This article summarizes the current understanding of the heterogeneity of type 1 diabetes from a June 2024 international Expert Forum organized by the editors of Diabetes, Diabetes Care, and Diabetologia. The Forum reviewed key factors contributing to the development and progression of type 1 diabetes and outlined specific, high-priority research questions. Knowledge gaps were identified, and, notably, opportunities to harness disease heterogeneity to develop personalized therapies were outlined. Herein, we summarize our discussions and review the heterogeneity of genetic risk and immunologic and metabolic phenotypes that influence and characterize type 1 diabetes progression (presented as a palette of risk factors). We discuss how these age-related factors determine disease aggressiveness (along gradients) and describe how variable immunogenetic pathways aggregate (into networks) to affect β-cell and other pancreatic pathologies to cause clinical disease at different ages and with variable severity (described as disease-related thresholds). Heterogeneity of pathogenesis and clinical severity opens avenues to prevention and intervention, including the potential of disease-modifying immunotherapy and islet cell replacement. We conclude with a call for 1) continued research to identify more factors contributing to the disease, both overall and in specific subgroups; 2) investigations focusing on both individuals who surpass metabolic and immune thresholds and develop diabetes and those who remain disease free with the same level of immunogenetic risk; and 3) efforts to identify where the current type 1 diabetes staging system may fall short and determine how it can be improved to capture and leverage heterogeneity in prevention and intervention strategies.

In type 1 diabetes (T1D), insulin (INS) deficiency results from immune-mediated destruction of β-cells. The majority of functional β-cell mass is typically lost within months to years of disease diagnosis, but the timing and nature of this loss, particularly in early disease stages, remain unclear. We developed a whole-slide scanned image analysis pipeline for semiautomated quantitation of endocrine area, islet frequency, interislet distance, and endocrine object size distribution in 145 human pancreata from 60 donors without diabetes, 19 donors with single autoantibody positivity, 10 with multiple autoantibody positivity (mAAb+), and 16 with recent-onset (duration 0-1 year), 23 with medium-duration (1-7 years), and 17 with long-duration T1D (7+ years). We observed age-related differences in endocrine composition and islet frequency in pancreata from donors without diabetes. Age-corrected data revealed decreased islet frequency and greater interislet distance in the T1D pancreas. INS+ single cells (≤10 μm), cell clusters (>10 to <35 μm), small- and medium-sized islets (35-100 and 100-200 μm, respectively) were significantly lost at T1D onset, whereas large INS+ islets (>200 μm) were preserved. Moreover, changes in endocrine composition also occurred in pancreata from mAAb+ donors, including a significant decrease in the INS+ islet fraction. These data suggest preferential loss of INS+ small endocrine objects early in T1D development.

An acute increase of lipids in the upper small intestine (USI) of rodents and humans triggers lipid-sensing pathways to reduce food intake. However, USI lipid sensing does not reduce feeding in high-fat (HF) fed conditions, and the underlying mechanism remains elusive. Here, we report that HF feeding in male rats impaired USI lipid infusion to stimulate glucose-dependent insulinotropic polypeptide (GIP) secretion and decrease refeeding, and the defects of USI lipid sensing were restored by metformin. Next, we found that infusion of GIP receptor (GIPR) agonist in the nucleus of the solitary tract (NTS), but not mediobasal hypothalamus or area postrema, resulted in decreased refeeding in chow-fed rats. The anorectic effect of NTS GIPR agonist remained intact in HF rats and was inhibited by a genetic knockdown of GIPR. Finally, an inhibition of NTS GIPR also negated the ability of USI lipid sensing with metformin to decrease refeeding despite an increase in plasma GIP levels in HF rats. Thus, USI lipid sensing in HF rats is enhanced by metformin to trigger an endocrine GIP to NTS GIPR axis to reduce food intake, thereby unveiling small intestinal lipid-sensing pathways as potential targets to enhance GIP action and reduce weight in obesity.

