chain and the closure of ATP-sensitive K+ (KATP) channels. The resulting plasma membrane depolarization, followed by Ca2+ influx through L-type Ca2+ channels, then induces insulin granule fusion. Merrins and colleagues have recently proposed an alternative model whereby KATP channels are controlled by pyruvate kinase, using glycolytic and mitochondrial phosphoenolpyruvate (PEP) to generate microdomains of high ATP/ADP immediately adjacent to KATP channels. This model presents several challenges. First, how mitochondrially generated PEP, but not ATP produced abundantly by the mitochondrial F1F0-ATP synthase, can gain access to the proposed microdomains is unclear. Second, ATP/ADP fluctuations imaged immediately beneath the plasma membrane closely resemble those in the bulk cytosol. Third, ADP privation of the respiratory chain at high glucose, suggested to drive alternating, phased-locked generation by mitochondria of ATP or PEP, has yet to be directly demonstrated. Finally, the approaches used to explore these questions may be complicated by off-target effects. We suggest instead that Ca2+ changes, well known to affect both ATP generation and consumption, likely drive cytosolic ATP/ADP oscillations that in turn regulate KATP channels and membrane potential. Thus, it remains to be demonstrated that a new model is required to replace the existing, mitochondrial bioenergetics-based model.

In 2014, the American Diabetes Association instituted a novel funding paradigm to support diabetes research through its Pathway to Stop Diabetes program. This program took a multifaceted approach to providing key funding to diabetes researchers to advance a broad spectrum of research programs on all aspects of understanding, managing, and treating diabetes. Here, the personal perspective of a 2019 Pathway Accelerator awardee is offered, describing a research program seeking to advance a materials-centered approach to engineering glucose-responsive devices and new delivery tools for better therapeutic outcomes in treating diabetes. This is offered alongside a personal reflection on 5 years of support from the ADA Pathway Program.

In 2014, the American Diabetes Association instituted a novel funding paradigm to support diabetes research through its Pathway to Stop Diabetes® Program. Pathway took a multifaceted approach to provide key funding to diabetes researchers in advancing a broad spectrum of research programs centered on all aspects of understanding, managing, and treating diabetes. Herein the personal perspective of a 2019 Pathway Accelerator awardee is offered, describing a research program seeking to advance a materials-centered approach to engineering glucose-responsive devices and new delivery tools for better therapeutic outcomes in treating diabetes. This is offered alongside a personal reflection on five years of support from the ADA Pathway Program.