There is currently a revolution in the pharmacologic treatment of obesity and diabetes with newly available agonists of incretin receptors. The health benefits of these novel treatments include not only metabolic effects but also improvements in brain neurodegenerative conditions. Receptors for incretins have been described in the hypothalamic appetite regulatory center; however, their expression in the peripheral nervous system (PNS) has been largely overlooked, despite likely contributing important effects. For example, the PNS is essential for the control of numerous metabolically relevant pathways in tissues such as liver, adipose, intestine, and muscle, and incretin receptors are found on nerves innervating some, if not all, of these metabolically important tissues. In this article, we summarize the knowledge to date regarding incretin receptors and incretin drug actions in the PNS, as well as PNS control over incretin release, and the related implications for metabolic disease states that are accompanied by peripheral neuropathy.

We undertook this study to estimate the causal role of circulating branched-chain amino acids (BCAAs) in metabolic health using genetics. Are circulating BCAAs a cause or consequence of metabolic health? We found that a higher circulating level of BCAAs likely reflects poorer metabolic health. There is a potential bidirectional causal link between BCAAs and dyslipidemia that warrants further tissue-specific functional studies. Our findings suggest that BCAAs may causally affect lipid metabolism, with adipocytes as a key site. Understanding tissue-specific pathways of BCAA-induced lipid dysregulation could guide BCAAs' potential as a clinical intervention target.

FoxO1 and PPARα share significant DNA binding sites, regulating a coordinated transcriptional network in hepatic metabolism. FoxO1 and PPARα orchestrate distinct yet overlapping roles in gluconeogenesis and fatty acid/lipid metabolism. High-fat diet amplifies the metabolic interplay between FoxO1 and PPARα, with implications for insulin resistance management. Targeting the FoxO1-PPARα interplay offers novel strategies for treating selective insulin resistance and metabolic disorders.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) cause an increase in hepatic glucose production (HGP). We previously showed that SGLT2i cause a rapid (within 4 h) increase in the total-body norepinephrine (NE) turnover rate, which could explain the increase in HGP. Because the increase in HGP caused by SGLT2i is long-lasting, we examined the long-term effect of SGLT2i on the NE turnover rate. Empagliflozin caused a decrease in total-body NE turnover at 1 day and at 12 weeks after starting therapy, despite an increase in glucose production, and the magnitude of decrease in NE turnover inversely correlated with the increase in HGP caused by empagliflozin.

Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with poorly managed type 2 diabetes, despite treatment with multiple glucose-lowering agents, have endogenous hypersecretion of cortisol as a causative factor for their hyperglycemia. In vivo and in vitro studies in animals and humans have demonstrated that excess exposure to glucocorticoids can promote insulin resistance in muscle, liver, and adipocytes and impair insulin secretion. We propose a reverberating cycle in which hypercortisolism disrupts the normal circadian rhythm causing insulin resistance and hyperinsulinemia, which in turn further disrupts the hypothalamic-pituitary-adrenal axis.

Metabolic and energy reprogramming significantly affects renal cell function in diabetic kidney disease (DKD). We developed unique metabolic mouse models with varying levels of lipoic acid synthase (Lias) gene expression and correspondingly varying levels of protein lipoylation and metabolic activity. Using these metabolic mouse models, our study demonstrates that increased protein lipoylation can alleviate DKD through metabolic and energetic regulation. Our unique metabolic mouse models can serve as a preclinical platform to evaluate new therapeutic strategies, ultimately guiding translational studies for patients with DKD.

Glucagon-like peptide-1 receptor agonists are promising therapies in treating various obesity-associated diseases; however, the mechanisms are convoluted with the benefits of weight loss. Dulaglutide has weight-independent therapeutic effects on the liver, reducing hepatic steatosis and improving liver function. Dulaglutide reduces de novo lipogenesis, lipid droplet stability, inflammation, and oxidative stress in the liver and lipolysis in adipose tissue. Weight loss may play an important role in glucagon-like peptide-1 receptor agonists' effect on decreasing coronary vascular disease risk.

Current research and development are ushering in a new era of novel islet β-cell replacement therapies that can no longer be considered solely a rescue treatment for those with unstable glucose management. Clinical trial design must ensure that the application of islet β-cell replacement is broadened beyond the indication of severe hypoglycemia given the potential for establishing insulin-independent normoglycemia. It is imperative that people with type 1 diabetes and their clinicians are at the center of the risk-benefit equipoise as evidence for the safety of cellular products, transplant sites, and immune protection strategies accumulates and an increasing number of options for intervention become available.

The dorsal raphe nucleus (DRN) is a key regulator of food intake and body weight. The DRN has historically been associated with feeding, as it houses the single largest population of serotonergic neurons in the mammalian brain. Few studies have demonstrated a direct role for DRN serotonergic neurons in regulating feeding; none of these studies have demonstrated effects near those elicited by serotonin, itself. There are many nonserotonergic cell types in the DRN that play an integral role in feeding. These DRN cell types play important roles in both hunger and satiation.

The underlying molecular pathogenesis of the Asian phenotype of insulin resistance remains to be understood. We carried out metabolic phenotyping of study participants without diabetes according to insulin sensitivity indices derived from hyperinsulinemic-euglycemic clamp procedures. We identified lipidomic signatures of insulin resistance and metabolic plasticity. These lipidomic signatures have the potential to help in risk stratification of insulin resistance and metabolic dysfunction for early intervention.

Sarcopenic obesity, a subtype of obesity, is marked by reduced skeletal muscle mass and function, or sarcopenia, and poses a significant health challenge to older adults as it affects an estimated 28.3% of people aged >60 years. This subtype is unique to older adults as aging exacerbates sarcopenia and obesity due to changes in energy metabolism, hormones and inflammatory markers, and lifestyle factors. Traditional treatments for sarcopenic obesity have been focused on exercise and dietary modifications to reduce fat while maintaining muscle mass. Newer glucagon-like peptide 1 receptor agonists (GLP-1RA) and dual gastric inhibitory polypeptide/GLP-1 receptor agonists (GIP/GLP-1RAs), including liraglutide, semaglutide, and tirzepatide, have shown great promise to reduce weight, treat obesity-related complications, improve physical function, and improve quality of life, in younger clinical trial populations. However, the use of GLP-1RAs and GIP/GLP-1RAs has not been exhaustively evaluated in older adults with sarcopenic obesity. These medications come with the risk of loss of muscle mass and an increased rate of adverse events. Thus, clinicians should use them cautiously by weighing the potential benefits against their risks. Herein, we discuss a possible approach to using GLP-1RAs and GIP/GLP-1RAs in patients with sarcopenic obesity, including considerations for patient identification, monitoring, maintenance, and discontinuation. In this article we also discuss the emerging treatments that will be available, which may include activin type II receptor antibodies and selective androgen receptor agonists. We conclude by highlighting the advancement of geroscience as a promising field for individualizing treatments in the future.

Although imeglimin promotes β-cell proliferation and ameliorates β-cell apoptosis, the detailed metabolic changes induced by imeglimin in β-cells are unknown. Imeglimin increases adenylosuccinate (S-AMP), which is produced by adenylosuccinate synthase (ADSS) from inosine monophosphate and aspartate, and imeglimin also increases amino acid content, including aspartate, in mouse islets. Inhibition of S-AMP production by an ADSS inhibitor reduces the ability of imeglimin to increase β-cell proliferation and ameliorate β-cell apoptosis in mouse islets, human islets, porcine islets, and human pluripotent stem cell-derived β-cells. Imeglimin increases S-AMP to promote β-cell proliferation and ameliorate β-cell apoptosis.

The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.

Cerebral microvascular disease can be triggered in people with diabetes who have chronic hyperglycemia. The aim of our study was to understand what effect diabetes has on the cerebral vasculature. In a rodent model, diabetes caused varying degrees of reduced cerebral vascular density and slowed cerebral blood flow in the brain striatum, basal forebrain, thalamus, hypothalamus, and hippocampus. There is a correlation between vessel density and blood flow velocity and the correlation changes in the diabetic state.

We aimed to explore sustainability of lowered glycated hemoglobin (HbA1c) and weight with tirzepatide in a post hoc analysis. The question we wanted to answer was what predicted achieving and sustaining HbA1c and weight reduction in A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4). We found greater weight loss and improved β-cell function were the main predictors for sustained glycemic control with tirzepatide therapy. No clinically relevant predictor was identified for sustained weight loss. Simple clinical measures may predict initial and sustained glycemic control and initial weight loss with tirzepatide.